Capsaicin (red pepper)

[Rich66]

Oncogene. 2010 Jan 14;29(2):285-96. Epub 2009 Oct 26.
Capsaicin causes cell-cycle arrest and apoptosis in ER-positive and -negative breast cancer cells by modulating the EGFR/HER-2 pathway.

Thoennissen NH, O'Kelly J, Lu D, Iwanski GB, La DT, Abbassi S, Leiter A, Karlan B, Mehta R, Koeffler HP.
Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA 90048, USA. Nils.Thoennissen@cshs.org
Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is an ingredient of chili peppers with inhibitory effects against cancer cells of different origin. We examined the activity of capsaicin on breast cancer cells in vitro and in vivo. The drug potently inhibited growth of ER-positive (MCF-7, T47D, BT-474) and ER-negative (SKBR-3, MDA-MB231) breast cancer cell lines, which was associated with G(0)/G(1) cell-cycle arrest, increased levels of apoptosis and reduced protein expression of human epidermal growth factor receptor (EGFR), HER-2, activated extracellular-regulated kinase (ERK) and cyclin D1. In contrast, cell-cycle regulator p27(KIP1), caspase activity as well as poly-ADP ribose polymerase (PARP) cleavage were increased. Notably, capsaicin blocked breast cancer cell migration in vitro and decreased by 50% the size of MDA-MB231 breast cancer tumors growing orthotopically in immunodeficient mice without noticeable drug side effects. in vivo activation of ERK was clearly decreased, as well as expression of HER-2 and cyclin D1, whereas caspase activity and PARP cleavage products were increased in tumors of drug-treated mice. Besides, capsaicin potently inhibited the development of pre-neoplastic breast lesions by up to 80% without evidence of toxicity. Our data indicate that capsaicin is a novel modulator of the EGFR/HER-2 pathway in both ER-positive and -negative breast cancer cells with a potential role in the treatment and prevention of human breast cancer.

PMID: 19855437 [PubMed - in process]




http://www.nature.com/onc/journal/v2...nc2009335a.pdf

The aggressive, EGFR-positive, p53 mutant MDAMB231 breast cancer cells were grown orthotopically in the breast tissue of female BNX nu/nu mice; and capsaicin (5 mg/kg per day) or vehicle was administered by oral gavage three times per week.

April 19 2009
Hot Peppers Make Prostate Cancer Cells Die and Taste Buds Come to Life

LINK

Moderate dose of capsaicin makes 80 percent of prostate cancer cells die

In 2006, a team of researchers from the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center, found that capsaicin induced 80 percent of human prostate cancer cells growing in mice to follow pathways leading to certain death. They also found that prostate cancer tumors in mice fed with capsaicin were about one-fifth the size of tumors in non-treated mice. Additionally, capsaicin had a profound anti-proliferative effect on cultured human cancer cells according to a scientist at the UCLA School of Medicine. It dramatically slowed the development of prostate tumors formed by cells from the same lines as those grown for the mouse models.

The scientists estimated that the dose of pepper extract fed to the mice was equivalent to giving 400 milligrams of capsaicin three times a week to a 200 pound man. This would be about the amount found in three to eight fresh habanero peppers, depending on how hot the peppers were.

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Capsaicin is effective against other types of cancer

Research from India recently investigated the effect of capsaicin on fat metabolism during induced lung cancer in mice showing abnormal changes in tissue and serum lipids, lipoproteins, and lipid metabolizing enzymes. Treatment of 10 mg per kg of body weight showed an ability to reduce all of these alterations and restore normality that they described as "remarkable". (Archives of Pharmacal Research, February).

In another study investigating how oxidative stress mediated lung cancer, lysomal damage was found to be an indispensable event in the development of some lung cancers. Capsaicin was able to completely prevent lysomal damage, and was effective against induced lung cancer. (Fundamental Clinical Pharmacology, February).

Scientists investing the effects of capsaicin against human breast cancer noted that the compound has been shown to exert powerful biological activity including anticarginogenic, antimutagenic and chemoprotective effects against many cancer cell lines. When they tested it against a highly malignant breast cell line, they found that treatment with capsaicin for 24 hours resulted in dose-dependent death of the cancerous cells. (Oncology Report, March).

A recent study investigating capsaicin on highly metastatic melanoma cells found its anti-mutagenic activity inhibited the migration of melanoma cells at low doses without showing obvious cytotoxicity. The scientists concluded that capsaicin administration should be considered an effective approach for the suppression of invasion and metastasis in malignant melanoma. (Experimental and Molecular Medicine, October, 2008).

In an earlier study at M.D Anderson Cancer Center in Houston, researchers tested capsaicin on human skin cancer cells to analyze how the cells would react. They found that the majority of skin cancer cells exposed to the substance died. Capsaicin seemed to kill cancerous cells by damaging their membranes and limiting the amount of oxygen that could reach them. Drug companies have long searched for a drug that could do just that. Any compound that could limit oxygen in targeted cells would be highly effective against many forms of cancer.

High intake of capsaicin correlates with lower death rates from cancer

In countries where high intake of capsaicin is the dietary norm, cancer death rates for men and women are significantly lower than they are in countries with less chili pepper consumption according to statistics from the World Health Organization. Experiments have shown that capsaicin seems to be able to detoxify a wide range of chemical carcinogens which, if left to roam the body, could create mutations leading to full blown cancers.

Capsaicin soothes digestive tract stress

Contrary to popular belief, a study has found that ulcer sufferers are helped by eating hot spicy foods. Capsaicin increases blood flow in the stomach's mucous lining, helping to heal stomach tissue. It is effective against H. pylori bacteria, and stimulates circulation sequentially, from the internal organs to the skin surface, and on throughout the entire body. A Duke University study has found that capsaicin may lead to a cure for inflammatory bowel disease. Eating chili peppers has also been shown to protect against the effects to the stomach of aspirin

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Can Urol Assoc J. 2010 Feb;4(1):E9-E11.
Capsaicin may slow PSA doubling time: case report and literature review.

Jankovic B, Loblaw DA, Nam R.
Faculty of Medicine, UBC, Vancouver, BC;
Capsaicin is the main pungent component of chili peppers. This is the first case, to our knowledge, that describes prostate-specific antigen (PSA) stabilization in a patient with prostate cancer, who had biochemical failure after radiation therapy. A 66-year-old male underwent radiotherapy treatment for a T2b, Gleason 7 (3+4) adenocarcinoma of the prostate, with a PSA level of 13.3 ng/mL in April 2001. He had 3-dimensional conformal radiotherapy of 46 Gy in 23 fractions to the prostate and pelvis, and a prostate boost of 30 Gy in 15 fractions. Radiotherapy was completed in May 2001 and PSA nadired in January 2002 (0.57). Due to the continued PSA rise, the patient was started on bicalutamide (50 mg orally, daily) and leuprolide acetate (1 dose of 22.5 mg intramuscularly) in July 2005 when PSA was 38.5 ng/mL. Due to poor tolerance of androgen ablation therapy, the patient discontinued treatment and started taking 2.5 mL of habaneros chili sauce, containing capsaicin, 1 to 2 times a week in April 2006. Prostate-specific antigen doubling time (PSAdt) increased from 4 weeks before capsaicin to 7.3 months by October 2006. From October 2006 until November 2007, the patient remained on capsaicin (2.5 to 15 mL daily) and his PSA was stable (between 11 to 14 ng/mL). By January 2008, his PSA rose to 22.3 and he has maintained a PSAdt between 4 and 5 months, where it presently remains. Due to the patient's continued PSA rise, he was restarted on bicalutamide (12.5 mg daily). Apart from PSA relapse, the patient remains free of signs or symptoms of recurrence.

PMID: 20174488 [PubMed - in process]





Indian J Cancer. 2010 Jan-Mar;47(1):53-8.
Capsaicin: a novel chemopreventive molecule and its underlying molecular mechanisms of action.




Oyagbemi AA, Saba AB, Azeez OI.
Department of Veterinary Physiology, Biochemistry and Pharmacology, Faculty of Veterinary Medicine, University of Ibadan, Oyo State, Nigeria.
Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is the a principal pungent ingredient of hot red and chili peppers that belong to the plant genus Capsicum (Solanaceae). Capsaicin is a cancer-suppressing agent. It blocks the translocation of nuclear factor kappa B (NF-kB), activator protein 1 (AP-1), and signal transducer and activator of transcription (STAT3) signaling pathway that are required for carcinogenesis. The anti-inflammatory potential of capsaicin is attributed to its inhibitory effect on inducible COX-2 mRNA expression. Cytochrome P4502E1 mediates the activation of xenobiotics such as vinyl carbamate and dimethyl nitrosamine to their toxic metabolites. This metabolic activation of xenobiotics by Cytochrome P4502E1 has been shown to be inhibited by capsaicin. Capsaicin also generates reactive oxygen species in cells with resultant induction of apoptosis and cell cycle arrest, which is beneficial for cancer chemoprevention. Therefore, the use of capsaicin as a chemopreventive agent is of immense benefit for cancer chemoprevention. The search strategy included printed journals, pubmed, and medline, using the terms 'capsaicin' and 'anticancer' citations, relevant to anticancer properties of capsaicin.

PMID: 20071791 [PubMed - in process]







Nat Prod Res. 2009;23(8):763-74.
Effect of capsaicin on glucose metabolism studied in experimental lung carcinogenesis.

Anandakumar P, Kamaraj S, Jagan S, Ramakrishnan G, Devaki T.
Department of Biochemistry, University of Madras, Guindy Campus, Chennai, India.
In the present study, we have assessed the chemopreventive effect of capsaicin (CAP) on glucose metabolism with reference to blood glucose and liver glycogen levels, key glycolytic, and gluconeogenic enzymes along with electron transport chain (ETC) complexes during benzo(a)pyrene (B(a)P)-induced lung cancer in Swiss albino mice. B(a)P (50 mg kg(-1) body weight)-induced lung cancer animals showed marked decline in blood glucose levels, glycogen levels, elevations in the activities of key glycolytic enzymes (hexokinase, phosphoglucoisomerase and aldolase), and gluconeogenic enzymes (glucose-6-phosphatase and fructose-6-phosphatase) together with a decrease in the activities of ETC complexes. Supplementation of CAP (10 mg kg(-1) body weight) inhibited all the above alterations during lung cancer and restored near normalcy. Histochemical analysis by periodic acid Schiff's staining further confirmed the biochemical findings that highlighted the chemopreventive action of CAP during B(a)P-induced experimental lung tumourigenesis.

PMID: 19418359 [PubMed - indexed for MEDLINE]



Cancer Lett. 2009 Jun 29. [Epub ahead of print]
Fas-associated factor 1 is a negative regulator in capsaicin induced cancer cell apoptosis.

Ghosh AK, Basu S.
Center for Immunotherapy of Cancer and Infectious Diseases, University of Connecticut School of Medicine, MC1601, Farmington, CT 06030-1601, USA.
Vanilloid receptor1 (VR1/TRPV1) is expressed on peripheral nerves and involved in sensing of temperature and pain. Recent reports have demonstrated that tumor cells express TRPV1 and that capsaicin (CP), a ligand for TRPV1, induces apoptosis in cancer cells. The mechanism underlying CP-induced tumor cell apoptosis remains unclear. Here, we investigated the role of TRPV1 in tumor apoptosis using TRPV1-expressing cancer cell lines. We demonstrate that iodo-resiniferatoxin (I-RTX), an antagonist of TRPV1 does not inhibit CP mediated apoptosis nor is it cytotoxic by itself, but acts as a partial agonist and shows synergistic effect with CP. We further demonstrate that CP treatment degrades Fas-associated factor1 (FAF1); a TRPV1 associated protein. Moreover, using RNA interference with small inhibitory RNAs (siRNA) for FAF1 we observed that down-regulation of FAF1 by siRNA makes the cell susceptible to enhanced apoptosis with CP. In summary, our data shows for the first time that the underlying mechanisms of CP-induced cancer cell apoptosis involves FAF1, a TRPV1 associated protein and serves as an important foundation for further understanding of anticancer activity of CP.

PMID: 19570606 [PubMed - as supplied by publisher]




Indian J Cancer. 2010 Jan-Mar;47(1):53-8.
Capsaicin: a novel chemopreventive molecule and its underlying molecular mechanisms of action.

Oyagbemi AA, Saba AB, Azeez OI.
Department of Veterinary Physiology, Biochemistry and Pharmacology, Faculty of Veterinary Medicine, University of Ibadan, Oyo State, Nigeria.
Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is the a principal pungent ingredient of hot red and chili peppers that belong to the plant genus Capsicum (Solanaceae). Capsaicin is a cancer-suppressing agent. It blocks the translocation of nuclear factor kappa B (NF-kB), activator protein 1 (AP-1), and signal transducer and activator of transcription (STAT3) signaling pathway that are required for carcinogenesis. The anti-inflammatory potential of capsaicin is attributed to its inhibitory effect on inducible COX-2 mRNA expression. Cytochrome P4502E1 mediates the activation of xenobiotics such as vinyl carbamate and dimethyl nitrosamine to their toxic metabolites. This metabolic activation of xenobiotics by Cytochrome P4502E1 has been shown to be inhibited by capsaicin. Capsaicin also generates reactive oxygen species in cells with resultant induction of apoptosis and cell cycle arrest, which is beneficial for cancer chemoprevention. Therefore, the use of capsaicin as a chemopreventive agent is of immense benefit for cancer chemoprevention. The search strategy included printed journals, pubmed, and medline, using the terms 'capsaicin' and 'anticancer' citations, relevant to anticancer properties of capsaicin.

PMID: 20071791 [PubMed - in process]




Exp Mol Med. 2008 Oct 31;40(5):486-94.
Inhibitory effect of capsaicin on B16-F10 melanoma cell migration via the phosphatidylinositol 3-kinase/Akt/Rac1 signal pathway.

Shin DH, Kim OH, Jun HS, Kang MK.
Department of General Surgery, Kosin University College of Medicine, Busan 602-739, Korea.
Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), the major pungent ingredient of red pepper, has been reported to possess anti-carcinogenic and anti-mutagenic activities. In this study, the anti-migration activity of capsaicin on highly metastatic B16-F10 melanoma cells was investigated. Capsaicin significantly inhibited the migration of melanoma cells without showing obvious cellular cytotoxicity at low doses. This effect correlated with the down-regulation of phosphatidylinositol 3-kinase (PI3-K) and its downstream target, Akt. Although B16-F10 cell migration was increased by the PI3-K activator through the activation of Akt, these PI3-K activator-induced phenomena were attenuated by capsaicin. Moreover, capsaicin was found to significantly inhibit Rac1 activity in a pull-down assay. These results demonstrate that capsaicin inhibits the migration of B16-F10 cells through the inhibition of the PI3-K/Akt/Rac1 signal pathway. The present investigation suggests that capsaicin targets PI3-K/Akt/ Rac1-mediated cellular events in B16-F10 melanoma cells. Consequently, capsaicin administration should be considered an effective approach for the suppression of invasion and metastasis in malignant melanoma chemotherapy.

PMID: 18985006 [PubMed - indexed for MEDLINE]




Oncol Rep. 2009 Mar;21(3):665-71.
Capsaicin-induced apoptosis in human breast cancer MCF-7 cells through caspase-independent pathway.

Chou CC, Wu YC, Wang YF, Chou MJ, Kuo SJ, Chen DR.
Department of Emergency Medicine, Changhua Christian Hospital, Changhua, Taiwan, R.O.C.
Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), a significant pungent ingredient in a variety of red peppers of the genus Capsicum, is a type of vanilloid. It has been shown to exert biological activities (anticarcinogenic, antimutagenic and chemopreventive) in many cancer cell lines. It was found that capsaicin induces dose-dependent growth inhibition of MCF-7 cells, which does not express caspase-3. In this study, we investigated the molecular mechanism of capsaicin-induced apoptosis in MCF-7 cells. Treatment with capsaicin for 24 h resulted in dose-dependent apoptosis in these cells. After the addition of capsaicin, the levels of reactive oxygen species were reduced slightly in the earlier stage of treatment. Interestingly, an elevation of intracellular calcium ion concentration was detected in the MCF-7 cells. In time course and dosage studies, the mitochondrial membrane potential of MCF-7 cells decreased. However, the change was not significant. It is worth noting that the apoptosis-inducing factor translocated into the cytosol and nucleus from the mitochondria. Our results suggest that capsaicin induces cellular apoptosis through a caspase-independent pathway in MCF-7 cells, and that reactive oxygen species and intracellular calcium ion fluctuation has a minimal role in the process.

PMID: 19212624 [PubMed - indexed for MEDLINE]



Rejuvenation Res. 2006 Spring;9(1):45-55.
Catechin-vanilloid synergies with potential clinical applications in cancer.

Morré DM, Morré DJ.
Department of Foods and Nutrition, Purdue University, West Lafayette, Indiana 47907-2059, USA. morredm@purdue.edu
A cancer-specific cell surface protein, tNOX, has been identified as a target for low-dose cell killing (apoptosis) of cancer cells by green tea catechins and Capsicum vanilloid combinations. This protein is uniquely associated with all forms of cancer and is absent from normal cells and tissues. Its activity is correlated with cancer growth. When blocked, cancer cells fail to enlarge after division and eventually die. Among the most potent and effective inhibitors of tNOX are naturally occurring polyphenols exemplified by the principal green tea catechin (-)-epigallocatechin gallate (EGCg) and the vanilloid capsaicin. Catechin-vanilloid combinations are 10 to 100 times more effective than either catechins or vanilloids alone. Vector-forced overexpression of tNOX cDNA and antisense has demonstrated that the tNOX target is both necessary and sufficient to explain the anticancer properties of green tea catechins alone and in vanilloid-containing combinations. The necessity and sufficiency of tNOX was validated as the catechin target with transgenic mice overexpressing the processed form of tNOX. Transgenic mice grew faster and the increased growth caused by tNOX overexpression was blocked by EGCg in the drinking water. A catechin-vanilloid mixture where one 350-mg capsule is equivalent to 16 cups of green tea in its ability to inhibit tNOX and growth of cancer cells in culture is undergoing clinical evaluation as a therapeutic aid for cancer patients.

PMID: 16608395 [PubMed - indexed for MEDLINE]


Botanicals for age-related diseases: from field to practice 2008
FULL TEXT

Botanical preparations that most inhibited cancer cell growth involved synergies between a decaffeinated green tea concentrate and vanilloid containing Capsicum preparations (Figure 2) (12). A 25:1 ratio of green tea concentrate to Capsicum preparation killed cancer cells in culture 100-times greater, by weight, than did green tea.
Assuming 2 g green tea per cup in preparing a usual green tea infusion, our findings suggest that a 350-mg capsule of the commercially available green tea extract–Capsicum preparations (Capsibiol-T or Capsol-T; BND Service Company, West Union, IL) is equivalent to drinking 16 cups of green tea on the basis of the comparative responses of growth of 4T1 and HeLa cells in
culture (12).

In a series of open-label sequential trials, 36% of 50 cancer participants with active cancer receiving Capsol-T had a significant prolongation of life or remained alive, 32% improved, and the rest had a normal course of disease (15).APhase II/III clinical study (toxicology and pharmacokinetics) of Capsol-T with renal cancer and melanoma directed by Theodore Logan at the Indiana University School of Medicine is underway, and a more extensive clinical study to evaluate efficacy is under development at the Goshen Cancer Center, Goshen, IN. A favorable interaction between a tea catechin–Capsicum preparation and radiation therapy was previously indicated from compassionate intervention studies with 5 cancer patients (16).

Capsibiol-T
http://www.newcancerresearch.com/about.htm

Biofactors. 2004;20(4):235-49.
tNOX is both necessary and sufficient as a cellular target for the anticancer actions of capsaicin and the green tea catechin (-)-epigallocatechin-3-gallate.

Chueh PJ, Wu LY, Morré DM, Morré DJ.
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
Capsaicin and the principal green tea catechin, (-)-epigallocatechin-3-gallate (EGCg), target tNOX, a tumor (cancer)-specific surface hydroquinone (NADH) oxidase with protein disulfide-thiol interchange activity (ECTO-NOX protein). Accordingly vector-forced over expression of tNOX in MCF-10A mammary epithelia or COS cells that lack tNOX or in COS cells that underexpress tNOX enhanced the susceptibility of growth and apoptosis to both EGCg and capsaicin. Additionally, the tNOX-transfected MCF-10A cells proliferated in Matrigel, a measure of invasiveness. In contrast, oligomeric antisense tNOX DNA abrogated growth inhibition by EGCg and capsaicin and reduced anchorage-dependent growth of HeLa (human cervical carcinoma) cells that naturally overexpress tNOX. The findings show cell surface expression of tNOX as both necessary and sufficient for the cellular anticancer activities attributed to both EGCg and capsaicin.

PMID: 15706060 [PubMed - indexed for MEDLINE]


Mol Cell Biochem. 2009 Nov;331(1-2):135-43. Epub 2009 May 18.
Capsaicin alleviates the imbalance in xenobiotic metabolizing enzymes and tumor markers during experimental lung tumorigenesis.

Anandakumar P, Kamaraj S, Jagan S, Ramakrishnan G, Naveenkumar C, Asokkumar S, Devaki T.
Department of Biochemistry, University of Madras, Guindy Campus, Chennai, 600-025, Tamil Nadu, India.
Lung cancer is currently a leading cause of death all over the world. Environmental risk factors, particularly genotoxic chemicals such as polycyclic aromatic hydrocarbons (PAH), are likely to account for a much higher mortality. Xenobiotic metabolizing enzymes are potentially chief determinants in both the susceptibility to the mutagenic effects of chemical carcinogens and in the response of tumors to chemotherapy. The well-known carcinogen benzo(a)pyrene (B(a)P) of PAH family was given orally (50 mg/kg body weight) to induce lung cancer in Swiss albino mice. B(a)P induction altered the levels of cytochromes (P450, b5), activities of phase I biotransformation enzymes (NADPH-cytochrome P450 reductase, NADH-cytochrome b5 reductase and epoxide hydrolase), phase II enzymes (glutathione-S-transferase, UDP-glucuronyl transferase and DT-diaphorase), and the levels of serum tumor markers. Treatment with capsaicin (CAP) (10 mg/kg body weight) to the lung carcinoma mice restored back the activities of phase I and II biotransformation enzymes and the levels of tumor markers to near normalcy. The above findings were substantiated by immunoblotting and immunohistochemical analysis of cytochrome P450 1A1 (CYP1A1) in the lung tissues. Our present study unravels that CAP can effectively detoxify the carcinogens which discloses its anti-carcinogenic effect during experimental lung cancer.

PMID: 19449198 [PubMed - indexed for MEDLINE]






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Breast Cancer Res Treat. 2006 Oct;99(3):351-64. Epub 2006 Apr 1.
Capsaicin-induced inactivation of sensory neurons promotes a more aggressive gene expression phenotype in breast cancer cells.

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Erin N, Zhao W, Bylander J, Chase G, Clawson G.
Department of Pathology, Gittlen Cancer Research Foundation, Hershey Medical Center, H059, Pennsylvania State University, 500 University drive, Hershey, PA 17033, USA.
Capsaicin-induced inactivation of sensory neurons has been reported to enhance metastasis of a murine breast cancer cell line, specifically enhancing myocardial metastases. Here we characterized changes in gene expression patterns in primary tumors which developed in capsaicin-treated vs. control mice. We identified a small cohort of genes (17) which all showed significant decreases in expression levels. All of the identified genes have been linked to cell growth, differentiation, and/or cancer progression. Three representative genes, Caspase-7 (an executor of apoptosis), ADAM-10 (A Disintegrin and Metalloprotease), and Elk-3 (a transcriptional repressor of the ternary factor subfamily of the Ets factors) were further investigated. All three showed dramatic downregulation at the protein level in primary tumors from capsaicin-treated animals compared with control (vehicle-treated) animals, and their expression was also lost in cell culture. Elk-3 and Caspase-7 were not expressed in vitro in cultured cell lines, suggesting that their expression was induced by the tumor microenvironment. Loss of Caspase-7 expression can be expected to result in loss of function of apoptotic pathways. At first glance, loss of ADAM-10 expression would be expected to result in decreased invasive capability, due to loss of matrix metalloprotease activity. However, just the opposite appears to be true. We found that ADAM-10 actually hydrolyzes Substance P. Specifically ADAM-10 produces the same growth-inhibitory products from Substance P (i.e., SP (1-7)) that Neprilysin does, so that loss of ADAM-10 expression actually results in loss of production of growth inhibitory peptides from Substance P. Similarly, ADAM-10 also efficiently hydrolyzes Calcitonin Gene-Related Peptide, which may act in concert with Substance P. Finally, overactivity of Ets transcriptional suppressor functions has been linked to inhibition of tumorigenesis (e.g., Erf and Mef), and in addition loss of Elk-3 expression might also be be linked to tumorigenesis via loss of its putative anti-inflammatory activities. There is anecdotal evidence in the literature to indicate that the rest of the down-regulated genes may also contribute to development of a more aggressive phenotype in this breast cancer model.

PMID: 16583263 [PubMed - indexed for MEDLINE]




Anticancer Res. 2004 Mar-Apr;24(2B):1003-9.
Capsaicin-mediated denervation of sensory neurons promotes mammary tumor metastasis to lung and heart.

Erin N, Boyer PJ, Bonneau RH, Clawson GA, Welch DR.
Jake Gittlen Cancer Research Institute, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
Capsaicin specifically activates or destroys small diameter nociceptive sensory neurons that contain the capsaicin receptor, also called vanilloid receptor 1. Neurons sensitive to capsaicin mediate inflammatory pain and are important targets for management of chronic pain. These neurons also regulate local tissue homeostasis, inflammation, healing and development, especially under conditions of psychological stress. Stress contributes to increased cancer recurrence and metastasis through as yet undefined mechanisms. Likewise, activity of capsaicin-sensitive neurons is altered by pathological conditions that may lead to metastatic growth (e.g. stress). Therefore, we examined effects of a treatment that induces sensory nerve denervation on breast cancer metastases. Systemic denervation of sensory neurons caused by treatment with 125 mg/kg capsaicin resulted in significantly more lung and cardiac metastases in adult mice injected orthotopically with syngeneic 4T1 mammary carcinoma cells than was observed in vehicle-treated controls. Heart metastases, normally very rare, occurred as pericardial nodules, intra-myocardial nodules, or combined pericardial-myocardial lesions. Since the rate of primary tumor growth was unaffected, effects on metastases appear to be host tissue-specific. Although preliminary, these observations provide one possible explanation for resistance of cardiac tissue to tumor involvement and highlight contributions of host tissue, including sensory neurons, in the efficiency of cancer metastasis.

[Rich66]

Oncogene. 2010 Jan 14;29(2):285-96. Epub 2009 Oct 26.
Capsaicin causes cell-cycle arrest and apoptosis in ER-positive and -negative breast cancer cells by modulating the EGFR/HER-2 pathway.

Thoennissen NH, O'Kelly J, Lu D, Iwanski GB, La DT, Abbassi S, Leiter A, Karlan B, Mehta R, Koeffler HP.
Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA 90048, USA. Nils.Thoennissen@cshs.org
Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is an ingredient of chili peppers with inhibitory effects against cancer cells of different origin. We examined the activity of capsaicin on breast cancer cells in vitro and in vivo. The drug potently inhibited growth of ER-positive (MCF-7, T47D, BT-474) and ER-negative (SKBR-3, MDA-MB231) breast cancer cell lines, which was associated with G(0)/G(1) cell-cycle arrest, increased levels of apoptosis and reduced protein expression of human epidermal growth factor receptor (EGFR), HER-2, activated extracellular-regulated kinase (ERK) and cyclin D1. In contrast, cell-cycle regulator p27(KIP1), caspase activity as well as poly-ADP ribose polymerase (PARP) cleavage were increased. Notably, capsaicin blocked breast cancer cell migration in vitro and decreased by 50% the size of MDA-MB231 breast cancer tumors growing orthotopically in immunodeficient mice without noticeable drug side effects. in vivo activation of ERK was clearly decreased, as well as expression of HER-2 and cyclin D1, whereas caspase activity and PARP cleavage products were increased in tumors of drug-treated mice. Besides, capsaicin potently inhibited the development of pre-neoplastic breast lesions by up to 80% without evidence of toxicity. Our data indicate that capsaicin is a novel modulator of the EGFR/HER-2 pathway in both ER-positive and -negative breast cancer cells with a potential role in the treatment and prevention of human breast cancer.

PMID: 19855437 [PubMed - in process]




http://www.nature.com/onc/journal/v2...nc2009335a.pdf

The aggressive, EGFR-positive, p53 mutant MDAMB231 breast cancer cells were grown orthotopically in the breast tissue of female BNX nu/nu mice; and capsaicin (5 mg/kg per day) or vehicle was administered by oral gavage three times per week.

April 19 2009
Hot Peppers Make Prostate Cancer Cells Die and Taste Buds Come to Life

LINK

Moderate dose of capsaicin makes 80 percent of prostate cancer cells die

In 2006, a team of researchers from the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center, found that capsaicin induced 80 percent of human prostate cancer cells growing in mice to follow pathways leading to certain death. They also found that prostate cancer tumors in mice fed with capsaicin were about one-fifth the size of tumors in non-treated mice. Additionally, capsaicin had a profound anti-proliferative effect on cultured human cancer cells according to a scientist at the UCLA School of Medicine. It dramatically slowed the development of prostate tumors formed by cells from the same lines as those grown for the mouse models.

The scientists estimated that the dose of pepper extract fed to the mice was equivalent to giving 400 milligrams of capsaicin three times a week to a 200 pound man. This would be about the amount found in three to eight fresh habanero peppers, depending on how hot the peppers were.

<

Capsaicin is effective against other types of cancer

Research from India recently investigated the effect of capsaicin on fat metabolism during induced lung cancer in mice showing abnormal changes in tissue and serum lipids, lipoproteins, and lipid metabolizing enzymes. Treatment of 10 mg per kg of body weight showed an ability to reduce all of these alterations and restore normality that they described as "remarkable". (Archives of Pharmacal Research, February).

In another study investigating how oxidative stress mediated lung cancer, lysomal damage was found to be an indispensable event in the development of some lung cancers. Capsaicin was able to completely prevent lysomal damage, and was effective against induced lung cancer. (Fundamental Clinical Pharmacology, February).

Scientists investing the effects of capsaicin against human breast cancer noted that the compound has been shown to exert powerful biological activity including anticarginogenic, antimutagenic and chemoprotective effects against many cancer cell lines. When they tested it against a highly malignant breast cell line, they found that treatment with capsaicin for 24 hours resulted in dose-dependent death of the cancerous cells. (Oncology Report, March).

A recent study investigating capsaicin on highly metastatic melanoma cells found its anti-mutagenic activity inhibited the migration of melanoma cells at low doses without showing obvious cytotoxicity. The scientists concluded that capsaicin administration should be considered an effective approach for the suppression of invasion and metastasis in malignant melanoma. (Experimental and Molecular Medicine, October, 2008).

In an earlier study at M.D Anderson Cancer Center in Houston, researchers tested capsaicin on human skin cancer cells to analyze how the cells would react. They found that the majority of skin cancer cells exposed to the substance died. Capsaicin seemed to kill cancerous cells by damaging their membranes and limiting the amount of oxygen that could reach them. Drug companies have long searched for a drug that could do just that. Any compound that could limit oxygen in targeted cells would be highly effective against many forms of cancer.

High intake of capsaicin correlates with lower death rates from cancer

In countries where high intake of capsaicin is the dietary norm, cancer death rates for men and women are significantly lower than they are in countries with less chili pepper consumption according to statistics from the World Health Organization. Experiments have shown that capsaicin seems to be able to detoxify a wide range of chemical carcinogens which, if left to roam the body, could create mutations leading to full blown cancers.

Capsaicin soothes digestive tract stress

Contrary to popular belief, a study has found that ulcer sufferers are helped by eating hot spicy foods. Capsaicin increases blood flow in the stomach's mucous lining, helping to heal stomach tissue. It is effective against H. pylori bacteria, and stimulates circulation sequentially, from the internal organs to the skin surface, and on throughout the entire body. A Duke University study has found that capsaicin may lead to a cure for inflammatory bowel disease. Eating chili peppers has also been shown to protect against the effects to the stomach of aspirin

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Can Urol Assoc J. 2010 Feb;4(1):E9-E11.
Capsaicin may slow PSA doubling time: case report and literature review.

Jankovic B, Loblaw DA, Nam R.
Faculty of Medicine, UBC, Vancouver, BC;
Capsaicin is the main pungent component of chili peppers. This is the first case, to our knowledge, that describes prostate-specific antigen (PSA) stabilization in a patient with prostate cancer, who had biochemical failure after radiation therapy. A 66-year-old male underwent radiotherapy treatment for a T2b, Gleason 7 (3+4) adenocarcinoma of the prostate, with a PSA level of 13.3 ng/mL in April 2001. He had 3-dimensional conformal radiotherapy of 46 Gy in 23 fractions to the prostate and pelvis, and a prostate boost of 30 Gy in 15 fractions. Radiotherapy was completed in May 2001 and PSA nadired in January 2002 (0.57). Due to the continued PSA rise, the patient was started on bicalutamide (50 mg orally, daily) and leuprolide acetate (1 dose of 22.5 mg intramuscularly) in July 2005 when PSA was 38.5 ng/mL. Due to poor tolerance of androgen ablation therapy, the patient discontinued treatment and started taking 2.5 mL of habaneros chili sauce, containing capsaicin, 1 to 2 times a week in April 2006. Prostate-specific antigen doubling time (PSAdt) increased from 4 weeks before capsaicin to 7.3 months by October 2006. From October 2006 until November 2007, the patient remained on capsaicin (2.5 to 15 mL daily) and his PSA was stable (between 11 to 14 ng/mL). By January 2008, his PSA rose to 22.3 and he has maintained a PSAdt between 4 and 5 months, where it presently remains. Due to the patient's continued PSA rise, he was restarted on bicalutamide (12.5 mg daily). Apart from PSA relapse, the patient remains free of signs or symptoms of recurrence.

PMID: 20174488 [PubMed - in process]





Indian J Cancer. 2010 Jan-Mar;47(1):53-8.
Capsaicin: a novel chemopreventive molecule and its underlying molecular mechanisms of action.

Oyagbemi AA, Saba AB, Azeez OI.
Department of Veterinary Physiology, Biochemistry and Pharmacology, Faculty of Veterinary Medicine, University of Ibadan, Oyo State, Nigeria.
Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is the a principal pungent ingredient of hot red and chili peppers that belong to the plant genus Capsicum (Solanaceae). Capsaicin is a cancer-suppressing agent. It blocks the translocation of nuclear factor kappa B (NF-kB), activator protein 1 (AP-1), and signal transducer and activator of transcription (STAT3) signaling pathway that are required for carcinogenesis. The anti-inflammatory potential of capsaicin is attributed to its inhibitory effect on inducible COX-2 mRNA expression. Cytochrome P4502E1 mediates the activation of xenobiotics such as vinyl carbamate and dimethyl nitrosamine to their toxic metabolites. This metabolic activation of xenobiotics by Cytochrome P4502E1 has been shown to be inhibited by capsaicin. Capsaicin also generates reactive oxygen species in cells with resultant induction of apoptosis and cell cycle arrest, which is beneficial for cancer chemoprevention. Therefore, the use of capsaicin as a chemopreventive agent is of immense benefit for cancer chemoprevention. The search strategy included printed journals, pubmed, and medline, using the terms 'capsaicin' and 'anticancer' citations, relevant to anticancer properties of capsaicin.

PMID: 20071791 [PubMed - in process]







Nat Prod Res. 2009;23(8):763-74.
Effect of capsaicin on glucose metabolism studied in experimental lung carcinogenesis.

Anandakumar P, Kamaraj S, Jagan S, Ramakrishnan G, Devaki T.
Department of Biochemistry, University of Madras, Guindy Campus, Chennai, India.
In the present study, we have assessed the chemopreventive effect of capsaicin (CAP) on glucose metabolism with reference to blood glucose and liver glycogen levels, key glycolytic, and gluconeogenic enzymes along with electron transport chain (ETC) complexes during benzo(a)pyrene (B(a)P)-induced lung cancer in Swiss albino mice. B(a)P (50 mg kg(-1) body weight)-induced lung cancer animals showed marked decline in blood glucose levels, glycogen levels, elevations in the activities of key glycolytic enzymes (hexokinase, phosphoglucoisomerase and aldolase), and gluconeogenic enzymes (glucose-6-phosphatase and fructose-6-phosphatase) together with a decrease in the activities of ETC complexes. Supplementation of CAP (10 mg kg(-1) body weight) inhibited all the above alterations during lung cancer and restored near normalcy. Histochemical analysis by periodic acid Schiff's staining further confirmed the biochemical findings that highlighted the chemopreventive action of CAP during B(a)P-induced experimental lung tumourigenesis.

PMID: 19418359 [PubMed - indexed for MEDLINE]



Cancer Lett. 2009 Jun 29. [Epub ahead of print]
Fas-associated factor 1 is a negative regulator in capsaicin induced cancer cell apoptosis.

Ghosh AK, Basu S.
Center for Immunotherapy of Cancer and Infectious Diseases, University of Connecticut School of Medicine, MC1601, Farmington, CT 06030-1601, USA.
Vanilloid receptor1 (VR1/TRPV1) is expressed on peripheral nerves and involved in sensing of temperature and pain. Recent reports have demonstrated that tumor cells express TRPV1 and that capsaicin (CP), a ligand for TRPV1, induces apoptosis in cancer cells. The mechanism underlying CP-induced tumor cell apoptosis remains unclear. Here, we investigated the role of TRPV1 in tumor apoptosis using TRPV1-expressing cancer cell lines. We demonstrate that iodo-resiniferatoxin (I-RTX), an antagonist of TRPV1 does not inhibit CP mediated apoptosis nor is it cytotoxic by itself, but acts as a partial agonist and shows synergistic effect with CP. We further demonstrate that CP treatment degrades Fas-associated factor1 (FAF1); a TRPV1 associated protein. Moreover, using RNA interference with small inhibitory RNAs (siRNA) for FAF1 we observed that down-regulation of FAF1 by siRNA makes the cell susceptible to enhanced apoptosis with CP. In summary, our data shows for the first time that the underlying mechanisms of CP-induced cancer cell apoptosis involves FAF1, a TRPV1 associated protein and serves as an important foundation for further understanding of anticancer activity of CP.

PMID: 19570606 [PubMed - as supplied by publisher]




Indian J Cancer. 2010 Jan-Mar;47(1):53-8.
Capsaicin: a novel chemopreventive molecule and its underlying molecular mechanisms of action.

Oyagbemi AA, Saba AB, Azeez OI.
Department of Veterinary Physiology, Biochemistry and Pharmacology, Faculty of Veterinary Medicine, University of Ibadan, Oyo State, Nigeria.
Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is the a principal pungent ingredient of hot red and chili peppers that belong to the plant genus Capsicum (Solanaceae). Capsaicin is a cancer-suppressing agent. It blocks the translocation of nuclear factor kappa B (NF-kB), activator protein 1 (AP-1), and signal transducer and activator of transcription (STAT3) signaling pathway that are required for carcinogenesis. The anti-inflammatory potential of capsaicin is attributed to its inhibitory effect on inducible COX-2 mRNA expression. Cytochrome P4502E1 mediates the activation of xenobiotics such as vinyl carbamate and dimethyl nitrosamine to their toxic metabolites. This metabolic activation of xenobiotics by Cytochrome P4502E1 has been shown to be inhibited by capsaicin. Capsaicin also generates reactive oxygen species in cells with resultant induction of apoptosis and cell cycle arrest, which is beneficial for cancer chemoprevention. Therefore, the use of capsaicin as a chemopreventive agent is of immense benefit for cancer chemoprevention. The search strategy included printed journals, pubmed, and medline, using the terms 'capsaicin' and 'anticancer' citations, relevant to anticancer properties of capsaicin.

PMID: 20071791 [PubMed - in process]




Exp Mol Med. 2008 Oct 31;40(5):486-94.
Inhibitory effect of capsaicin on B16-F10 melanoma cell migration via the phosphatidylinositol 3-kinase/Akt/Rac1 signal pathway.

Shin DH, Kim OH, Jun HS, Kang MK.
Department of General Surgery, Kosin University College of Medicine, Busan 602-739, Korea.
Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), the major pungent ingredient of red pepper, has been reported to possess anti-carcinogenic and anti-mutagenic activities. In this study, the anti-migration activity of capsaicin on highly metastatic B16-F10 melanoma cells was investigated. Capsaicin significantly inhibited the migration of melanoma cells without showing obvious cellular cytotoxicity at low doses. This effect correlated with the down-regulation of phosphatidylinositol 3-kinase (PI3-K) and its downstream target, Akt. Although B16-F10 cell migration was increased by the PI3-K activator through the activation of Akt, these PI3-K activator-induced phenomena were attenuated by capsaicin. Moreover, capsaicin was found to significantly inhibit Rac1 activity in a pull-down assay. These results demonstrate that capsaicin inhibits the migration of B16-F10 cells through the inhibition of the PI3-K/Akt/Rac1 signal pathway. The present investigation suggests that capsaicin targets PI3-K/Akt/ Rac1-mediated cellular events in B16-F10 melanoma cells. Consequently, capsaicin administration should be considered an effective approach for the suppression of invasion and metastasis in malignant melanoma chemotherapy.

PMID: 18985006 [PubMed - indexed for MEDLINE]




Oncol Rep. 2009 Mar;21(3):665-71.
Capsaicin-induced apoptosis in human breast cancer MCF-7 cells through caspase-independent pathway.

Chou CC, Wu YC, Wang YF, Chou MJ, Kuo SJ, Chen DR.
Department of Emergency Medicine, Changhua Christian Hospital, Changhua, Taiwan, R.O.C.
Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), a significant pungent ingredient in a variety of red peppers of the genus Capsicum, is a type of vanilloid. It has been shown to exert biological activities (anticarcinogenic, antimutagenic and chemopreventive) in many cancer cell lines. It was found that capsaicin induces dose-dependent growth inhibition of MCF-7 cells, which does not express caspase-3. In this study, we investigated the molecular mechanism of capsaicin-induced apoptosis in MCF-7 cells. Treatment with capsaicin for 24 h resulted in dose-dependent apoptosis in these cells. After the addition of capsaicin, the levels of reactive oxygen species were reduced slightly in the earlier stage of treatment. Interestingly, an elevation of intracellular calcium ion concentration was detected in the MCF-7 cells. In time course and dosage studies, the mitochondrial membrane potential of MCF-7 cells decreased. However, the change was not significant. It is worth noting that the apoptosis-inducing factor translocated into the cytosol and nucleus from the mitochondria. Our results suggest that capsaicin induces cellular apoptosis through a caspase-independent pathway in MCF-7 cells, and that reactive oxygen species and intracellular calcium ion fluctuation has a minimal role in the process.

PMID: 19212624 [PubMed - indexed for MEDLINE]



Rejuvenation Res. 2006 Spring;9(1):45-55.
Catechin-vanilloid synergies with potential clinical applications in cancer.

Morré DM, Morré DJ.
Department of Foods and Nutrition, Purdue University, West Lafayette, Indiana 47907-2059, USA. morredm@purdue.edu
A cancer-specific cell surface protein, tNOX, has been identified as a target for low-dose cell killing (apoptosis) of cancer cells by green tea catechins and Capsicum vanilloid combinations. This protein is uniquely associated with all forms of cancer and is absent from normal cells and tissues. Its activity is correlated with cancer growth. When blocked, cancer cells fail to enlarge after division and eventually die. Among the most potent and effective inhibitors of tNOX are naturally occurring polyphenols exemplified by the principal green tea catechin (-)-epigallocatechin gallate (EGCg) and the vanilloid capsaicin. Catechin-vanilloid combinations are 10 to 100 times more effective than either catechins or vanilloids alone. Vector-forced overexpression of tNOX cDNA and antisense has demonstrated that the tNOX target is both necessary and sufficient to explain the anticancer properties of green tea catechins alone and in vanilloid-containing combinations. The necessity and sufficiency of tNOX was validated as the catechin target with transgenic mice overexpressing the processed form of tNOX. Transgenic mice grew faster and the increased growth caused by tNOX overexpression was blocked by EGCg in the drinking water. A catechin-vanilloid mixture where one 350-mg capsule is equivalent to 16 cups of green tea in its ability to inhibit tNOX and growth of cancer cells in culture is undergoing clinical evaluation as a therapeutic aid for cancer patients.

PMID: 16608395 [PubMed - indexed for MEDLINE]


Botanicals for age-related diseases: from field to practice 2008
FULL TEXT

Botanical preparations that most inhibited cancer cell growth involved synergies between a decaffeinated green tea concentrate and vanilloid containing Capsicum preparations (Figure 2) (12). A 25:1 ratio of green tea concentrate to Capsicum preparation killed cancer cells in culture 100-times greater, by weight, than did green tea.
Assuming 2 g green tea per cup in preparing a usual green tea infusion, our findings suggest that a 350-mg capsule of the commercially available green tea extract–Capsicum preparations (Capsibiol-T or Capsol-T; BND Service Company, West Union, IL) is equivalent to drinking 16 cups of green tea on the basis of the comparative responses of growth of 4T1 and HeLa cells in
culture (12).

In a series of open-label sequential trials, 36% of 50 cancer participants with active cancer receiving Capsol-T had a significant prolongation of life or remained alive, 32% improved, and the rest had a normal course of disease (15).APhase II/III clinical study (toxicology and pharmacokinetics) of Capsol-T with renal cancer and melanoma directed by Theodore Logan at the Indiana University School of Medicine is underway, and a more extensive clinical study to evaluate efficacy is under development at the Goshen Cancer Center, Goshen, IN. A favorable interaction between a tea catechin–Capsicum preparation and radiation therapy was previously indicated from compassionate intervention studies with 5 cancer patients (16).

Capsibiol-T
http://www.newcancerresearch.com/about.htm

Biofactors. 2004;20(4):235-49.
tNOX is both necessary and sufficient as a cellular target for the anticancer actions of capsaicin and the green tea catechin (-)-epigallocatechin-3-gallate.

Chueh PJ, Wu LY, Morré DM, Morré DJ.
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
Capsaicin and the principal green tea catechin, (-)-epigallocatechin-3-gallate (EGCg), target tNOX, a tumor (cancer)-specific surface hydroquinone (NADH) oxidase with protein disulfide-thiol interchange activity (ECTO-NOX protein). Accordingly vector-forced over expression of tNOX in MCF-10A mammary epithelia or COS cells that lack tNOX or in COS cells that underexpress tNOX enhanced the susceptibility of growth and apoptosis to both EGCg and capsaicin. Additionally, the tNOX-transfected MCF-10A cells proliferated in Matrigel, a measure of invasiveness. In contrast, oligomeric antisense tNOX DNA abrogated growth inhibition by EGCg and capsaicin and reduced anchorage-dependent growth of HeLa (human cervical carcinoma) cells that naturally overexpress tNOX. The findings show cell surface expression of tNOX as both necessary and sufficient for the cellular anticancer activities attributed to both EGCg and capsaicin.

PMID: 15706060 [PubMed - indexed for MEDLINE]


Mol Cell Biochem. 2009 Nov;331(1-2):135-43. Epub 2009 May 18.
Capsaicin alleviates the imbalance in xenobiotic metabolizing enzymes and tumor markers during experimental lung tumorigenesis.

Anandakumar P, Kamaraj S, Jagan S, Ramakrishnan G, Naveenkumar C, Asokkumar S, Devaki T.
Department of Biochemistry, University of Madras, Guindy Campus, Chennai, 600-025, Tamil Nadu, India.
Lung cancer is currently a leading cause of death all over the world. Environmental risk factors, particularly genotoxic chemicals such as polycyclic aromatic hydrocarbons (PAH), are likely to account for a much higher mortality. Xenobiotic metabolizing enzymes are potentially chief determinants in both the susceptibility to the mutagenic effects of chemical carcinogens and in the response of tumors to chemotherapy. The well-known carcinogen benzo(a)pyrene (B(a)P) of PAH family was given orally (50 mg/kg body weight) to induce lung cancer in Swiss albino mice. B(a)P induction altered the levels of cytochromes (P450, b5), activities of phase I biotransformation enzymes (NADPH-cytochrome P450 reductase, NADH-cytochrome b5 reductase and epoxide hydrolase), phase II enzymes (glutathione-S-transferase, UDP-glucuronyl transferase and DT-diaphorase), and the levels of serum tumor markers. Treatment with capsaicin (CAP) (10 mg/kg body weight) to the lung carcinoma mice restored back the activities of phase I and II biotransformation enzymes and the levels of tumor markers to near normalcy. The above findings were substantiated by immunoblotting and immunohistochemical analysis of cytochrome P450 1A1 (CYP1A1) in the lung tissues. Our present study unravels that CAP can effectively detoxify the carcinogens which discloses its anti-carcinogenic effect during experimental lung cancer.

PMID: 19449198 [PubMed - indexed for MEDLINE]






2 OLDER ABSTRACTS SAY DANGEROUS?:


Breast Cancer Res Treat. 2006 Oct;99(3):351-64. Epub 2006 Apr 1.
Capsaicin-induced inactivation of sensory neurons promotes a more aggressive gene expression phenotype in breast cancer cells.

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Erin N, Zhao W, Bylander J, Chase G, Clawson G.
Department of Pathology, Gittlen Cancer Research Foundation, Hershey Medical Center, H059, Pennsylvania State University, 500 University drive, Hershey, PA 17033, USA.
Capsaicin-induced inactivation of sensory neurons has been reported to enhance metastasis of a murine breast cancer cell line, specifically enhancing myocardial metastases. Here we characterized changes in gene expression patterns in primary tumors which developed in capsaicin-treated vs. control mice. We identified a small cohort of genes (17) which all showed significant decreases in expression levels. All of the identified genes have been linked to cell growth, differentiation, and/or cancer progression. Three representative genes, Caspase-7 (an executor of apoptosis), ADAM-10 (A Disintegrin and Metalloprotease), and Elk-3 (a transcriptional repressor of the ternary factor subfamily of the Ets factors) were further investigated. All three showed dramatic downregulation at the protein level in primary tumors from capsaicin-treated animals compared with control (vehicle-treated) animals, and their expression was also lost in cell culture. Elk-3 and Caspase-7 were not expressed in vitro in cultured cell lines, suggesting that their expression was induced by the tumor microenvironment. Loss of Caspase-7 expression can be expected to result in loss of function of apoptotic pathways. At first glance, loss of ADAM-10 expression would be expected to result in decreased invasive capability, due to loss of matrix metalloprotease activity. However, just the opposite appears to be true. We found that ADAM-10 actually hydrolyzes Substance P. Specifically ADAM-10 produces the same growth-inhibitory products from Substance P (i.e., SP (1-7)) that Neprilysin does, so that loss of ADAM-10 expression actually results in loss of production of growth inhibitory peptides from Substance P. Similarly, ADAM-10 also efficiently hydrolyzes Calcitonin Gene-Related Peptide, which may act in concert with Substance P. Finally, overactivity of Ets transcriptional suppressor functions has been linked to inhibition of tumorigenesis (e.g., Erf and Mef), and in addition loss of Elk-3 expression might also be be linked to tumorigenesis via loss of its putative anti-inflammatory activities. There is anecdotal evidence in the literature to indicate that the rest of the down-regulated genes may also contribute to development of a more aggressive phenotype in this breast cancer model.

PMID: 16583263 [PubMed - indexed for MEDLINE]




Anticancer Res. 2004 Mar-Apr;24(2B):1003-9.
Capsaicin-mediated denervation of sensory neurons promotes mammary tumor metastasis to lung and heart.

Erin N, Boyer PJ, Bonneau RH, Clawson GA, Welch DR.
Jake Gittlen Cancer Research Institute, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
Capsaicin specifically activates or destroys small diameter nociceptive sensory neurons that contain the capsaicin receptor, also called vanilloid receptor 1. Neurons sensitive to capsaicin mediate inflammatory pain and are important targets for management of chronic pain. These neurons also regulate local tissue homeostasis, inflammation, healing and development, especially under conditions of psychological stress. Stress contributes to increased cancer recurrence and metastasis through as yet undefined mechanisms. Likewise, activity of capsaicin-sensitive neurons is altered by pathological conditions that may lead to metastatic growth (e.g. stress). Therefore, we examined effects of a treatment that induces sensory nerve denervation on breast cancer metastases. Systemic denervation of sensory neurons caused by treatment with 125 mg/kg capsaicin resulted in significantly more lung and cardiac metastases in adult mice injected orthotopically with syngeneic 4T1 mammary carcinoma cells than was observed in vehicle-treated controls. Heart metastases, normally very rare, occurred as pericardial nodules, intra-myocardial nodules, or combined pericardial-myocardial lesions. Since the rate of primary tumor growth was unaffected, effects on metastases appear to be host tissue-specific. Although preliminary, these observations provide one possible explanation for resistance of cardiac tissue to tumor involvement and highlight contributions of host tissue, including sensory neurons, in the efficiency of cancer metastasis.


Eur J Nutr. 2003 Jan;42(1):2-9.
Non-pungent capsaicinoids from sweet pepper synthesis and evaluation of the chemopreventive and anticancer potential.

Macho A, Lucena C, Sancho R, Daddario N, Minassi A, Muñoz E, Appendino G.
Departamento de BiologÃ*a Celular, FisiologÃ*a e InmunologÃ*a, Univ. de Córdoba, Avda de Menéndez Pidal s/n, Spain.
BACKGROUND: Capsiate, the non-pungent ester isoster of capsaicin, and its dihydroderivative are the major capsaicinoids of sweet peppers. The remarkable difference between the sensory properties of capsaicin vs capsiate is solely due to the way the vanillyl and the acyl moieties of this basic structural motif are linked, via an amide bond in capsaicin-type compounds and via an ester bond in capsiate-type compounds. AIM OF THE STUDY: Since capsaicin induces apoptosis in tumoral cells by a vanilloid receptor type 1(VR1)-independent pathway, we examined the effects of capsiates derived from sweet peppers in the ROS generation and induction of apoptosis in tumoral cells and if these are mediated independently from VR1. METHODS: We have developed an expeditious synthesis of capsiates based on the esterification of vanillol with the Mitsunobu protocol. Capsiate-induction of apoptosis, generation of reactive oxygen species and disruption of the mitochondria transmembrane potential in tumoral cell lines were measured by flow cytometry. Chemopreventive activity was studied in a two-stage mouse skin carcinogenesis assay. RESULTS: Capsiates induce apoptosis that was preceded by an increase in the production of reactive oxygen species and by a subsequent loss of mitochondria transmembrane potential (DeltaPsi(m)). These properties were retained in simplified synthetic analogues of natural capsiates, one of which (nor-dihydrocapsiate) showed powerful chemopreventive activity. CONCLUSIONS: These results suggest that capsiates and related synthetic analogues target a variety of pathways involved in cancer development and inflammation, and have considerable potential for dietary health benefits as well as for pharmaceutical development.

PMID: 12594536 [PubMed - indexed for MEDLINE]

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Oncogene. 2010 Jan 14;29(2):285-96. Epub 2009 Oct 26.
Capsaicin causes cell-cycle arrest and apoptosis in ER-positive and -negative breast cancer cells by modulating the EGFR/HER-2 pathway.

Thoennissen NH, O'Kelly J, Lu D, Iwanski GB, La DT, Abbassi S, Leiter A, Karlan B, Mehta R, Koeffler HP.
Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA 90048, USA. Nils.Thoennissen@cshs.org
Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is an ingredient of chili peppers with inhibitory effects against cancer cells of different origin. We examined the activity of capsaicin on breast cancer cells in vitro and in vivo. The drug potently inhibited growth of ER-positive (MCF-7, T47D, BT-474) and ER-negative (SKBR-3, MDA-MB231) breast cancer cell lines, which was associated with G(0)/G(1) cell-cycle arrest, increased levels of apoptosis and reduced protein expression of human epidermal growth factor receptor (EGFR), HER-2, activated extracellular-regulated kinase (ERK) and cyclin D1. In contrast, cell-cycle regulator p27(KIP1), caspase activity as well as poly-ADP ribose polymerase (PARP) cleavage were increased. Notably, capsaicin blocked breast cancer cell migration in vitro and decreased by 50% the size of MDA-MB231 breast cancer tumors growing orthotopically in immunodeficient mice without noticeable drug side effects. in vivo activation of ERK was clearly decreased, as well as expression of HER-2 and cyclin D1, whereas caspase activity and PARP cleavage products were increased in tumors of drug-treated mice. Besides, capsaicin potently inhibited the development of pre-neoplastic breast lesions by up to 80% without evidence of toxicity. Our data indicate that capsaicin is a novel modulator of the EGFR/HER-2 pathway in both ER-positive and -negative breast cancer cells with a potential role in the treatment and prevention of human breast cancer.

PMID: 19855437 [PubMed - in process]




http://www.nature.com/onc/journal/v2...nc2009335a.pdf

The aggressive, EGFR-positive, p53 mutant MDAMB231 breast cancer cells were grown orthotopically in the breast tissue of female BNX nu/nu mice; and capsaicin (5 mg/kg per day) or vehicle was administered by oral gavage three times per week.

April 19 2009
Hot Peppers Make Prostate Cancer Cells Die and Taste Buds Come to Life

LINK

Moderate dose of capsaicin makes 80 percent of prostate cancer cells die

In 2006, a team of researchers from the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center, found that capsaicin induced 80 percent of human prostate cancer cells growing in mice to follow pathways leading to certain death. They also found that prostate cancer tumors in mice fed with capsaicin were about one-fifth the size of tumors in non-treated mice. Additionally, capsaicin had a profound anti-proliferative effect on cultured human cancer cells according to a scientist at the UCLA School of Medicine. It dramatically slowed the development of prostate tumors formed by cells from the same lines as those grown for the mouse models.

The scientists estimated that the dose of pepper extract fed to the mice was equivalent to giving 400 milligrams of capsaicin three times a week to a 200 pound man. This would be about the amount found in three to eight fresh habanero peppers, depending on how hot the peppers were.

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Capsaicin is effective against other types of cancer

Research from India recently investigated the effect of capsaicin on fat metabolism during induced lung cancer in mice showing abnormal changes in tissue and serum lipids, lipoproteins, and lipid metabolizing enzymes. Treatment of 10 mg per kg of body weight showed an ability to reduce all of these alterations and restore normality that they described as "remarkable". (Archives of Pharmacal Research, February).

In another study investigating how oxidative stress mediated lung cancer, lysomal damage was found to be an indispensable event in the development of some lung cancers. Capsaicin was able to completely prevent lysomal damage, and was effective against induced lung cancer. (Fundamental Clinical Pharmacology, February).

Scientists investing the effects of capsaicin against human breast cancer noted that the compound has been shown to exert powerful biological activity including anticarginogenic, antimutagenic and chemoprotective effects against many cancer cell lines. When they tested it against a highly malignant breast cell line, they found that treatment with capsaicin for 24 hours resulted in dose-dependent death of the cancerous cells. (Oncology Report, March).

A recent study investigating capsaicin on highly metastatic melanoma cells found its anti-mutagenic activity inhibited the migration of melanoma cells at low doses without showing obvious cytotoxicity. The scientists concluded that capsaicin administration should be considered an effective approach for the suppression of invasion and metastasis in malignant melanoma. (Experimental and Molecular Medicine, October, 2008).

In an earlier study at M.D Anderson Cancer Center in Houston, researchers tested capsaicin on human skin cancer cells to analyze how the cells would react. They found that the majority of skin cancer cells exposed to the substance died. Capsaicin seemed to kill cancerous cells by damaging their membranes and limiting the amount of oxygen that could reach them. Drug companies have long searched for a drug that could do just that. Any compound that could limit oxygen in targeted cells would be highly effective against many forms of cancer.

High intake of capsaicin correlates with lower death rates from cancer

In countries where high intake of capsaicin is the dietary norm, cancer death rates for men and women are significantly lower than they are in countries with less chili pepper consumption according to statistics from the World Health Organization. Experiments have shown that capsaicin seems to be able to detoxify a wide range of chemical carcinogens which, if left to roam the body, could create mutations leading to full blown cancers.

Capsaicin soothes digestive tract stress

Contrary to popular belief, a study has found that ulcer sufferers are helped by eating hot spicy foods. Capsaicin increases blood flow in the stomach's mucous lining, helping to heal stomach tissue. It is effective against H. pylori bacteria, and stimulates circulation sequentially, from the internal organs to the skin surface, and on throughout the entire body. A Duke University study has found that capsaicin may lead to a cure for inflammatory bowel disease. Eating chili peppers has also been shown to protect against the effects to the stomach of aspirin

< see link for more



Can Urol Assoc J. 2010 Feb;4(1):E9-E11.
Capsaicin may slow PSA doubling time: case report and literature review.

Jankovic B, Loblaw DA, Nam R.
Faculty of Medicine, UBC, Vancouver, BC;
Capsaicin is the main pungent component of chili peppers. This is the first case, to our knowledge, that describes prostate-specific antigen (PSA) stabilization in a patient with prostate cancer, who had biochemical failure after radiation therapy. A 66-year-old male underwent radiotherapy treatment for a T2b, Gleason 7 (3+4) adenocarcinoma of the prostate, with a PSA level of 13.3 ng/mL in April 2001. He had 3-dimensional conformal radiotherapy of 46 Gy in 23 fractions to the prostate and pelvis, and a prostate boost of 30 Gy in 15 fractions. Radiotherapy was completed in May 2001 and PSA nadired in January 2002 (0.57). Due to the continued PSA rise, the patient was started on bicalutamide (50 mg orally, daily) and leuprolide acetate (1 dose of 22.5 mg intramuscularly) in July 2005 when PSA was 38.5 ng/mL. Due to poor tolerance of androgen ablation therapy, the patient discontinued treatment and started taking 2.5 mL of habaneros chili sauce, containing capsaicin, 1 to 2 times a week in April 2006. Prostate-specific antigen doubling time (PSAdt) increased from 4 weeks before capsaicin to 7.3 months by October 2006. From October 2006 until November 2007, the patient remained on capsaicin (2.5 to 15 mL daily) and his PSA was stable (between 11 to 14 ng/mL). By January 2008, his PSA rose to 22.3 and he has maintained a PSAdt between 4 and 5 months, where it presently remains. Due to the patient's continued PSA rise, he was restarted on bicalutamide (12.5 mg daily). Apart from PSA relapse, the patient remains free of signs or symptoms of recurrence.

PMID: 20174488 [PubMed - in process]





Indian J Cancer. 2010 Jan-Mar;47(1):53-8.
Capsaicin: a novel chemopreventive molecule and its underlying molecular mechanisms of action.

Oyagbemi AA, Saba AB, Azeez OI.
Department of Veterinary Physiology, Biochemistry and Pharmacology, Faculty of Veterinary Medicine, University of Ibadan, Oyo State, Nigeria.
Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is the a principal pungent ingredient of hot red and chili peppers that belong to the plant genus Capsicum (Solanaceae). Capsaicin is a cancer-suppressing agent. It blocks the translocation of nuclear factor kappa B (NF-kB), activator protein 1 (AP-1), and signal transducer and activator of transcription (STAT3) signaling pathway that are required for carcinogenesis. The anti-inflammatory potential of capsaicin is attributed to its inhibitory effect on inducible COX-2 mRNA expression. Cytochrome P4502E1 mediates the activation of xenobiotics such as vinyl carbamate and dimethyl nitrosamine to their toxic metabolites. This metabolic activation of xenobiotics by Cytochrome P4502E1 has been shown to be inhibited by capsaicin. Capsaicin also generates reactive oxygen species in cells with resultant induction of apoptosis and cell cycle arrest, which is beneficial for cancer chemoprevention. Therefore, the use of capsaicin as a chemopreventive agent is of immense benefit for cancer chemoprevention. The search strategy included printed journals, pubmed, and medline, using the terms 'capsaicin' and 'anticancer' citations, relevant to anticancer properties of capsaicin.

PMID: 20071791 [PubMed - in process]







Nat Prod Res. 2009;23(8):763-74.
Effect of capsaicin on glucose metabolism studied in experimental lung carcinogenesis.

Anandakumar P, Kamaraj S, Jagan S, Ramakrishnan G, Devaki T.
Department of Biochemistry, University of Madras, Guindy Campus, Chennai, India.
In the present study, we have assessed the chemopreventive effect of capsaicin (CAP) on glucose metabolism with reference to blood glucose and liver glycogen levels, key glycolytic, and gluconeogenic enzymes along with electron transport chain (ETC) complexes during benzo(a)pyrene (B(a)P)-induced lung cancer in Swiss albino mice. B(a)P (50 mg kg(-1) body weight)-induced lung cancer animals showed marked decline in blood glucose levels, glycogen levels, elevations in the activities of key glycolytic enzymes (hexokinase, phosphoglucoisomerase and aldolase), and gluconeogenic enzymes (glucose-6-phosphatase and fructose-6-phosphatase) together with a decrease in the activities of ETC complexes. Supplementation of CAP (10 mg kg(-1) body weight) inhibited all the above alterations during lung cancer and restored near normalcy. Histochemical analysis by periodic acid Schiff's staining further confirmed the biochemical findings that highlighted the chemopreventive action of CAP during B(a)P-induced experimental lung tumourigenesis.

PMID: 19418359 [PubMed - indexed for MEDLINE]



Cancer Lett. 2009 Jun 29. [Epub ahead of print]
Fas-associated factor 1 is a negative regulator in capsaicin induced cancer cell apoptosis.

Ghosh AK, Basu S.
Center for Immunotherapy of Cancer and Infectious Diseases, University of Connecticut School of Medicine, MC1601, Farmington, CT 06030-1601, USA.
Vanilloid receptor1 (VR1/TRPV1) is expressed on peripheral nerves and involved in sensing of temperature and pain. Recent reports have demonstrated that tumor cells express TRPV1 and that capsaicin (CP), a ligand for TRPV1, induces apoptosis in cancer cells. The mechanism underlying CP-induced tumor cell apoptosis remains unclear. Here, we investigated the role of TRPV1 in tumor apoptosis using TRPV1-expressing cancer cell lines. We demonstrate that iodo-resiniferatoxin (I-RTX), an antagonist of TRPV1 does not inhibit CP mediated apoptosis nor is it cytotoxic by itself, but acts as a partial agonist and shows synergistic effect with CP. We further demonstrate that CP treatment degrades Fas-associated factor1 (FAF1); a TRPV1 associated protein. Moreover, using RNA interference with small inhibitory RNAs (siRNA) for FAF1 we observed that down-regulation of FAF1 by siRNA makes the cell susceptible to enhanced apoptosis with CP. In summary, our data shows for the first time that the underlying mechanisms of CP-induced cancer cell apoptosis involves FAF1, a TRPV1 associated protein and serves as an important foundation for further understanding of anticancer activity of CP.

PMID: 19570606 [PubMed - as supplied by publisher]




Indian J Cancer. 2010 Jan-Mar;47(1):53-8.
Capsaicin: a novel chemopreventive molecule and its underlying molecular mechanisms of action.

Oyagbemi AA, Saba AB, Azeez OI.
Department of Veterinary Physiology, Biochemistry and Pharmacology, Faculty of Veterinary Medicine, University of Ibadan, Oyo State, Nigeria.
Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is the a principal pungent ingredient of hot red and chili peppers that belong to the plant genus Capsicum (Solanaceae). Capsaicin is a cancer-suppressing agent. It blocks the translocation of nuclear factor kappa B (NF-kB), activator protein 1 (AP-1), and signal transducer and activator of transcription (STAT3) signaling pathway that are required for carcinogenesis. The anti-inflammatory potential of capsaicin is attributed to its inhibitory effect on inducible COX-2 mRNA expression. Cytochrome P4502E1 mediates the activation of xenobiotics such as vinyl carbamate and dimethyl nitrosamine to their toxic metabolites. This metabolic activation of xenobiotics by Cytochrome P4502E1 has been shown to be inhibited by capsaicin. Capsaicin also generates reactive oxygen species in cells with resultant induction of apoptosis and cell cycle arrest, which is beneficial for cancer chemoprevention. Therefore, the use of capsaicin as a chemopreventive agent is of immense benefit for cancer chemoprevention. The search strategy included printed journals, pubmed, and medline, using the terms 'capsaicin' and 'anticancer' citations, relevant to anticancer properties of capsaicin.

PMID: 20071791 [PubMed - in process]




Exp Mol Med. 2008 Oct 31;40(5):486-94.
Inhibitory effect of capsaicin on B16-F10 melanoma cell migration via the phosphatidylinositol 3-kinase/Akt/Rac1 signal pathway.

Shin DH, Kim OH, Jun HS, Kang MK.
Department of General Surgery, Kosin University College of Medicine, Busan 602-739, Korea.
Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), the major pungent ingredient of red pepper, has been reported to possess anti-carcinogenic and anti-mutagenic activities. In this study, the anti-migration activity of capsaicin on highly metastatic B16-F10 melanoma cells was investigated. Capsaicin significantly inhibited the migration of melanoma cells without showing obvious cellular cytotoxicity at low doses. This effect correlated with the down-regulation of phosphatidylinositol 3-kinase (PI3-K) and its downstream target, Akt. Although B16-F10 cell migration was increased by the PI3-K activator through the activation of Akt, these PI3-K activator-induced phenomena were attenuated by capsaicin. Moreover, capsaicin was found to significantly inhibit Rac1 activity in a pull-down assay. These results demonstrate that capsaicin inhibits the migration of B16-F10 cells through the inhibition of the PI3-K/Akt/Rac1 signal pathway. The present investigation suggests that capsaicin targets PI3-K/Akt/ Rac1-mediated cellular events in B16-F10 melanoma cells. Consequently, capsaicin administration should be considered an effective approach for the suppression of invasion and metastasis in malignant melanoma chemotherapy.

PMID: 18985006 [PubMed - indexed for MEDLINE]




Oncol Rep. 2009 Mar;21(3):665-71.
Capsaicin-induced apoptosis in human breast cancer MCF-7 cells through caspase-independent pathway.

Chou CC, Wu YC, Wang YF, Chou MJ, Kuo SJ, Chen DR.
Department of Emergency Medicine, Changhua Christian Hospital, Changhua, Taiwan, R.O.C.
Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), a significant pungent ingredient in a variety of red peppers of the genus Capsicum, is a type of vanilloid. It has been shown to exert biological activities (anticarcinogenic, antimutagenic and chemopreventive) in many cancer cell lines. It was found that capsaicin induces dose-dependent growth inhibition of MCF-7 cells, which does not express caspase-3. In this study, we investigated the molecular mechanism of capsaicin-induced apoptosis in MCF-7 cells. Treatment with capsaicin for 24 h resulted in dose-dependent apoptosis in these cells. After the addition of capsaicin, the levels of reactive oxygen species were reduced slightly in the earlier stage of treatment. Interestingly, an elevation of intracellular calcium ion concentration was detected in the MCF-7 cells. In time course and dosage studies, the mitochondrial membrane potential of MCF-7 cells decreased. However, the change was not significant. It is worth noting that the apoptosis-inducing factor translocated into the cytosol and nucleus from the mitochondria. Our results suggest that capsaicin induces cellular apoptosis through a caspase-independent pathway in MCF-7 cells, and that reactive oxygen species and intracellular calcium ion fluctuation has a minimal role in the process.

PMID: 19212624 [PubMed - indexed for MEDLINE]



Rejuvenation Res. 2006 Spring;9(1):45-55.
Catechin-vanilloid synergies with potential clinical applications in cancer.

Morré DM, Morré DJ.
Department of Foods and Nutrition, Purdue University, West Lafayette, Indiana 47907-2059, USA. morredm@purdue.edu
A cancer-specific cell surface protein, tNOX, has been identified as a target for low-dose cell killing (apoptosis) of cancer cells by green tea catechins and Capsicum vanilloid combinations. This protein is uniquely associated with all forms of cancer and is absent from normal cells and tissues. Its activity is correlated with cancer growth. When blocked, cancer cells fail to enlarge after division and eventually die. Among the most potent and effective inhibitors of tNOX are naturally occurring polyphenols exemplified by the principal green tea catechin (-)-epigallocatechin gallate (EGCg) and the vanilloid capsaicin. Catechin-vanilloid combinations are 10 to 100 times more effective than either catechins or vanilloids alone. Vector-forced overexpression of tNOX cDNA and antisense has demonstrated that the tNOX target is both necessary and sufficient to explain the anticancer properties of green tea catechins alone and in vanilloid-containing combinations. The necessity and sufficiency of tNOX was validated as the catechin target with transgenic mice overexpressing the processed form of tNOX. Transgenic mice grew faster and the increased growth caused by tNOX overexpression was blocked by EGCg in the drinking water. A catechin-vanilloid mixture where one 350-mg capsule is equivalent to 16 cups of green tea in its ability to inhibit tNOX and growth of cancer cells in culture is undergoing clinical evaluation as a therapeutic aid for cancer patients.

PMID: 16608395 [PubMed - indexed for MEDLINE]


Botanicals for age-related diseases: from field to practice 2008
FULL TEXT

Botanical preparations that most inhibited cancer cell growth involved synergies between a decaffeinated green tea concentrate and vanilloid containing Capsicum preparations (Figure 2) (12). A 25:1 ratio of green tea concentrate to Capsicum preparation killed cancer cells in culture 100-times greater, by weight, than did green tea.
Assuming 2 g green tea per cup in preparing a usual green tea infusion, our findings suggest that a 350-mg capsule of the commercially available green tea extract–Capsicum preparations (Capsibiol-T or Capsol-T; BND Service Company, West Union, IL) is equivalent to drinking 16 cups of green tea on the basis of the comparative responses of growth of 4T1 and HeLa cells in
culture (12).

In a series of open-label sequential trials, 36% of 50 cancer participants with active cancer receiving Capsol-T had a significant prolongation of life or remained alive, 32% improved, and the rest had a normal course of disease (15).APhase II/III clinical study (toxicology and pharmacokinetics) of Capsol-T with renal cancer and melanoma directed by Theodore Logan at the Indiana University School of Medicine is underway, and a more extensive clinical study to evaluate efficacy is under development at the Goshen Cancer Center, Goshen, IN. A favorable interaction between a tea catechin–Capsicum preparation and radiation therapy was previously indicated from compassionate intervention studies with 5 cancer patients (16).

Capsibiol-T
http://www.newcancerresearch.com/about.htm

Biofactors. 2004;20(4):235-49.
tNOX is both necessary and sufficient as a cellular target for the anticancer actions of capsaicin and the green tea catechin (-)-epigallocatechin-3-gallate.

Chueh PJ, Wu LY, Morré DM, Morré DJ.
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
Capsaicin and the principal green tea catechin, (-)-epigallocatechin-3-gallate (EGCg), target tNOX, a tumor (cancer)-specific surface hydroquinone (NADH) oxidase with protein disulfide-thiol interchange activity (ECTO-NOX protein). Accordingly vector-forced over expression of tNOX in MCF-10A mammary epithelia or COS cells that lack tNOX or in COS cells that underexpress tNOX enhanced the susceptibility of growth and apoptosis to both EGCg and capsaicin. Additionally, the tNOX-transfected MCF-10A cells proliferated in Matrigel, a measure of invasiveness. In contrast, oligomeric antisense tNOX DNA abrogated growth inhibition by EGCg and capsaicin and reduced anchorage-dependent growth of HeLa (human cervical carcinoma) cells that naturally overexpress tNOX. The findings show cell surface expression of tNOX as both necessary and sufficient for the cellular anticancer activities attributed to both EGCg and capsaicin.

PMID: 15706060 [PubMed - indexed for MEDLINE]


Mol Cell Biochem. 2009 Nov;331(1-2):135-43. Epub 2009 May 18.
Capsaicin alleviates the imbalance in xenobiotic metabolizing enzymes and tumor markers during experimental lung tumorigenesis.

Anandakumar P, Kamaraj S, Jagan S, Ramakrishnan G, Naveenkumar C, Asokkumar S, Devaki T.
Department of Biochemistry, University of Madras, Guindy Campus, Chennai, 600-025, Tamil Nadu, India.
Lung cancer is currently a leading cause of death all over the world. Environmental risk factors, particularly genotoxic chemicals such as polycyclic aromatic hydrocarbons (PAH), are likely to account for a much higher mortality. Xenobiotic metabolizing enzymes are potentially chief determinants in both the susceptibility to the mutagenic effects of chemical carcinogens and in the response of tumors to chemotherapy. The well-known carcinogen benzo(a)pyrene (B(a)P) of PAH family was given orally (50 mg/kg body weight) to induce lung cancer in Swiss albino mice. B(a)P induction altered the levels of cytochromes (P450, b5), activities of phase I biotransformation enzymes (NADPH-cytochrome P450 reductase, NADH-cytochrome b5 reductase and epoxide hydrolase), phase II enzymes (glutathione-S-transferase, UDP-glucuronyl transferase and DT-diaphorase), and the levels of serum tumor markers. Treatment with capsaicin (CAP) (10 mg/kg body weight) to the lung carcinoma mice restored back the activities of phase I and II biotransformation enzymes and the levels of tumor markers to near normalcy. The above findings were substantiated by immunoblotting and immunohistochemical analysis of cytochrome P450 1A1 (CYP1A1) in the lung tissues. Our present study unravels that CAP can effectively detoxify the carcinogens which discloses its anti-carcinogenic effect during experimental lung cancer.

PMID: 19449198 [PubMed - indexed for MEDLINE]






2 OLDER ABSTRACTS SAY DANGEROUS?:


Breast Cancer Res Treat. 2006 Oct;99(3):351-64. Epub 2006 Apr 1.
Capsaicin-induced inactivation of sensory neurons promotes a more aggressive gene expression phenotype in breast cancer cells.

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Erin N, Zhao W, Bylander J, Chase G, Clawson G.
Department of Pathology, Gittlen Cancer Research Foundation, Hershey Medical Center, H059, Pennsylvania State University, 500 University drive, Hershey, PA 17033, USA.
Capsaicin-induced inactivation of sensory neurons has been reported to enhance metastasis of a murine breast cancer cell line, specifically enhancing myocardial metastases. Here we characterized changes in gene expression patterns in primary tumors which developed in capsaicin-treated vs. control mice. We identified a small cohort of genes (17) which all showed significant decreases in expression levels. All of the identified genes have been linked to cell growth, differentiation, and/or cancer progression. Three representative genes, Caspase-7 (an executor of apoptosis), ADAM-10 (A Disintegrin and Metalloprotease), and Elk-3 (a transcriptional repressor of the ternary factor subfamily of the Ets factors) were further investigated. All three showed dramatic downregulation at the protein level in primary tumors from capsaicin-treated animals compared with control (vehicle-treated) animals, and their expression was also lost in cell culture. Elk-3 and Caspase-7 were not expressed in vitro in cultured cell lines, suggesting that their expression was induced by the tumor microenvironment. Loss of Caspase-7 expression can be expected to result in loss of function of apoptotic pathways. At first glance, loss of ADAM-10 expression would be expected to result in decreased invasive capability, due to loss of matrix metalloprotease activity. However, just the opposite appears to be true. We found that ADAM-10 actually hydrolyzes Substance P. Specifically ADAM-10 produces the same growth-inhibitory products from Substance P (i.e., SP (1-7)) that Neprilysin does, so that loss of ADAM-10 expression actually results in loss of production of growth inhibitory peptides from Substance P. Similarly, ADAM-10 also efficiently hydrolyzes Calcitonin Gene-Related Peptide, which may act in concert with Substance P. Finally, overactivity of Ets transcriptional suppressor functions has been linked to inhibition of tumorigenesis (e.g., Erf and Mef), and in addition loss of Elk-3 expression might also be be linked to tumorigenesis via loss of its putative anti-inflammatory activities. There is anecdotal evidence in the literature to indicate that the rest of the down-regulated genes may also contribute to development of a more aggressive phenotype in this breast cancer model.

PMID: 16583263 [PubMed - indexed for MEDLINE]




Anticancer Res. 2004 Mar-Apr;24(2B):1003-9.
Capsaicin-mediated denervation of sensory neurons promotes mammary tumor metastasis to lung and heart.

Erin N, Boyer PJ, Bonneau RH, Clawson GA, Welch DR.
Jake Gittlen Cancer Research Institute, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
Capsaicin specifically activates or destroys small diameter nociceptive sensory neurons that contain the capsaicin receptor, also called vanilloid receptor 1. Neurons sensitive to capsaicin mediate inflammatory pain and are important targets for management of chronic pain. These neurons also regulate local tissue homeostasis, inflammation, healing and development, especially under conditions of psychological stress. Stress contributes to increased cancer recurrence and metastasis through as yet undefined mechanisms. Likewise, activity of capsaicin-sensitive neurons is altered by pathological conditions that may lead to metastatic growth (e.g. stress). Therefore, we examined effects of a treatment that induces sensory nerve denervation on breast cancer metastases. Systemic denervation of sensory neurons caused by treatment with 125 mg/kg capsaicin resulted in significantly more lung and cardiac metastases in adult mice injected orthotopically with syngeneic 4T1 mammary carcinoma cells than was observed in vehicle-treated controls. Heart metastases, normally very rare, occurred as pericardial nodules, intra-myocardial nodules, or combined pericardial-myocardial lesions. Since the rate of primary tumor growth was unaffected, effects on metastases appear to be host tissue-specific. Although preliminary, these observations provide one possible explanation for resistance of cardiac tissue to tumor involvement and highlight contributions of host tissue, including sensory neurons, in the efficiency of cancer metastasis.


Eur J Nutr. 2003 Jan;42(1):2-9.
Non-pungent capsaicinoids from sweet pepper synthesis and evaluation of the chemopreventive and anticancer potential.

Macho A, Lucena C, Sancho R, Daddario N, Minassi A, Muñoz E, Appendino G.
Departamento de BiologÃ*a Celular, FisiologÃ*a e InmunologÃ*a, Univ. de Córdoba, Avda de Menéndez Pidal s/n, Spain.
BACKGROUND: Capsiate, the non-pungent ester isoster of capsaicin, and its dihydroderivative are the major capsaicinoids of sweet peppers. The remarkable difference between the sensory properties of capsaicin vs capsiate is solely due to the way the vanillyl and the acyl moieties of this basic structural motif are linked, via an amide bond in capsaicin-type compounds and via an ester bond in capsiate-type compounds. AIM OF THE STUDY: Since capsaicin induces apoptosis in tumoral cells by a vanilloid receptor type 1(VR1)-independent pathway, we examined the effects of capsiates derived from sweet peppers in the ROS generation and induction of apoptosis in tumoral cells and if these are mediated independently from VR1. METHODS: We have developed an expeditious synthesis of capsiates based on the esterification of vanillol with the Mitsunobu protocol. Capsiate-induction of apoptosis, generation of reactive oxygen species and disruption of the mitochondria transmembrane potential in tumoral cell lines were measured by flow cytometry. Chemopreventive activity was studied in a two-stage mouse skin carcinogenesis assay. RESULTS: Capsiates induce apoptosis that was preceded by an increase in the production of reactive oxygen species and by a subsequent loss of mitochondria transmembrane potential (DeltaPsi(m)). These properties were retained in simplified synthetic analogues of natural capsiates, one of which (nor-dihydrocapsiate) showed powerful chemopreventive activity. CONCLUSIONS: These results suggest that capsiates and related synthetic analogues target a variety of pathways involved in cancer development and inflammation, and have considerable potential for dietary health benefits as well as for pharmaceutical development.

PMID: 12594536 [PubMed - indexed for MEDLINE]