Curcumin suppresses the paclitaxel-induced nuclear factor-kappaB in breast cancer cel

[Rich66]

Original curcumin post/discussion by Lani: http://her2support.org/vbulletin/sho...light=Curcumin

Thread by Tom:http://her2support.org/vbulletin/sho...light=Curcumin


HUGE compilation by Marge, a curcumin evangelist:
http://margaret.healthblogs.org/life...y-of-curcumin/

Marge's warning/side effects page: avoid if gall bladder issues, taking blood thinners, stomach ulcers. See smoker issue below
Others say Curcumin treats gallstones. maybe depends on which type of gallstone (bile or cholesterol)
pubmed says:

Asia Pac J Clin Nutr. 2002;11(4):314-8.
Effect of different curcumin dosages on human gall bladder.

Rasyid A, Rahman AR, Jaalam K, Lelo A.
School of Medicine, University of North Sumatera, Medan, Indonesia. rasyid_1506@yahoo.com
Our previous study demonstrated that curcumin, an active compound of Curcuma xanthorrhiza and C. domestica, produces a positive cholekinetic effect. A 20 mg amount of curcumin is capable of contracting the gall bladder by up to 29% within an observation time of 2 h. The aim of the current study was to define the dosage of curcumin capable of producing a 50% contraction of the gall bladder, and to determine if there is a linear relationship between doubling the curcumin dosage and the doubling of gall bladder contraction. A randomised, single-blind, three-phase, crossover-designed examination was carried out on 12 healthy volunteers. Ultrasonography was carried out serially to measure the gall bladder volume. The data obtained was analysed by analysis of variance (ANOVA). The fasting volumes of gall bladders were similar (P > 0.50), with 17.28 +/- 5.47 mL for 20 mg curcumin, 18.34 +/- 3.75 mL for 40 mg and 18.24 +/- 3.72 mL for 80 mg. The percentage decrease in gall bladder volume 2 h after administration of 20, 40 and 80 mg was 34.10 +/- 10.16, 51.15 +/- 8.08 and 72.25 +/- 8.22, respectively, which was significantly different (P < 0.01). On the basis of the present findings, it appears that the dosage of cucumin capable of producing a 50% contraction of the bladder was 40 mg. This study did not show any linear relationship between doubling curcumin dosage and the doubling of gall bladder contraction.

PMID: 12495265 [PubMed - indexed for MEDLINE]



Ok...back to cancer related...



Dr. Aagarwal's extensive website: www.curcuminresearch.org

Interview with Dr. Aagarwal: http://www.naturalmedicinejournal.co...J_DEC09_RI.pdf


Curcumin discussion thread in Prostate Cancer forum





Breast J. 2009 May-Jun;15(3):223-9.
Curcumin suppresses the paclitaxel-induced nuclear factor-kappaB in breast cancer cells and potentiates the growth inhibitory effect of paclitaxel in a breast cancer nude mice model.

FULL TEXT(free)


Kang HJ, Lee SH, Price JE, Kim LS.
Division of Breast & Endocrine Surgery, Hallym Sacred Heart Hospital, College of Medicine, Hallym University, Dongan-Gu, Anyang, Korea.
Most anticancer agents activate nuclear factor kappa B (NF-kappaB), which can mediate cell survival, proliferation, and metastasis. Curcumin has been shown to inhibit the growth of various cancer cells, without toxicity to normal cells. The antitumor effects of curcumin could be due in part to the inactivation of NF-kappaB. We hypothesize that blocking NF-kappaB activity may augment paclitaxel cancer chemotherapy. In this study, we investigated whether the inactivation of NF-kappaB by curcumin would enhance the efficacy of paclitaxel for inhibiting breast cancer growth in vitro and in vivo. We confirmed that curcumin inhibited paclitaxel-induced activation of NF-kappaB and potentiated the growth inhibitory effect of paclitaxel in MDA-MB-231 breast cancer cells. The combination of curcumin with paclitaxel elicited significantly greater inhibition of cell growth and more apoptosis, compared with either agent alone. In an experimental breast cancer murine model using MDA-MB-231 cells, combination therapy with paclitaxel and curcumin significantly reduced tumor size and decreased tumor cell proliferation, increased apoptosis, and decreased the expression of matrix metalloprotease 9 compared with either agent alone. These results clearly suggest that a curcumin-paclitaxel combination could be a novel strategy for the treatment of breast cancer.

PMID: 19645775 [PubMed - indexed for MEDLINE]

[The below refers to lung cancer, not sure if related to other cancer mets. (Tom's friend had lung met reduction) ]

1: Carcinogenesis. 2009 Apr 9.

Lung tumor promotion by curcumin.

http://carcin.oxfordjournals.org/cgi...ract/30/6/1016

To whom correspondence should be addressed. Department of Cancer Biology, 1 Medical Center Boulevard, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. Tel: +1 336 716 0795; Fax: +1 336 716 0255; Email: msmiller@wfubmc.edu

Dance-Barnes ST, Kock ND, Moore JE, Lin EY, Mosley LJ, D'Agostino RB Jr, McCoy TP, Townsend AJ, Miller MS.
Department of Cancer Biology.
Curcumin exhibits anti-inflammatory and anti-tumor activity and is being tested in clinical trials as a chemopreventive agent for colon cancer. Curcumin's chemopreventive activity was tested in a transgenic mouse model of lung cancer that expresses the human Ki-ras(G12C) allele in a doxycycline (DOX) inducible and lung-specific manner. The effects of curcumin were compared to the lung tumor promoter, butylated hydroxytoluene (BHT), and the lung cancer chemopreventive agent, sulindac. Treatment of DOX-induced mice with dietary curcumin increased tumor multiplicity (36.3+/-0.9 vs. 24.3+/-0.2) and progression to later stage lesions, results which were similar to animals that were co-treated with DOX/BHT. Microscopic examination showed that the percentage of lung lesions that were adenomas and adenocarcinomas increased to 66% in DOX/BHT, 66% in DOX/curcumin, and 49% in DOX/BHT/curcumin treated groups relative to DOX only treated mice (19%). Immunohistochemical analysis also showed increased evidence of inflammation in DOX/BHT, DOX/curcumin, and DOX/BHT/curcumin mice relative to DOX only treated mice. In contrast, co-treatment of DOX/BHT mice with 80 ppm of sulindac inhibited the progression of lung lesions and reduced the inflammation. Lung tissue from DOX/curcumin treated mice demonstrated a significant increase (33%; p = 0.01) in oxidative damage, as assessed by the levels of carbonyl protein formation, relative to DOX-treated control mice after one week on the curcumin diet. These results suggest that curcumin may exhibit organ-specific effects to enhance reactive oxygen species formation in the damaged lung epithelium of smokers and ex-smokers. Ongoing clinical trials thus may need to exclude smokers and ex-smokers in chemopreventive trials of curcumin.

"The Dark side of Curcumin" PDF (oral availability, dose dependent effects etc)

1: Ann N Y Acad Sci. 2009 Feb;1155:278-83. Links

Curcumin as a possible lead compound against hormone-independent, multidrug-resistant breast cancer.

Labbozzetta M, Notarbartolo M, Poma P, Maurici A, Inguglia L, Marchetti P, Rizzi M, Baruchello R, Simoni D, D'Alessandro N.
Dipartimento di Scienze Farmacologiche Pietro Benigno, UniversitÃ* di Palermo, Palermo, Italy.
We examine the possible evidence that the phytochemical curcumin may overcome resistance to hormonal and cytotoxic agents in breast cancer. We present our observations on MCF-7R, a multidrug-resistant (MDR) variant of the MCF-7 breast cancer cell line. In contrast to MCF-7, MCF-7R lacks aromatase and estrogen receptor alpha (ERalpha) and overexpresses the multidrug transporter ABCB1 and the products of different genes implicated in cell proliferation and survival, like c-IAP-1, NAIP, survivin, and COX-2. Nevertheless, in cytotoxicity and cell death induction assays, we found that the antitumor activity of curcumin is substantial both in MCF-7 and in MCF-7R. We elaborated the diketone system of curcumin into different analogues; the benzyloxime and the isoxazole and pyrazole heterocycles showed remarkable increases in the antitumor potency both in the parental and in the MDR MCF-7 cells. Furthermore, curcumin or, more potently, the isoxazole analogue, produced early reductions in the amounts of relevant gene transcripts that were diverse (i.e., they were relative to Bcl-2 and Bcl-X(L) in MCF-7 and the inhibitory of apoptosis proteins and COX-2 in MCF-7R) in the two cell lines. Thus, the two compounds exhibited the remarkable property of being able to modify their molecular activities according to the distinct characteristics of the parental and MDR cells. We discuss also how curcumin may (1) exert antitumor effects in breast cancer through ER-dependent and ER-independent mechanisms; and (2) act as a drug transporter-mediated MDR reversal agent. Overall, the structure of curcumin may represent the basis for the development of new, effective anticancer agents in hormone-independent MDR breast cancer.

Some say oral Curcumin absorption is too low for cancer benefit and a different delivery approach is necessary.
Others say:

Mol Nutr Food Res. 2008 Sep;52(9):1010-30.
Multi-targeted therapy by curcumin: how spicy is it?

Goel A, Jhurani S, Aggarwal BB.
Gastrointestinal Cancer Research Laboratory, Department of Internal Medicine, Charles A Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA.
Comment in:

• Mol Nutr Food Res. 2009 Feb;53(2):308.

Although traditional medicines have been used for thousands of years, for most such medicines neither the active component nor their molecular targets have been very well identified. Curcumin, a yellow component of turmeric or curry powder, however, is an exception. Although inhibitors of cyclooxygenase-2, HER2, tumor necrosis factor, EGFR, Bcr-abl, proteosome, and vascular endothelial cell growth factor have been approved for human use by the United States Food and Drug Administration (FDA), curcumin as a single agent can down-regulate all these targets. Curcumin can also activate apoptosis, down-regulate cell survival gene products, and up-regulate p53, p21, and p27. Although curcumin is poorly absorbed after ingestion, multiple studies have suggested that even low levels of physiologically achievable concentrations of curcumin may be sufficient for its chemopreventive and chemotherapeutic activity. Thus, curcumin regulates multiple targets (multitargeted therapy), which is needed for treatment of most diseases, and it is inexpensive and has been found to be safe in human clinical trials. The present article reviews the key molecular mechanisms of curcumin action and compares this to some of the single-targeted therapies currently available for human cancer.

PMID: 18384098 [PubMed - indexed for MEDLINE]


Int J Cancer. 2009 Jul 1;125(1):1-8.
Liposome encapsulation of curcumin and resveratrol in combination reduces prostate cancer incidence in PTEN knockout mice.

Narayanan NK, Nargi D, Randolph C, Narayanan BA.
Department of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA. Narayanan.Narayanan@nyumc.org
Comment in:

• Int J Cancer. 2009 Oct 15;125(8):1992-3.

Increasing interest in the use of phytochemicals to reduce prostate cancer led us to investigate 2 potential agents, curcumin and resveratrol as preventive agents. However, there is concern about the bioavailability of these agents pertinent to the poor absorption and thereby limiting its clinical use. With the view to improve their bioavailability, we used the liposome encapsulated curcumin, and resveratrol individually and in combination in male B6C3F1/J mice. Further, we examined the chemopreventive effect of liposome encapsulated curcumin and resveratrol in combination in prostate-specific PTEN knockout mice. In vitro assays using PTEN-CaP8 cancer cells were performed to investigate the combined effects curcumin with resveratrol on (i) cell growth, apoptosis and cell cycle (ii) impact on activated p-Akt, cyclin D1, m-TOR and androgen receptor (AR) proteins involved in tumor progression. HPLC analysis of serum and prostate tissues showed a significant increase in curcumin level when liposome encapsulated curcumin coadministered with liposomal resveratrol (p < 0.001). Combination of liposomal forms of curcumin and resveratrol significantly decreased prostatic adenocarcinoma in vivo (p < 0.001). In vitro studies revealed that curcumin plus resveratrol effectively inhibit cell growth and induced apoptosis. Molecular targets activated due to the loss of phosphatase and tensin homolog (PTEN) including p-Akt, cyclin D1, mammalian target of rapamycin and AR were downregulated by these agents in combination. Findings from this study for the first time provide evidence on phytochemicals in combination to enhance chemopreventive efficacy in prostate cancer. These findings clearly suggest that phytochemicals in combination may reduce prostate cancer incidence due to the loss of the tumor suppressor gene PTEN.

PMID: 19326431 [PubMed - indexed for MEDLINE]






Ai Zheng. 2010 Jan;29(1):9-14.
The aromatase inhibitor letrozole combined with curcumin in the inhibition of xenografted endometrial carcinoma growth.

Liang YJ, Zhang HM, Wu YZ, Hao Q, Wang JD, Hu YL.
Department of Obstetrics and Gynecology, Jinling Hospital, Nanjing University School of Medicine,Nanjing, Jiangsu 210002, P. R. China. yuanjiao1965@126.com.
Background and Objective: Letrozole is an aromatase inhibitor that is used in the treatment of estrogen-sensitive tumors such as endometrial carcinoma. Tumor inhibition to a certain extent has been demonstrated, however, the therapeutic effects need improvement. Curcumin is reported to have antitumor capabilities and can enhance the sensitivity of tumor cells to anticancer agents. The present study promoted the inhibitory effect on implanted endometrial tumor growth by combining letrozole and curcumin. Methods: Endometrial carcinoma was implanted into nude mice. Tumor-laden mice were treated with the aromatase inhibitor letrozole (Let), curcumin (Cur), or both. The tumor growth was monitored. Tumor cell apoptosis was detected in both the control and treated groups. The expression of bcl-2 mRNA and Bcl-2 protein was detected with reverse transcription polymerase chain reaction (RT-PCR) and Western blot. Results: A total of 50 mice successfully received implants of endometrial tumors. Treatment with letrozole markedly inhibited tumor growth, and the inhibitory effect was enhanced by the combination of letrozole and curcumin. The inhibitory rates in the Let(1), Let(10), Cur, and Let+Cur groups were 15.95%, 22.49%, 21.57%, and 35.89%, respectively. Treatment with curcumin inhibited the expression of Bcl-2 in tumor cells at the mRNA and protein levels. The rates of apoptosis in the control group and the above-mentioned groups were 16.97%, 32.90%, 35.80%, 34.16%, and 47.24%, respectively. Tumor cell apoptosis was observed in mice treated with either letrozole or curcumin; however, the combination of letrozole and curcumin enhanced the inhibition rate in tumor growth. Conclusions: Treatment with either letrozole or curcumin could inhibit xenografted endometrial tumor growth by inducing apoptosis in tumor cells. The combination of letrozole and curcumin enhanced the inhibitory effect.

PMID: 20038303 [PubMed - in process]

[Rich66]

NOTE: THIS RESEARCHER SAYS CURCUMIN MAY CONFLICT WITH CHEMO (!?)

Breast Cancer Res Treat. 2009 Nov 7. [Epub ahead of print]
Targeting breast stem cells with the cancer preventive compounds curcumin and piperine.
Kakarala M, Brenner DE, Korkaya H, Cheng C, Tazi K, Ginestier C, Liu S, Dontu G, Wicha MS.

Division of Hematology/Oncology, Department of Internal Medicine and Comprehensive Cancer Center, University of Michigan, 2150 Cancer Center, 1500 E. Medical Center Dr., Ann Arbor, MI, USA, mkakaral@umich.edu.
The cancer stem cell hypothesis asserts that malignancies arise in tissue stem and/or progenitor cells through the dysregulation or acquisition of self-renewal. In order to determine whether the dietary polyphenols, curcumin, and piperine are able to modulate the self-renewal of normal and malignant breast stem cells, we examined the effects of these compounds on mammosphere formation, expression of the breast stem cell marker aldehyde dehydrogenase (ALDH), and Wnt signaling. Mammosphere formation assays were performed after curcumin, piperine, and control treatment in unsorted normal breast epithelial cells and normal stem and early progenitor cells, selected by ALDH positivity. Wnt signaling was examined using a Topflash assay. Both curcumin and piperine inhibited mammosphere formation, serial passaging, and percent of ALDH+ cells by 50% at 5 muM and completely at 10 muM concentration in normal and malignant breast cells. There was no effect on cellular differentiation. Wnt signaling was inhibited by both curcumin and piperine by 50% at 5 muM and completely at 10 muM. Curcumin and piperine separately, and in combination, inhibit breast stem cell self-renewal but do not cause toxicity to differentiated cells. These compounds could be potential cancer preventive agents. Mammosphere formation assays may be a quantifiable biomarker to assess cancer preventive agent efficacy and Wnt signaling assessment can be a mechanistic biomarker for use in human clinical trials.

PMID: 19898931




Mol Carcinog. 2009 Dec 18. [Epub ahead of print]
Curcumin inhibits the Sonic Hedgehog signaling pathway and triggers apoptosis in medulloblastoma cells.

Elamin MH, Shinwari Z, Hendrayani SF, Al-Hindi H, Al-Shail E, Khafaga Y, Al-Kofide A, Aboussekhra A.
Department of Biological and Medical Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Medulloblastoma is an aggressive primary brain tumor that arises in the cerebellum of children and young adults. The Sonic Hedgehog (Shh) signaling pathway that plays important roles in the pathology of this aggressive disease is a promising therapeutic target. In the present report we have shown that curcumin has cytotoxic effects on medulloblastoma cells. Curcumin suppressed also cell proliferation and triggered cell-cycle arrest at G(2)/M phase. Moreover, curcumin inhibited the Shh-Gli1 signaling pathway by downregulating the Shh protein and its most important downstream targets GLI1 and PTCH1. Furthermore, curcumin reduced the levels of beta-catenin, the activate/phosphorylated form of Akt and NF-kappaB, which led to downregulating the three common key effectors, namely C-myc, N-myc, and Cyclin D1. Consequently, apoptosis was triggered by curcumin through the mitochondrial pathway via downregulation of Bcl-2, a downstream anti-apoptotic effector of the Shh signaling. Importantly, the resistant cells that exhibited no decrease in the levels of Shh and Bcl-2, were sensitized to curcumin by the addition of the Shh antogonist, cyclopamine. Furthermore, we have shown that curcumin enhances the killing efficiency of nontoxic doses of cisplatin and gamma-rays. In addition, we present clear evidence that piperine, an enhancer of curcumin bioavailability in humans, potentiates the apoptotic effect of curcumin against medulloblastoma cells. This effect was mediated through strong downregulation of Bcl-2. These results indicate that curcumin, a natural nontoxic compound, represents great promise as Shh-targeted therapy for medulloblastomas. (c) 2009 Wiley-Liss, Inc.

PMID: 20025076 [PubMed - as supplied by publisher]


Related cancer stem cell/Cyclopamine/Hedgehog info HERE



Basic Clin Pharmacol Toxicol. 2007 Dec;101(6):427-33. Epub 2007 Oct 9.
Curcumin, both histone deacetylase and p300/CBP-specific inhibitor, represses the activity of nuclear factor kappa B and Notch 1 in Raji cells.

Chen Y, Shu W, Chen W, Wu Q, Liu H, Cui G.
Department of Haematology Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. yanchen@public.wh.hb.cn
Curcumin, the active chemical of the Asian spice turmeric, exhibits anticancer activity in several human cancer cell lines. We previously have proved that curcumin was a new member of the histone deacetylases (HDAC) inhibitors, while constitutive nuclear factor kappa B (NF-kappaB) is believed to be a crucial event for enhanced proliferation and survival of malignant cells. Here, we investigate the effect of curcumin on the activation of NF-kappaB signal molecule in Raji cells to explore its relationship with HDACs or p300/CREB binding protein (CBP). Curcumin presented striking proliferation inhibition potency on Raji cells in vitro, with the IC(50) value for 24 hr being 25 micromol/l. Significant decreases in the amounts of p300, HDAC1 and HDAC3 were detected after treatment with curcumin. These suppressing effects were more pronounced when the administered dose increased. The protection degradation of HDAC1 and p300 by MG-132 could be partially reversed by curcumin. Furthermore, curcumin could also prevent degradation of I kappaB alpha and inhibit nuclear translocation of the NF-kappaB/p65 subunit, as well as expression of Notch 1, induced by tumour necrosis factor-alpha. The results suggest that the depressive effect of curcumin on NF-kappaB signal transduction pathway may be mediated via the various components of the HDACs and p300/Notch 1 signal molecules, and may represent a new remedy for acute leukaemia.

PMID: 17927689 [PubMed - indexed for MEDLINE]




Int J Radiat Oncol Biol Phys. 2009 Oct 1;75(2):534-42.
Curcumin modulates the radiosensitivity of colorectal cancer cells by suppressing constitutive and inducible NF-kappaB activity.

Sandur SK, Deorukhkar A, Pandey MK, Pabón AM, Shentu S, Guha S, Aggarwal BB, Krishnan S.
Department of Experimental Therapeutics, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA.
PURPOSE: Radiation therapy is an integral part of the preoperative treatment of rectal cancers. However, only a minority of patients achieve a complete pathologic response to therapy because of resistance of these tumors to radiation therapy. This resistance may be mediated by constitutively active pro-survival signaling pathways or by inducible/acquired mechanisms in response to radiation therapy. Simultaneous inhibition of these pathways can sensitize these tumors to radiation therapy. METHODS AND MATERIALS: Human colorectal cancer cells were exposed to clinically relevant doses of gamma rays, and the mechanism of their radioresistance was investigated. We characterized the transcription factor nuclear factor-kappaB (NF-kappaB) activation as a mechanism of inducible radioresistance in colorectal cancer and used curcumin, the active ingredient in the yellow spice turmeric, to overcome this resistance. RESULTS: Curcumin inhibited the proliferation and the post-irradiation clonogenic survival of multiple colorectal cancer cell lines. Radiation stimulated NF-kappaB activity in a dose- and time-dependent manner, whereas curcumin suppressed this radiation-induced NF-kappaB activation via inhibition of radiation-induced phosphorylation and degradation of inhibitor of kappaB alpha, inhibition of inhibitor of kappaB kinase activity, and inhibition of Akt phosphorylation. Curcumin also suppressed NF-kappaB-regulated gene products (Bcl-2, Bcl-x(L), inhibitor of apoptosis protein-2, cyclooxygenase-2, and cyclin D1). CONCLUSIONS: Our results suggest that transient inducible NF-kappaB activation provides a prosurvival response to radiation that may account for development of radioresistance. Curcumin blocks this signaling pathway and potentiates the antitumor effects of radiation therapy.

PMID: 19735878 [PubMed - indexed for MEDLINE]

[Rich66]

Original curcumin post/discussion by Lani: http://her2support.org/vbulletin/sho...light=Curcumin


Cancer Biol Ther. 2010 Jan 21;9(1). [Epub ahead of print]
Phase I dose escalation trial of docetaxel plus curcumin in patients with advanced and metastatic breast cancer.

Bayet-Robert M, Kwiatkowski F, Leheurteur M, Gachon F, Planchat E, Abrial C, Mouret-Reynier MA, Durando X, Barthomeuf C, Chollet P.
Centre Jean Perrin, Division de Recherche Clinique, EA4231, Université d'Auvergne, Centre d'Investigation Clinique, Clermont-Ferrand, France.
Background: Since the improvement of chemotherapy with safe molecules is needed for a better efficacy without supplementary toxicity, we investigated the feasibility and tolerability of the combination of docetaxel and curcumin, a polyphenolic derivative extracted from Curcuma longa root. Results: Fourteen patients were accrued in this open-label phase I trial. At the last dose level of curcumin, 3 dose-limiting toxicities were observed and 2 out of 3 patients at this dose level refused to continue treatment, leading us to define the maximal tolerated dose of curcumin at 8,000 mg/d. Eight patients out of 14 had measurable lesions according to RECIST criteria, with 5 PR and 3 SD. Some improvements as biological and clinical responses were observed in most patients. Patients and methods: Patients with advanced or metastatic breast cancer were eligible. Docetaxel (100 mg/m(2)) was administered as a 1-hour i.v. infusion every 3 weeks on d1 for 6 cycles. Curcumin was orally given from 500 mg/d for 7 consecutive days by cycle (from d-4 to d+2) and escalated until a dose-limiting toxicity should occur. The primary endpoint of this study was to determine the maximal tolerated dose of the combination of dose-escalating curcumin and standard dose of docetaxel chemotherapy in advanced and metastatic breast cancer patients. Secondary objectives included toxicity, safety, vascular endothelial growth factor and tumor markers measurements, and assessment of objective and clinical responses to the combination therapy. Conclusion: The recommended dose of curcumin is 6,000 mg/d for 7 consecutive days every 3 weeks in combination with a standard dose of docetaxel. From the encouraging efficacy results, a comparative phase II trial of this regimen plus docetaxel versus docetaxel alone is ongoing in advanced and metastatic breast cancer patients.

PMID: 19901561 [PubMed - as supplied by publisher]



Breast Cancer Res Treat. 2009 Nov 7. [Epub ahead of print]
Targeting breast stem cells with the cancer preventive compounds curcumin and piperine.
PDF of full text

Kakarala M, Brenner DE, Korkaya H, Cheng C, Tazi K, Ginestier C, Liu S, Dontu G, Wicha MS.
Division of Hematology/Oncology, Department of Internal Medicine and Comprehensive Cancer Center, University of Michigan, 2150 Cancer Center, 1500 E. Medical Center Dr., Ann Arbor, MI, USA, mkakaral@umich.edu.
The cancer stem cell hypothesis asserts that malignancies arise in tissue stem and/or progenitor cells through the dysregulation or acquisition of self-renewal. In order to determine whether the dietary polyphenols, curcumin, and piperine are able to modulate the self-renewal of normal and malignant breast stem cells, we examined the effects of these compounds on mammosphere formation, expression of the breast stem cell marker aldehyde dehydrogenase (ALDH), and Wnt signaling. Mammosphere formation assays were performed after curcumin, piperine, and control treatment in unsorted normal breast epithelial cells and normal stem and early progenitor cells, selected by ALDH positivity. Wnt signaling was examined using a Topflash assay. Both curcumin and piperine inhibited mammosphere formation, serial passaging, and percent of ALDH+ cells by 50% at 5 muM and completely at 10 muM concentration in normal and malignant breast cells. There was no effect on cellular differentiation. Wnt signaling was inhibited by both curcumin and piperine by 50% at 5 muM and completely at 10 muM. Curcumin and piperine separately, and in combination, inhibit breast stem cell self-renewal but do not cause toxicity to differentiated cells. These compounds could be potential cancer preventive agents. Mammosphere formation assays may be a quantifiable biomarker to assess cancer preventive agent efficacy and Wnt signaling assessment can be a mechanistic biomarker for use in human clinical trials.

PMID: 19898931 [PubMed - as supplied by publisher]

Discussion
The cancer stem cell hypothesis proposes that cancers arise in tissue stem cells through dysregulation of the normally, tightly regulated process of self-renewal or in progenitor cells through acquisition of this capacity [1]. If stem/progenitor cells are targets for transformation, then strategies aimed at limiting these cell populations through inhibition of self-renewal represent rational cancer preventive strategies.
Furthermore, since these interventions are based on the regulation of self-renewal, rather than the induction of toxicity, they have the potential of being less toxic than
compounds such as tamoxifen, which affect the bulk differentiated cell populations [10, 35]. Our data suggest that the dietary polyphenols, curcumin and piperine, may have these characteristics. We demonstrate that these dietary polyphenols affect normal stem/progenitor cells, as documented by decreased mammosphere formation upon serial passage and by decrease in the proportion of cells expressing the stem cell marker ALDH-1A1. In contrast, these compounds had little or no effect on differentiated cells. The relative lack of effect of these compounds on differentiated cells may account for their lack of toxicity in animal models and clinical studies [15, 36].
Cancer preventive agents such as curcumin and other polyphenols have been shown to have pleiotrophic mechanisms of action, including NFjB suppression, Cox2 down regulation, and Wnt and Notch pathway downregulation [34, 37–42]. We demonstrated that curcumin was able to inhibit Wnt signaling in MCF7 cells utilizing a TCF-Lef reporter assay system. These results support work in other systems showing the ability of curcumin to inhibit Wnt signaling [33, 43, 44], a pathway which we have previously demonstrated to play an important role in breast stem cell self-renewal and which is frequently dysregulated during breast carcinogenesis [11, 12, 31].
In addition to curcumin, we demonstrate that the dietary polyphenol piperine also is able to inhibit breast stem cell self-renewal and Wnt signaling. Previous studies have suggested that piperine could enhance curcumin’s effects by enhancing bioavailability through inhibition of curcumin’s efflux via P glycoprotein (ABCB1 or MDR1) efflux pump [45–47] as well as through the downregulation of NFjB
release [48]. Our studies demonstrating that piperine affects mammosphere size and colony formation suggest that piperine may affect progenitor cell proliferation as well as enhance curcumin’s effects on breast stem cell self-renewal.

Conclusions
If systemic bioavailability of curcumin can be improved to allow bioactive concentrations of curcumin and piperine in vivo, then this combination may serve as an effective cancer preventive intervention to limit stem cell self renewal, since these cells and dysregulation of self-renewal pathways may be involved in carcinogenesis. Strategies aimed at reducing stem cell number and inhibiting their self-renewal could be an effective approach in cancer prevention. If this is the case, then assays such as mammospher formation and ALDH expression may serve as biomarkers for cancer prevention studies in clinical trials. Curcumin, even at large doses, has been demonstrated to be non-toxic in clinical trials. Piperine has been shown in a small, phase I clinical trial to enhance the systemic bioavailability of curcumin [25]. However, a more systematic phase I trial with pharmacokinetic, pharmacodynamic, and toxicity endpoints of repeated dosing of these agents in combination is still needed. If proven safe and efficacious, dietary polyphenols could be an acceptable non-toxic longterm cancer risk reduction strategy.

LINK:

Turmeric and black pepper: can they be absorbed when taken orally?
Flickr.com

According to a December 8, 2009 University of Michigan, Ann Arbor, Comprehensive Cancer Center press release, "Spices halt growth of breast stem cells, U-M study finds," curcumin, a substance in turmeric and piperine, derived from black peppers, could play role in preventing breast cancer by stopping the growth of breast tumor cells.
The big question for the average consumer to ask is whether the study worked with breast cancer cells only in a culture such as a test tube or Petri dish, but will the substances derived from those spices work on human breast tumor cells in the body? And will the human digestive juices destroy the spices potency before they enter the rest of the body?
The whole idea or goal is to stop breast tumor cells from developing blood vessels that enables them to grow into cancerous lumps. Can turmeric and pepper work in the human body when taken orally as well as they worked in a culture of cells and spice extracts in the laboratory?

A new study finds that compounds derived from the spices turmeric and pepper could help prevent breast cancer by limiting the growth of stem cells, the small number of cells that fuel a tumor’s growth. Researchers at the University of Michigan Comprehensive Cancer Center have found that when the dietary compounds curcumin, which is derived from the Indian spice turmeric, and piperine, derived from black peppers, were applied to breast cells in culture, they decreased the number of stem cells while having no effect on normal differentiated cells.

“If we can limit the number of stem cells, we can limit the number of cells with potential to form tumors,� says lead author Madhuri Kakarala, M.D., Ph.D., R.D., clinical lecturer in internal medicine at the U-M Medical School and a research investigator at the VA Ann Arbor Healthcare System.

Cancer stem cells are the small number of cells within a tumor that fuel the tumor’s growth. Current chemotherapies do not work against these cells, which is why cancer recurs and spreads. Researchers believe that eliminating the cancer stem cells is key to controlling cancer. In addition, decreasing the number of normal stem cells – unspecialized cells that can give rise to any type of cell in that organ – can decrease the risk of cancer.

In this study, a solution of curcumin and piperine was applied to the cell cultures at the equivalent of about 20 times the potency of what could be consumed through diet. The compounds are available at this potency in a capsule form that could be taken by mouth. (Note: This work has not been tested in patients, and patients are not encouraged to add curcumin or piperine supplements to their diet at this time.)

The researchers applied a series of tests to the cells, looking at markers for breast stem cells and the effects of curcumin and piperine, both alone and combined, on the stem cell levels. They found that piperine enhanced the effects of curcumin, and that the compounds interrupted the self-renewal process that is the hallmark of cancer-initiating stem cells. At the same time, the compounds had no affect on cell differentiation, which is the normal process of cell development.

“This shows that these compounds are not toxic to normal breast tissue,� Kakarala says. “Women at high risk of breast cancer right now can choose to take the drugs tamoxifen or raloxifene for prevention, but most women won’t take these drugs because there is too much toxicity. The concept that dietary compounds can help is attractive, and curcumin and piperine appear to have very low toxicity.�

Curcumin and piperine have been explored by other researchers as a potential cancer treatment. But this paper, published online in the journal Breast Cancer Research and Treatment, is the first to suggest these dietary compounds could prevent cancer by targeting stem cells.

In addition, tamoxifen or raloxifene are designed to affect estrogen, which is a factor in most, but not all breast cancers. In fact, the aggressive tumors that tend to occur more often in women with a family history or genetic susceptibility are typically not affected by estrogen. Because curcumin and piperine limit the self renewal of stem cells, they would impact cancers that are not estrogen sensitive as well as those that are.

Researchers are planning an initial Phase I clinical trial to determine what dose of curcumin or piperine can be tolerated in people. The trial is not expected to begin accruing participants until spring. For further information, look at the breast cancer statistics. This year, 194,280 Americans will be diagnosed with breast cancer, and 40,610 will die from the disease, according to the American Cancer Society.

The funding for this study came from the National Institutes of Health. Curcumin and piperine for this study were donated by Sabinsa Co. Additional authors: Dean Brenner, Hasan Korkaya, Connie Cheng, Karim Tazi, Christophe Ginestier, Suling Liu, Gabriel Dontu and Max Wicha, all from the University of Michigan, Ann Arbor.
To read the study, see: "Targeting breast stem cells with the cancer preventive compounds curcumin and piperine," Breast Cancer Research and Treatment, 2009; DOI: 10.1007/s10549-009-0612-x. Authors: Madhuri Kakarala, Dean E. Brenner, Hasan Korkaya, Connie Cheng, Karim Tazi, Christophe Ginestier, Suling Liu, Gabriela Dontu and Max S. Wicha.
Resources
U-M Cancer AnswerLine, 800-865-1125
U-M Comprehensive Cancer Center
Cancer’s Stem Cell Revolution


Cancer Res. 2009 Feb 1;69(3):1000-8. Epub 2009 Jan 27.
Curcumin disrupts the Mammalian target of rapamycin-raptor complex.

Beevers CS, Chen L, Liu L, Luo Y, Webster NJ, Huang S.
Department of Biochemistry and Molecular Biology, Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932, USA.
Curcumin (diferuloylmethane), a polyphenol natural product of the plant Curcuma longa, is undergoing early clinical trials as a novel anticancer agent. However, the anticancer mechanism of curcumin remains to be elucidated. Recently, we have shown that curcumin inhibits phosphorylation of p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), two downstream effector molecules of the mammalian target of rapamycin complex 1 (mTORC1) in numerous cancer cell lines. This study was designed to elucidate the underlying mechanism. We observed that curcumin inhibited mTORC1 signaling not by inhibition of the upstream kinases, such as insulin-like growth factor 1 receptor (IGF-IR) and phosphoinositide-dependent kinase 1 (PDK1). Further, we found that curcumin inhibited mTORC1 signaling independently of protein phosphatase 2A (PP2A) or AMP-activated protein kinase AMPK-tuberous sclerosis complex (TSC). This is evidenced by the findings that curcumin was able to inhibit phosphorylation of S6K1 and 4E-BP1 in the cells pretreated with PP2A inhibitor (okadaic acid) or AMPK inhibitor (compound C), or in the cells expressing dominant-negative (dn) PP2A, shRNA to PP2A-A subunit, or dn-AMPKalpha. Curcumin did not alter the TSC1/2 interaction. Knockout of TSC2 did not affect curcumin inhibition of mTOR signaling. Finally, we identified that curcumin was able to dissociate raptor from mTOR, leading to inhibition of mTORC1 activity. Therefore, our data indicate that curcumin may represent a new class of mTOR inhibitor.

PMID: 19176385 [PubMed - indexed for MEDLIN


mTOR thread HERE





J Immunol. 2004 May 15;172(10):5940-7.
Curcumin (diferuloylmethane) inhibits receptor activator of NF-kappa B ligand-induced NF-kappa B activation in osteoclast precursors and suppresses osteoclastogenesis.


FULL TEXT



Bharti AC, Takada Y, Aggarwal BB.
Cytokine Research Section, Department of Bioimmunotherapy, Unit 143, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Numerous studies have indicated that inflammatory cytokines play a major role in osteoclastogenesis, leading to the bone resorption that is frequently associated with cancers and other diseases. Gene deletion studies have shown that receptor activator of NF-kappaB ligand (RANKL) is one of the critical mediators of osteoclastogenesis. How RANKL mediates osteoclastogenesis is not fully understood, but an agent that suppresses RANKL signaling has potential to inhibit osteoclastogenesis. In this report, we examine the ability of curcumin (diferuloylmethane), a pigment derived from turmeric, to suppress RANKL signaling and osteoclastogenesis in RAW 264.7 cells, a murine monocytic cell line. Treatment of these cells with RANKL activated NF-kappaB, and preexposure of the cells to curcumin completely suppressed RANKL-induced NF-kappaB activation. Curcumin inhibited the pathway leading from activation of IkappaBalpha kinase and IkappaBalpha phosphorylation to IkappaBalpha degradation. RANKL induced osteoclastogenesis in these monocytic cells, and curcumin inhibited both RANKL- and TNF-induced osteoclastogenesis and pit formation. Curcumin suppressed osteoclastogenesis maximally when added together with RANKL and minimally when it was added 2 days after RANKL. Whether curcumin inhibits RANKL-induced osteoclastogenesis through suppression of NF-kappaB was also confirmed independently, as RANKL failed to activate NF-kappaB in cells stably transfected with a dominant-negative form of IkappaBalpha and concurrently failed to induce osteoclastogenesis. Thus overall these results indicate that RANKL induces osteoclastogenesis through the activation of NF-kappaB, and treatment with curcumin inhibits both the NF-kappaB activation and osteoclastogenesis induced by RANKL.

PMID: 15128775 [PubMed - indexed for MEDLINE]

[Rich66]

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