Rich66
02-14-2010, 12:35 PM
(w/TAM, various mechanisms, HDAC inhib, brazil nuts, garlic)
Breast Cancer Res Treat. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Breast%20Ca ncer%20Res%20Treat.%27%29;) 2009 Nov;118(1):33-43. Epub 2008 Oct 15.
Combination of methylselenocysteine with tamoxifen inhibits MCF-7 breast cancer xenografts in nude mice through elevated apoptosis and reduced angiogenesis.
Li Z (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Li%20Z%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Carrier L (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Carrier%20L%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Belame A (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Belame%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Thiyagarajah A (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Thiyagarajah%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Salvo VA (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Salvo%20VA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Burow ME (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Burow%20ME%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Rowan BG (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Rowan%20BG%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Department of Structural & Cellular Biology, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA, 70112, USA.
To investigate the therapeutic effect of methylselenocysteine (MSC) combined with tamoxifen in MCF-7 breast cancer xenograft and the underlying mechanisms. MCF-7 breast cancer xenograft was established in ovariectomized female athymic nude mice and treated with tamoxifen and/or MSC. Tumor size was measured twice a week. Immunohistochemistry and TUNEL assays were used to measure ERalpha expression, ERalpha target genes (progesterone receptor (PR) and cyclin D1 expression), Ki-67 index, apoptosis and microvessel density. Combined treatment with tamoxifen and MSC synergistically inhibited tumor growth compared to MSC alone and tamoxifen alone. MSC alone or MSC + tamoxifen significantly reduced ERalpha, PR and cyclin D1, Ki67 index and microvessel density while increasing apoptosis in tumor tissues. These findings demonstrate synergistic growth inhibition of ERalpha positive breast cancer xenografts by combination of tamoxifen with organic selenium compounds. Organic selenium may provide added benefit when combined with tamoxifen in adjuvant therapy or prevention.
PMID: 18855134 [PubMed - indexed for MEDLINE]
(http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Mini%20Rev% 20Med%20Chem.%27%29;)
(http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Mini%20Rev% 20Med%20Chem.%27%29;)
Mol Cancer Ther. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Mol%20Cance r%20Ther.%27%29;) 2005 Aug;4(8):1239-49.
Selenium disrupts estrogen receptor (alpha) signaling and potentiates tamoxifen antagonism in endometrial cancer cells and tamoxifen-resistant breast cancer cells.
Shah YM (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Shah%20YM%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Al-Dhaheri M (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Al-Dhaheri%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Dong Y (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Dong%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Ip C (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Ip%20C%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Jones FE (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Jones%20FE%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Rowan BG (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Rowan%20BG%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Department of Structural and Cellular Biology, SL49, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
Tamoxifen, a selective estrogen receptor (ER) modulator, is the most widely prescribed hormonal therapy treatment for breast cancer. Despite the benefits of tamoxifen therapy, almost all tamoxifen-responsive breast cancer patients develop resistance to therapy. In addition, tamoxifen displays estrogen-like effects in the endometrium increasing the incidence of endometrial cancer. New therapeutic strategies are needed to circumvent tamoxifen resistance in breast cancer as well as tamoxifen toxicity in endometrium. Organic selenium compounds are highly effective chemopreventive agents with well-documented benefits in reducing total cancer incidence and mortality rates for a number of cancers. The present study shows that the organic selenium compound methylseleninic acid (MSA, 2.5 micromol/L) can potentiate growth inhibition of 4-hydroxytamoxifen (10(-7) mol/L) in tamoxifen-sensitive MCF-7 and T47D breast cancer cell lines. Remarkably, in tamoxifen-resistant MCF-7-LCC2 and MCF7-H2Delta16 breast cancer cell lines and endometrial-derived HEC1A and Ishikawa cells, coincubation of 4-hydroxytamoxifen with MSA resulted in a marked growth inhibition that was substantially greater than MSA alone. Growth inhibition by MSA and MSA + 4-hydroxytamoxifen in all cell lines was preceded by a specific decrease in ER(alpha) mRNA and protein without an effect on ER(beta) levels. Estradiol and 4-hydroxytamoxifen induction of endogenous ER-dependent gene expression (pS2 and c-myc) as well as ER-dependent reporter gene expression (ERE(2)e1b-luciferase) was also attenuated by MSA in all cell lines before effect on growth inhibition. Taken together, these data strongly suggest that specific decrease in ER(alpha) levels by MSA is required for both MSA potentiation of the growth inhibitory effects of 4-hydroxytamoxifen and resensitization of tamoxifen-resistant cell lines.
PMID: 16093440 [PubMed - indexed for MEDLINE]
(http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Mini%20Rev% 20Med%20Chem.%27%29;)
(http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Mini%20Rev% 20Med%20Chem.%27%29;)
(http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Mini%20Rev% 20Med%20Chem.%27%29;)
Mini Rev Med Chem. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Mini%20Rev% 20Med%20Chem.%27%29;) 2008 Sep;8(10):1020-31.
Selenium compounds and apoptotic modulation: a new perspective in cancer therapy.
SanmartĂ*n C (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Sanmart%C3%ADn%20C%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Plano D (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Plano%20D%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Palop JA (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Palop%20JA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Department of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Navarra, Irunlarrea 1, E-31008, Pamplona, Spain. sanmartin@unav.es
Recent epidemiological studies have demonstrated that selenium may be an effective chemopreventive and anticancer agent with a broad spectrum against several human cancer cells (prostate, colon, bladder, lung, liver, ovarian, leukemia). A wide range of potential mechanisms have been proposed for the antitumorigenic effects of selenium and these include antiandrogen activity, growth inhibitory effects by regulation of p53 and antioxidant function, and through DNA damage. However, apoptosis is one of the most plausible mechanisms for the anticancer activity. The regulating mechanisms of apoptosis are extremely complex and for selenium compounds they mainly involve a mitochondrial pathway, protein kinases, tumor necrosis factor, activation of caspases and reactive oxygen species. The aim of this review is to summarize the current knowledge about more than twenty eight selenium-containing molecules and to discuss the implications for apoptosis and the impact in cancer therapy.
PMID: 18782054 [PubMed - indexed for MEDLINE]
Br J Nutr. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Br%20J%20Nu tr.%27%29;) 2009 Jan;101(2):182-9. Epub 2008 Jun 13.
Differential sensitivity of various human tumour-derived cell types to apoptosis by organic derivatives of selenium.
Jariwalla RJ (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Jariwalla%20RJ%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Gangapurkar B (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Gangapurkar%20B%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Nakamura D (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Nakamura%20D%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Laboratory of Viral, Immune and Malignant Diseases, California Institute for Medical Research, San Jose, CA 95128, USA. r.jariwalla@drrath.com
Selenium is an important trace element with anti-cancer properties. In the present study, the apoptosis-inducing effects of organic selenium derivatives, namely methyl-L-selenocysteine and selenomethionine, were evaluated in vitro on human tumour-derived cell lines from breast, liver, colon, brain, skin and a non-tumorigenic line of epithelial origin. Apoptosis was assessed by cell-death detection immunoassay on cytoplasmic cell lysates. Breast carcinoma cells were highly sensitive to the organic selenium compounds, manifesting apoptosis at concentrations as low as 0.113 microm (0.0205 microg/ml) selenium. By contrast, non-tumorigenic mammary epithelial cells displayed poor sensitivity to selenium, requiring a substantially high concentration of the trace element of 87.9 microm (16.0 microg/ml). The cell lines derived from hepatoma and neuroblastoma showed intermediate sensitivity, with colon carcinoma cells manifesting the lowest sensitivity to the trace element. These results indicate intrinsic differences in the sensitivity of human tumour derivatives to selenium-mediated apoptosis, providing experimental support for the development of organic selenium compounds as anti-neoplastic agents against solid tumours displaying selective apoptotic sensitivity to these compounds.
PMID: 18549510 [PubMed - indexed for MEDLINE]
Clin Colorectal Cancer. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Clin%20Colo rectal%20Cancer.%27%29;) 2005 Jul;5(2):132-5.
Selenium protects against toxicity induced by anticancer drugs and augments antitumor activity: a highly selective, new, and novel approach for the treatment of solid tumors.
Fakih M (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Fakih%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Cao S (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Cao%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Durrani FA (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Durrani%20FA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Rustum YM (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Rustum%20YM%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Limited therapeutic selectivity and tumor resistance are major obstacles to current chemotherapy. The development of new therapeutic modalities for solid tumor remains a challenge. The use of selenium, 5-methylselenocysteine (MSC), or seleno-L-methionine (SLM) as selective modulators of anticancer drugs is novel and has not been previously investigated. Selenium deficiency is associated with an increased risk of cancer and cancer death. Although low-dose selenium supplementation has been investigated in a large randomized prevention trial, its potential in chemotherapy toxicity prevention and enhancement of antitumor activity of anticancer drugs has not been evaluated. An ideal biomodulator of anticancer drugs would allow escalation of drug dose with the hope of enhancing antitumor activity and possibly reversing drug resistance. Results from this laboratory have demonstrated that MSC and SLM are highly effective modulators of irinotecan cure rates in de novo sensitive and resistant human tumor xenografts. Studies in mice have documented that the minimum effective dose of MSC when combined with irinotecan is 0.01 mg daily. The optimal schedule is to administer MSC orally for 7 days before and concurrently with irinotecan. The observed effects were not drug-specific, as similar results were obtained with taxanes, platinum agents, 5-fluorouracil, and anthracyclines; nor were they species-specific, as selective effects were obtained in mice and rats and are currently being confirmed in ongoing clinical trials.
PMID: 16098255 [PubMed - indexed for MEDLINE]
Mol Cancer Ther. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Mol%20Cance r%20Ther.%27%29;) 2008 May;7(5):1297-308.
PBISe, a novel selenium-containing drug for the treatment of malignant melanoma.
Madhunapantula SV (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Madhunapantula%20SV%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Desai D (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Desai%20D%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Sharma A (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Sharma%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Huh SJ (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Huh%20SJ%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Amin S (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Amin%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Robertson GP (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Robertson%20GP%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Department of Pharmacology, The Pennsylvania State University College of Medicine, 500 University Drive, R130, Hershey, PA 17033, USA.
Malignant melanoma is the most deadly form of skin cancer due to its highly metastatic nature. Untargeted therapies are ineffective for treating metastatic disease, leading to the development of agents specifically inhibiting proteins or pathways deregulated in melanoma. The deregulation of inducible nitric oxide synthase (iNOS) is one such event occurring in melanoma, and is correlated with poor survival. Current iNOS inhibitors, such as PBIT [S,S'-1,4-phenylenebis(1,2-ethanediyl)bis-isothiourea], require high concentrations for clinical efficacy causing systemic toxicity. To develop more potent agents effective at significantly lower concentrations, a novel isosteric analogue of PBIT was synthesized, called PBISe [S,S'-1,4-phenylenebis(1,2-ethanediyl)bis-isoselenourea], in which sulfur was replaced with selenium. PBISe kills melanoma cells >10-fold more effectively than PBIT, and cultured cancer cells are 2- to 5-fold more sensitive than normal cells. Like PBIT, PBISe targets iNOS but also has new inhibitory properties acting as an Akt3 pathway inhibitor and mitogen-activated protein kinase (MAPK) cascade activator, which causes decreased cancer cell proliferation and increased apoptosis. Inhibition of cellular proliferation mediated by PBISe induced a G2-M phase cell cycle block linked to excessively high MAPK activity causing decreased cyclin D1 and increased p21 as well as p27 levels. PBISe promotes apoptosis by inhibiting Akt3 signaling, elevating cleaved caspase-3 and PARP levels. Compared with PBIT, PBISe reduced tumor development by 30% to 50% in mice inducing a 2-fold increase in apoptosis with negligible associated systemic toxicity. Collectively, these results suggest that PBISe is a potent chemotherapeutic agent with novel properties enabling the targeting of iNOS, Akt3, and MAPK signaling, thereby promoting melanoma cell apoptosis and inhibition of proliferation.
PMID: 18483317 [PubMed - indexed for MEDLINE]
Cancer Prev Res (Phila Pa). (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Cancer%20Pr ev%20Res%20%28Phila%20Pa%29.%27%29;) 2008 Jul;1(2):119-27.
Chemopreventive doses of methylselenocysteine alter circadian rhythm in rat mammary tissue.
Zhang X (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Zhang%20X%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Zarbl H (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Zarbl%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Division of Human Biology, Fred Hutchinson Cancer, University of Washington, Seattle, Washington, USA.
It is known that organic forms of selenium inhibit chemically induced rat mammary carcinogenesis, although the molecular basis remains to be elucidated. To identify signaling pathways involved in carcinogenesis that are also modulated by methylselenocysteine, we compared the global gene expression profiles in mammary tissues from pubescent female rats maintained on a selenium-supplemented (3 ppm) diet with those on a standardized diet after N-nitroso-N-methylurea. Whereas the selenium-enriched diet altered the steady-state levels of genes involved in various cellular functions, the most dramatic effect was the coordinated changes in the expression of multiple genes that regulate circadian rhythm. Normal mammary tissue of rats fed a standardized diet showed little circadian oscillation relative to liver tissue. By contrast, mammary tissue of rats maintained on the selenium-enriched diet showed a progressive, time-dependent increase in the expression of circadian gene Per2 and circadian-regulated transcription factor DBP. Our results further showed that the expression of Per2 and DBP mRNAs was significantly decreased in mammary tumors arising in rats on the selenium-enriched diet, but not in tumors of rats on the control diet, suggesting that selenium-induced elevation in the expression of circadian genes was incompatible with mammary carcinogenesis. Given the previously reported role of Per2 as a tumor suppressor, these observations suggest that Per2 is an important target of methylselenocysteine during chemoprevention in N-nitroso-N-methylurea-induced rat mammary carcinogenesis, and for the first time provide a link between chemoprevention and circadian rhythm.
PMID: 19122877 [PubMed - indexed for MEDLINE]
Natural Compounds, Chemotherapeutic Drugs May Become Partners In Cancer Therapy
ScienceDaily (Sep. 7, 2009) — Research in the Linus Pauling Institute at Oregon State University suggests that some natural food compounds, which previously have been studied for their ability to prevent cancer, may be able to play a more significant role in treating it – working side-by-side with the conventional drugs that are now used in chemotherapy.
A new study just published in the International Journal of Cancer examined the activity of chlorophyllin and found that, on a dose-by-dose basis, it was 10 times more potent at causing death of colon cancer cells than hydroxyurea, a chemotherapeutic drug commonly used in cancer treatment.
Beyond that, chlorophyllin kills cancer cells by blocking the same phase of cellular division that hydroxyurea does, but by a different mechanism. This suggests that it – and possibly other “cocktails” of natural products – might be developed to have a synergistic effect with conventional cancer drugs, helping them to work better or require less toxic dosages, researchers said.
“We conclude that chlorophyllin has the potential to be effective in the clinical setting, when used alone or in combination with currently available cancer therapeutic agents,” the researchers wrote in their study.
The concept of combining conventional or new cancer drugs with natural compounds that have been shown to have anti-cancer properties is very promising, said Rod Dashwood, professor and director of the Cancer Chemoprotection Program in the Linus Pauling Institute.
“Most chemotherapeutic approaches to cancer try to target cancer cells specifically and do something that slows or stops their cell growth process,” Dashwood said. “We’re now identifying such mechanisms of action for natural compounds, including dietary agents. With further research we may be able to make the two approaches work together to enhance the effectiveness of cancer therapies.”
Chlorophyllin is a water-soluble derivative of chlorophyll – the green pigment found in most plants and many food products that makes possible the process of photosynthesis and plant growth from the sun’s energy. Chlorophyllin is inexpensive, and animal studies plus human clinical data suggest that it can be ingested at relatively high levels without toxicity.
In the new study, researchers found that pharmacologic doses of chlorophyllin caused colon cancer cells to spend more time than normal in their “synthesis phase” in which DNA is duplicated. Timing is critical to the various phases of cell growth, researchers said, and this disruption started a process that ultimately led to cell death, the study found.
In particular, the presence of high levels of chlorophyllin caused a major reduction in the level of ribonucleotide reductase, an enzyme critical to DNA synthesis, researchers found. This is also the mechanism of action of hydroxyurea, one drug already being used for cancer chemotherapy.
“In cancer research right now there’s interest in approaches that can reduce ribonucleotide reductase,” Dashwood said. “At the doses used in our experiments, chlorophyllin almost completely stops the activity of this enzyme.”
Further research is needed both in laboratory and animal studies, with combinations of chlorophyllin and existing cancer drugs, before it would be appropriate for human trials, Dashwood said. Chlorophyllin, in general, is poorly absorbed from the human gastrointestinal tract, so it’s unclear what levels might be needed for therapeutic purposes or how well they would work.
Other dietary agents also might have similar potential. Work just published by LPI researchers in the journals Carcinogenesis and Cancer Prevention Research explored the role of organic selenium compounds in killing human prostate and colon cancer cells. Colorectal and prostate cancers are consistently among the leading causes of cancer mortality in the United States, and will account respectively for 18 percent and 9 percent of all cancer deaths in 2009, according to estimates from the American Cancer Society.
In the recent studies, a form of organic selenium found naturally in garlic and Brazil nuts was converted in cancer cells to metabolites that acted as “HDAC inhibitors” – a promising field of research in which silenced tumor suppressor genes are re-activated, triggering cancer cell death.
“Whether it’s HDAC inhibition leading to one manner of cancer cell growth arrest, or loss of ribonucleotide reductase activity leading to another, as seen with chlorophyllin, there’s significant promise in the use of natural products for combined cancer therapies,” Dashwood said. “These are areas that merit continued research.”
These studies were supported by the National Cancer Institute and the National Institute of Environmental Health Sciences. Other collaborators included researchers from the New York Medical College and the Penn State College of Medicine. Further information on chlorophylls and selenium compounds can be found on the web at: http://lpi.oregonstate.edu/infocenter
Breast Cancer Res Treat. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Breast%20Ca ncer%20Res%20Treat.%27%29;) 2009 Nov;118(1):33-43. Epub 2008 Oct 15.
Combination of methylselenocysteine with tamoxifen inhibits MCF-7 breast cancer xenografts in nude mice through elevated apoptosis and reduced angiogenesis.
Li Z (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Li%20Z%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Carrier L (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Carrier%20L%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Belame A (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Belame%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Thiyagarajah A (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Thiyagarajah%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Salvo VA (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Salvo%20VA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Burow ME (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Burow%20ME%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Rowan BG (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Rowan%20BG%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Department of Structural & Cellular Biology, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA, 70112, USA.
To investigate the therapeutic effect of methylselenocysteine (MSC) combined with tamoxifen in MCF-7 breast cancer xenograft and the underlying mechanisms. MCF-7 breast cancer xenograft was established in ovariectomized female athymic nude mice and treated with tamoxifen and/or MSC. Tumor size was measured twice a week. Immunohistochemistry and TUNEL assays were used to measure ERalpha expression, ERalpha target genes (progesterone receptor (PR) and cyclin D1 expression), Ki-67 index, apoptosis and microvessel density. Combined treatment with tamoxifen and MSC synergistically inhibited tumor growth compared to MSC alone and tamoxifen alone. MSC alone or MSC + tamoxifen significantly reduced ERalpha, PR and cyclin D1, Ki67 index and microvessel density while increasing apoptosis in tumor tissues. These findings demonstrate synergistic growth inhibition of ERalpha positive breast cancer xenografts by combination of tamoxifen with organic selenium compounds. Organic selenium may provide added benefit when combined with tamoxifen in adjuvant therapy or prevention.
PMID: 18855134 [PubMed - indexed for MEDLINE]
(http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Mini%20Rev% 20Med%20Chem.%27%29;)
(http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Mini%20Rev% 20Med%20Chem.%27%29;)
Mol Cancer Ther. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Mol%20Cance r%20Ther.%27%29;) 2005 Aug;4(8):1239-49.
Selenium disrupts estrogen receptor (alpha) signaling and potentiates tamoxifen antagonism in endometrial cancer cells and tamoxifen-resistant breast cancer cells.
Shah YM (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Shah%20YM%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Al-Dhaheri M (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Al-Dhaheri%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Dong Y (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Dong%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Ip C (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Ip%20C%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Jones FE (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Jones%20FE%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Rowan BG (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Rowan%20BG%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Department of Structural and Cellular Biology, SL49, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
Tamoxifen, a selective estrogen receptor (ER) modulator, is the most widely prescribed hormonal therapy treatment for breast cancer. Despite the benefits of tamoxifen therapy, almost all tamoxifen-responsive breast cancer patients develop resistance to therapy. In addition, tamoxifen displays estrogen-like effects in the endometrium increasing the incidence of endometrial cancer. New therapeutic strategies are needed to circumvent tamoxifen resistance in breast cancer as well as tamoxifen toxicity in endometrium. Organic selenium compounds are highly effective chemopreventive agents with well-documented benefits in reducing total cancer incidence and mortality rates for a number of cancers. The present study shows that the organic selenium compound methylseleninic acid (MSA, 2.5 micromol/L) can potentiate growth inhibition of 4-hydroxytamoxifen (10(-7) mol/L) in tamoxifen-sensitive MCF-7 and T47D breast cancer cell lines. Remarkably, in tamoxifen-resistant MCF-7-LCC2 and MCF7-H2Delta16 breast cancer cell lines and endometrial-derived HEC1A and Ishikawa cells, coincubation of 4-hydroxytamoxifen with MSA resulted in a marked growth inhibition that was substantially greater than MSA alone. Growth inhibition by MSA and MSA + 4-hydroxytamoxifen in all cell lines was preceded by a specific decrease in ER(alpha) mRNA and protein without an effect on ER(beta) levels. Estradiol and 4-hydroxytamoxifen induction of endogenous ER-dependent gene expression (pS2 and c-myc) as well as ER-dependent reporter gene expression (ERE(2)e1b-luciferase) was also attenuated by MSA in all cell lines before effect on growth inhibition. Taken together, these data strongly suggest that specific decrease in ER(alpha) levels by MSA is required for both MSA potentiation of the growth inhibitory effects of 4-hydroxytamoxifen and resensitization of tamoxifen-resistant cell lines.
PMID: 16093440 [PubMed - indexed for MEDLINE]
(http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Mini%20Rev% 20Med%20Chem.%27%29;)
(http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Mini%20Rev% 20Med%20Chem.%27%29;)
(http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Mini%20Rev% 20Med%20Chem.%27%29;)
Mini Rev Med Chem. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Mini%20Rev% 20Med%20Chem.%27%29;) 2008 Sep;8(10):1020-31.
Selenium compounds and apoptotic modulation: a new perspective in cancer therapy.
SanmartĂ*n C (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Sanmart%C3%ADn%20C%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Plano D (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Plano%20D%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Palop JA (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Palop%20JA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Department of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Navarra, Irunlarrea 1, E-31008, Pamplona, Spain. sanmartin@unav.es
Recent epidemiological studies have demonstrated that selenium may be an effective chemopreventive and anticancer agent with a broad spectrum against several human cancer cells (prostate, colon, bladder, lung, liver, ovarian, leukemia). A wide range of potential mechanisms have been proposed for the antitumorigenic effects of selenium and these include antiandrogen activity, growth inhibitory effects by regulation of p53 and antioxidant function, and through DNA damage. However, apoptosis is one of the most plausible mechanisms for the anticancer activity. The regulating mechanisms of apoptosis are extremely complex and for selenium compounds they mainly involve a mitochondrial pathway, protein kinases, tumor necrosis factor, activation of caspases and reactive oxygen species. The aim of this review is to summarize the current knowledge about more than twenty eight selenium-containing molecules and to discuss the implications for apoptosis and the impact in cancer therapy.
PMID: 18782054 [PubMed - indexed for MEDLINE]
Br J Nutr. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Br%20J%20Nu tr.%27%29;) 2009 Jan;101(2):182-9. Epub 2008 Jun 13.
Differential sensitivity of various human tumour-derived cell types to apoptosis by organic derivatives of selenium.
Jariwalla RJ (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Jariwalla%20RJ%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Gangapurkar B (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Gangapurkar%20B%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Nakamura D (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Nakamura%20D%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Laboratory of Viral, Immune and Malignant Diseases, California Institute for Medical Research, San Jose, CA 95128, USA. r.jariwalla@drrath.com
Selenium is an important trace element with anti-cancer properties. In the present study, the apoptosis-inducing effects of organic selenium derivatives, namely methyl-L-selenocysteine and selenomethionine, were evaluated in vitro on human tumour-derived cell lines from breast, liver, colon, brain, skin and a non-tumorigenic line of epithelial origin. Apoptosis was assessed by cell-death detection immunoassay on cytoplasmic cell lysates. Breast carcinoma cells were highly sensitive to the organic selenium compounds, manifesting apoptosis at concentrations as low as 0.113 microm (0.0205 microg/ml) selenium. By contrast, non-tumorigenic mammary epithelial cells displayed poor sensitivity to selenium, requiring a substantially high concentration of the trace element of 87.9 microm (16.0 microg/ml). The cell lines derived from hepatoma and neuroblastoma showed intermediate sensitivity, with colon carcinoma cells manifesting the lowest sensitivity to the trace element. These results indicate intrinsic differences in the sensitivity of human tumour derivatives to selenium-mediated apoptosis, providing experimental support for the development of organic selenium compounds as anti-neoplastic agents against solid tumours displaying selective apoptotic sensitivity to these compounds.
PMID: 18549510 [PubMed - indexed for MEDLINE]
Clin Colorectal Cancer. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Clin%20Colo rectal%20Cancer.%27%29;) 2005 Jul;5(2):132-5.
Selenium protects against toxicity induced by anticancer drugs and augments antitumor activity: a highly selective, new, and novel approach for the treatment of solid tumors.
Fakih M (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Fakih%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Cao S (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Cao%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Durrani FA (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Durrani%20FA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Rustum YM (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Rustum%20YM%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Limited therapeutic selectivity and tumor resistance are major obstacles to current chemotherapy. The development of new therapeutic modalities for solid tumor remains a challenge. The use of selenium, 5-methylselenocysteine (MSC), or seleno-L-methionine (SLM) as selective modulators of anticancer drugs is novel and has not been previously investigated. Selenium deficiency is associated with an increased risk of cancer and cancer death. Although low-dose selenium supplementation has been investigated in a large randomized prevention trial, its potential in chemotherapy toxicity prevention and enhancement of antitumor activity of anticancer drugs has not been evaluated. An ideal biomodulator of anticancer drugs would allow escalation of drug dose with the hope of enhancing antitumor activity and possibly reversing drug resistance. Results from this laboratory have demonstrated that MSC and SLM are highly effective modulators of irinotecan cure rates in de novo sensitive and resistant human tumor xenografts. Studies in mice have documented that the minimum effective dose of MSC when combined with irinotecan is 0.01 mg daily. The optimal schedule is to administer MSC orally for 7 days before and concurrently with irinotecan. The observed effects were not drug-specific, as similar results were obtained with taxanes, platinum agents, 5-fluorouracil, and anthracyclines; nor were they species-specific, as selective effects were obtained in mice and rats and are currently being confirmed in ongoing clinical trials.
PMID: 16098255 [PubMed - indexed for MEDLINE]
Mol Cancer Ther. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Mol%20Cance r%20Ther.%27%29;) 2008 May;7(5):1297-308.
PBISe, a novel selenium-containing drug for the treatment of malignant melanoma.
Madhunapantula SV (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Madhunapantula%20SV%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Desai D (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Desai%20D%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Sharma A (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Sharma%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Huh SJ (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Huh%20SJ%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Amin S (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Amin%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Robertson GP (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Robertson%20GP%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Department of Pharmacology, The Pennsylvania State University College of Medicine, 500 University Drive, R130, Hershey, PA 17033, USA.
Malignant melanoma is the most deadly form of skin cancer due to its highly metastatic nature. Untargeted therapies are ineffective for treating metastatic disease, leading to the development of agents specifically inhibiting proteins or pathways deregulated in melanoma. The deregulation of inducible nitric oxide synthase (iNOS) is one such event occurring in melanoma, and is correlated with poor survival. Current iNOS inhibitors, such as PBIT [S,S'-1,4-phenylenebis(1,2-ethanediyl)bis-isothiourea], require high concentrations for clinical efficacy causing systemic toxicity. To develop more potent agents effective at significantly lower concentrations, a novel isosteric analogue of PBIT was synthesized, called PBISe [S,S'-1,4-phenylenebis(1,2-ethanediyl)bis-isoselenourea], in which sulfur was replaced with selenium. PBISe kills melanoma cells >10-fold more effectively than PBIT, and cultured cancer cells are 2- to 5-fold more sensitive than normal cells. Like PBIT, PBISe targets iNOS but also has new inhibitory properties acting as an Akt3 pathway inhibitor and mitogen-activated protein kinase (MAPK) cascade activator, which causes decreased cancer cell proliferation and increased apoptosis. Inhibition of cellular proliferation mediated by PBISe induced a G2-M phase cell cycle block linked to excessively high MAPK activity causing decreased cyclin D1 and increased p21 as well as p27 levels. PBISe promotes apoptosis by inhibiting Akt3 signaling, elevating cleaved caspase-3 and PARP levels. Compared with PBIT, PBISe reduced tumor development by 30% to 50% in mice inducing a 2-fold increase in apoptosis with negligible associated systemic toxicity. Collectively, these results suggest that PBISe is a potent chemotherapeutic agent with novel properties enabling the targeting of iNOS, Akt3, and MAPK signaling, thereby promoting melanoma cell apoptosis and inhibition of proliferation.
PMID: 18483317 [PubMed - indexed for MEDLINE]
Cancer Prev Res (Phila Pa). (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Cancer%20Pr ev%20Res%20%28Phila%20Pa%29.%27%29;) 2008 Jul;1(2):119-27.
Chemopreventive doses of methylselenocysteine alter circadian rhythm in rat mammary tissue.
Zhang X (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Zhang%20X%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Zarbl H (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Zarbl%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Division of Human Biology, Fred Hutchinson Cancer, University of Washington, Seattle, Washington, USA.
It is known that organic forms of selenium inhibit chemically induced rat mammary carcinogenesis, although the molecular basis remains to be elucidated. To identify signaling pathways involved in carcinogenesis that are also modulated by methylselenocysteine, we compared the global gene expression profiles in mammary tissues from pubescent female rats maintained on a selenium-supplemented (3 ppm) diet with those on a standardized diet after N-nitroso-N-methylurea. Whereas the selenium-enriched diet altered the steady-state levels of genes involved in various cellular functions, the most dramatic effect was the coordinated changes in the expression of multiple genes that regulate circadian rhythm. Normal mammary tissue of rats fed a standardized diet showed little circadian oscillation relative to liver tissue. By contrast, mammary tissue of rats maintained on the selenium-enriched diet showed a progressive, time-dependent increase in the expression of circadian gene Per2 and circadian-regulated transcription factor DBP. Our results further showed that the expression of Per2 and DBP mRNAs was significantly decreased in mammary tumors arising in rats on the selenium-enriched diet, but not in tumors of rats on the control diet, suggesting that selenium-induced elevation in the expression of circadian genes was incompatible with mammary carcinogenesis. Given the previously reported role of Per2 as a tumor suppressor, these observations suggest that Per2 is an important target of methylselenocysteine during chemoprevention in N-nitroso-N-methylurea-induced rat mammary carcinogenesis, and for the first time provide a link between chemoprevention and circadian rhythm.
PMID: 19122877 [PubMed - indexed for MEDLINE]
Natural Compounds, Chemotherapeutic Drugs May Become Partners In Cancer Therapy
ScienceDaily (Sep. 7, 2009) — Research in the Linus Pauling Institute at Oregon State University suggests that some natural food compounds, which previously have been studied for their ability to prevent cancer, may be able to play a more significant role in treating it – working side-by-side with the conventional drugs that are now used in chemotherapy.
A new study just published in the International Journal of Cancer examined the activity of chlorophyllin and found that, on a dose-by-dose basis, it was 10 times more potent at causing death of colon cancer cells than hydroxyurea, a chemotherapeutic drug commonly used in cancer treatment.
Beyond that, chlorophyllin kills cancer cells by blocking the same phase of cellular division that hydroxyurea does, but by a different mechanism. This suggests that it – and possibly other “cocktails” of natural products – might be developed to have a synergistic effect with conventional cancer drugs, helping them to work better or require less toxic dosages, researchers said.
“We conclude that chlorophyllin has the potential to be effective in the clinical setting, when used alone or in combination with currently available cancer therapeutic agents,” the researchers wrote in their study.
The concept of combining conventional or new cancer drugs with natural compounds that have been shown to have anti-cancer properties is very promising, said Rod Dashwood, professor and director of the Cancer Chemoprotection Program in the Linus Pauling Institute.
“Most chemotherapeutic approaches to cancer try to target cancer cells specifically and do something that slows or stops their cell growth process,” Dashwood said. “We’re now identifying such mechanisms of action for natural compounds, including dietary agents. With further research we may be able to make the two approaches work together to enhance the effectiveness of cancer therapies.”
Chlorophyllin is a water-soluble derivative of chlorophyll – the green pigment found in most plants and many food products that makes possible the process of photosynthesis and plant growth from the sun’s energy. Chlorophyllin is inexpensive, and animal studies plus human clinical data suggest that it can be ingested at relatively high levels without toxicity.
In the new study, researchers found that pharmacologic doses of chlorophyllin caused colon cancer cells to spend more time than normal in their “synthesis phase” in which DNA is duplicated. Timing is critical to the various phases of cell growth, researchers said, and this disruption started a process that ultimately led to cell death, the study found.
In particular, the presence of high levels of chlorophyllin caused a major reduction in the level of ribonucleotide reductase, an enzyme critical to DNA synthesis, researchers found. This is also the mechanism of action of hydroxyurea, one drug already being used for cancer chemotherapy.
“In cancer research right now there’s interest in approaches that can reduce ribonucleotide reductase,” Dashwood said. “At the doses used in our experiments, chlorophyllin almost completely stops the activity of this enzyme.”
Further research is needed both in laboratory and animal studies, with combinations of chlorophyllin and existing cancer drugs, before it would be appropriate for human trials, Dashwood said. Chlorophyllin, in general, is poorly absorbed from the human gastrointestinal tract, so it’s unclear what levels might be needed for therapeutic purposes or how well they would work.
Other dietary agents also might have similar potential. Work just published by LPI researchers in the journals Carcinogenesis and Cancer Prevention Research explored the role of organic selenium compounds in killing human prostate and colon cancer cells. Colorectal and prostate cancers are consistently among the leading causes of cancer mortality in the United States, and will account respectively for 18 percent and 9 percent of all cancer deaths in 2009, according to estimates from the American Cancer Society.
In the recent studies, a form of organic selenium found naturally in garlic and Brazil nuts was converted in cancer cells to metabolites that acted as “HDAC inhibitors” – a promising field of research in which silenced tumor suppressor genes are re-activated, triggering cancer cell death.
“Whether it’s HDAC inhibition leading to one manner of cancer cell growth arrest, or loss of ribonucleotide reductase activity leading to another, as seen with chlorophyllin, there’s significant promise in the use of natural products for combined cancer therapies,” Dashwood said. “These are areas that merit continued research.”
These studies were supported by the National Cancer Institute and the National Institute of Environmental Health Sciences. Other collaborators included researchers from the New York Medical College and the Penn State College of Medicine. Further information on chlorophylls and selenium compounds can be found on the web at: http://lpi.oregonstate.edu/infocenter