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Natural Compound in Broccoli Slows Breast Cancer Stem Cells

Pam Stephan, Guide to Breast Cancer, Tuesday May 11, 2010

The area of cancer stem cells is very hot. To give an example, the pharmaceutical company GSK recently purchased the cancer stem cell company Oncomed for more than a billion dollars, at a time when Oncomed's cancer stem cell-targeting drugs were not even tested in humans. This area is of great interest because it suggests that the way to kill cancer is not to block the fast multiplying cells, but that the cancer has a "root cause" that scientists for decades have been ignoring.

Cancer stem cells are usually not destroyed by chemotherapy or radiation therapy because they are slow dividing cells that possess numerous proteins to protect themselves from toxicity such as multiple drug resistance proteins. These proteins have the function of identifying chemotherapy inside of the cancer cell and actively pumping it out. It is believed that the reason why these proteins exist is to protect cells from damage to DNA. In cancer stem cells these proteins appear to play a role in causing relapse after chemotherapy.

Previously it was reported that the chicken feed antibiotic salinomycin has the ability to selectively kill cancer stem cells (Gupta PB. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009 Aug 21;138(4):645-59. Epub 2009 Aug 13), additionally, using similar testing scenarios researchers found the anti-diabetic drug metfomin inhibits breast cancer stem cells (Vazquez-Martin et al. The anti-diabetic drug metformin suppresses self-renewal and proliferation of trastuzumab-resistant tumor-initiating breast cancer stem cells. Breast Cancer Res Treat. 2010 May 11). Given the recent nature of these findings, their use in humans has not yet been reported in the scientific literature. In the current study which will be discussed, another compound with similar anti-breast cancer stem cell activity was identified.

A recent study (Li et al. Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells. Clin Cancer Res. 2010 May 1;16(9):2580-90) demonstrated that a natural chemical compound found in broccoli and other cruciferous vegetables called sulforaphane has the ability to slow down multiplication of breast cancer stem cells. Essentially this means that sulforaphane can block the cells that cause cancer from being activated and thus could be an effective cancer therapy if high enough doses can be safely administered.

The scientists purified human breast cancer stem cells using the Aldefluor assay made by the company Aldagen, which selects for cells expressing the enzyme aldehyde dehydrogenase, an enzyme found in normal and cancer stem cells. The stem cells were tested to see if they would form tumors in mice lacking an immune system called nonobese diabetic/severe combined immunodeficient mice.

It was found that sulforaphane administered at a concentration of 1-5 micromol/L was sufficient to suppress multiplication of the aldehyde dehydrogenase-positive stem cell population by 65% to 80% and reduce the size and number of primary mammospheres by 8- to 125-fold and 45% to 75%, respectively. Mammospheres are round tumor-like structures that grow in tissue culture plates that represent a three-dimensional cancer.

Daily injection with 50 mg/kg sulforaphane for 2 weeks reduced aldehyde dehydrogenase-positive cells by >50% in nonobese diabetic/severe combined immunodeficient xenograft tumors. Since it appeared that the administration of sulforaphane eliminated breast cancer stem cells in the animal, the next step was to assess the ability of the growing tumors to cause secondary tumors when transplanted into other animals. This indeed was demonstrated to be the case. Ability to block transfer of tumors to secondary recipients is associated with possibility of cure since it represents targeting of the functional tumor stem cell compartment.

Mechanistically it appears that sulforaphane works on the cancer stem cells through suppression of the Wnt/beta-catenin self-renewal pathway, which is found in numerous tumor and non-malignant stem cells. This of course poses the question of whether the high doses of sulforaphane that were used in the study would have unwanted effects on healthy stem cells in the body. The most relevant side effect of chemotherapeutic drugs is suppression of blood cell production from the bone marrow stem cell. Indeed the scientists found that there was no alteration of blood cell parameters in treated animals, suggesting at least a partial degree of selectivity.

Sulforaphane is believed to exert at least some of its anticancer biological effects through its ability to suppress histone deacetylase (HDAC) activity. HDAC are proteins that are involved in "bundling" of the DNA. If DNA from one cell was stretched out, it would be 7 meters from end-to-end. The histone that are acetylated bind DNA in a loose manner and allow for new genes from the DNA to be expressed that normally would not be expressed. In the area of cancer, the treatment with HDAC inhibitors is believed to cause brand new expression of tumor suppressor genes. These genes, such as p53, instruct the tumor cell to undergo cellular suicide, called apoptosis.

The controversial "Burzynski Therapy" involving antineoplastons, which are naturally occurring compounds is believed to function through induction of histone acetylation and induction of tumor suppressor genes (Burzynski, The present state of antineoplaston research, Integr Cancer Ther. 2004 Mar;3(1):47-58). It would be interesting to examine whether some of the reported positive effects of this non-toxic cancer therapy is mediated by suppression of tumor stem cell activity.

A recent paper (Ho et al. Dietary sulforaphane, a histone deacetylase inhibitor for cancer prevention. J Nutr. 2009 Dec;139(12):2393-6. Epub 2009 Oct 7) demonstrated that sulforaphane inhibits HDAC activity in human colorectal and prostate cancer cells. Based on the similarity of sulforaphane metabolites and other phytochemicals to known HDAC inhibitors, it was previously demonstrated that sulforaphane acted as an HDAC inhibitor in the prostate, causing enhanced histone acetylation, derepression of P21 and Bax, and induction of cell cycle arrest/apoptosis, leading to cancer prevention. The possible ability of sulforaphane to target aberrant acetylation patterns, in addition to effects on phase 2 enzymes, may make it an effective agent in suppressing cancer cells in a non-toxic manner.

This study also poses the question if HDAC inhibitors in general can alter tumor stem cell ability. It is known that valproic acid, the HDAC inhibitor actually increases ability of stem cells to self renew while being selectively toxic to leukemic cells

An interesting note regarding cancer stem cells is that many approaches traditionally supported by practitioners of alternative medicine may actually be targeting these cells. In alternative medicine the main theme is providing the body with nutrients to "heal itself". Practitioners of alternative medicine have had some degree of success treating cancer in a "nontoxic" manner using dramatic dietary modifications, nutrient therapy, and administration of agents that induce differentiation. It may be possible that these interventions act to reduce the localized inflammation in the tumor mass. This inflammation is believed by some to be what stimulates the cancer stem cell to enter cell cycle. Accordingly, it is interesting to see that components of broccoli inhibit cancer stem cells. It will be interesting to examine other nutrients for ability to target cancer stem cells.

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