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
http://www.youtube.com/watch?v=3Hc4LCUOSiA.
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.
