November 30, 2006
Androgen Insensitive Prostate Cancer Stopped With SIRT1 Gene
This report appears to point to a potential prostate cancer treatment benefit from resveratrol since the SIRT1 gene they speak of is the one that resveratrol activates.
Cancer scientists at the Kimmel Cancer Center at Thomas Jefferson University in Philadelphia have shown that a gene that is involved in regulating aging also blocks prostate cancer cell growth. The researchers, led by Kimmel Cancer Center director Richard Pestell, M.D., Ph.D., hope the newly found connection will aid in better understanding the development of prostate cancer and lead to new drugs against the disease.
SIRT1 is a member of a family of enzymes called sirtuins that have far-reaching influence in all organisms, including roles in metabolism, gene expression and aging.
SIRT1 is the target of the Sirtris Pharmaceutical efforts to develop a more potent and longer lasting variation on resveratrol. High doses of resveratrol turn on the SIRT1 gene. So one obvious implication of this research is that resveratrol might restore the androgen sensitivity of androgen insensitive prostate cancer by turning on SIRT1 which will somehow change mutated androgen receptors and make them no longer stimulate prostate cancer cell growth. That, in turn, would make that fatal form of prostate cancer back into a form that can be controlled with Lupron and other testosterone suppressor drugs.
“We know that sirtuins play a role in aging, and that the risk for prostate cancer increases with aging, but no one has ever linked the two until now,” says Dr. Pestell, who is also professor and chair of cancer biology at Jefferson Medical College.
“We’ve shown that by making a prostate cancer with cells overexpressing a mutation for the androgen receptor, which is resistant to current forms of therapy, we can almost completely block the growth of these cells with SIRT1,” he says. Dr. Pestell and his team report their findings in November in the journal Molecular and Cellular Biology.
Turning on SIRT1 stopped cancer growth.
According to Dr. Pestell, prostate cancer cells can express a mutation that makes patients resistant to current forms of treatment such as hormonal therapy. Such therapy focuses on inactivating the androgen receptor by giving agents that shut off testosterone production.
In one experiment, the scientists took a series of mutations in androgen receptors from prostate cancer patients who are resistant to hormonal therapy and showed that SIRT1 blocks receptor activity, halting cancer growth. “We systematically tested each androgen receptor mutation,” Dr. Pestell explains. “These mutant receptors are resistant to current therapies and are all blocked by expression of SIRT1,” adding that prostate specific antigen (PSA) levels were used to confirm this. Rising PSA levels are frequently an indication of prostate cancer growth or recurrence, whereas falling levels indicate tumor shrinkage.
This result does not suggest (at least not to me) that resveratrol will reduce the risk of getting prostate cancer in the first place. The SIRT1 gene's protein product probably prevents mutated androgen receptors from stimulating an existing prostate cancer. But usually prostate cancer grows with non-mutated androgen receptors in its early stage. Though I can't rule out the possibility that higher activation of SIRT1 (using resveratrol or Sirtris' SRT501 experimental drug or another drug) might reduce prostate cancer risks.
If resveratrol or Sirtris's SRT501 work to restore androgen sensitivity to prostate cancers they will buy prostate cancer sufferers months or perhaps years of additional life. Still, this is not an ideal solution. The testosterone suppressor drugs that would likely still be necessary probably reduce cognitive function, certainly cause muscle mass loss, and cause other harmful side effects. But if cancer cell growth can be stopped by this method the cells might also become more amenable to other treatments such as vaccines and monoclonal antibodies.
Thanks to Robert Silvetz for the heads up on this report. Also see my previous posts on resveratrol: Resveratrol Increases Energy In Humans, Mice and Wine Compound Resveratrol Protects Mice From Obesity Damage.
While I was working for an R&D outfit in Australia one of the senior managers was diagnosed with prostate cancer. It must have been very advanced as he died only a few months later on. The surgeons opened him up but decided there was little they could do, as the cancer had already spread into his spine. The thing was he reckoned he had not experienced symptoms or pain until quite late in the piece.
This new discovery is interesting. I hope it leads to active application of a therapy that helps people to survive this rotten disease.
Does anyone know why prostate cancer occurs in older men? It has been suggested it will occur in ALL men. It's just a matter of time (how old you get). Sooner or later all will develop it. Surely that can't be right?
BTW what exactly is the function of this organ? What is its task?
The prostate produces the fluid portion of semen.
Complexity(multi-cellular organisms) to chaos(cancer and aging). Both cancer and aging involve DNA copying errors. Therefore,as we age,our natural defense against cancer fails.
That's interesting. I thought that was the role of the Cowpers gland. If not, then what is the Cowpers supposed to achieve? Is there redundancy? Complex.
Yes, frightening stuff.
Is it true everyone gets prostate cancer though? In other words, that protate cancer is a necessary part of aging (women excepted of course)?
There's no evidence that everyone gets prostate cancer. It's simply very, very common: autopsy finds that many men who die from other reasons have prostate cancer, though it's possible that many of these cancers were very slow growing. One of the controversies of prostate treatment is the question of how many prostate cancers detected through screening would actually eventually become lifethreatening.
I read this research to say that the cancer growth was stopped by SIRT1, not by a combination of SIRT1 and other treatment. Am I misreading that? Also, did they use the enzyme SIRT1 directly, or did they turn on the gene that produces it?? I couldn't open the link to the study report.
It is not clear to me either. But here's what I know:
1) If a cell retained both androgen-sensitive and androgen-insensitive versions of the androgen receptor gene then even if the androgen-insensitive version was totally deactivated by SIRT1 the androgen-sensitive version might still stimulate cell growth in response to testosterone binding to it.
2) I can't tell whether they are saying the SIRT1 made the mutant receptors sensitive again or just deactivated them entirely.
3) They do speak of the SIRT1 interacting with the receptors. So that argues against a downstream effect as the mechanism of action.
4) Even if a person has androgen-insensitive prostate cancer in some cells they are going to retain androgen-sensitive prostate cancer in other cells. So unless SIRT1 stopped prostate cancer cell growth in all prostate cancer cells the need would remain for use of Lupron or some other testosterone production suppressor drug.
But bottom line: I want a way to kill cancer cells rather than just suppress their growth.
Sione, I agree with Nick,we are most likely to die from the effects of aging than prostate cancer. When you think of the ammount of damage our DNA receives on a daily basis,so that our cells are supplied with electricity,then we must all carry a very good communication system against cancer. How does a highly evolved communication system fail? Perhaps it doesn`t,it just needs amplifying.
I suspect cancer incidence rises due to aging of the immune system. Rejuvenate the immune system and I bet the incidence of cancer would fall greatly.
Maybe Vitamin D reduces the risk for cancer in part by improving the function of the immune system.
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