Cholesterol, RO 48-8071 & PCa

RO 48-8071 is getting some attention at the moment [1].  Hard to know if it is worth the fuss.  RO 48-8071 is described as: "a compound initially developed as a cholesterol-fighting molecule".  The compound reduces PCa cell growth in dish & mouse.

"The study, “Cholesterol biosynthesis inhibitor RO 48-8071 suppresses growth of hormone-dependent and castration-resistant prostate cancer cells,” has been accepted for publication in the journal, OncoTargets and Therapy ..."

Charles Powell White first reported cholesterol accumulation in tumors in 1909 [2].  (The date is not a typo.)

Seems a long time from 1909 to 2002 when Zhuang, et al, described the activities of cholesterol-rich lipid rafts in LNCaP cells [3].  Too bad about this comment: "... our observations may help provide a mechanistic link between cholesterol-rich diets and ...".  The body makes cholesterol.  There is no shortage of it, even on a vegan diet, in the absence of cholesterol-lowering drugs.  The issue is that PCa cells have a higher uptake than normal prostatic epithelial cells.

Li, et al, 2006 [4]: "the prostate cancer cell lines contained more lipid rafts and were more sensitive to cholesterol depletion-induced cell death than their normal counterparts. These results indicate that cancer cells contain increased levels of rafts and suggest a potential use of raft-modulating agents as anti-cancer drugs."

In a review paper (2011) [5], Roy et al: "argue that prevention of PCa progression is a better strategy compared to trying to cure the disease once it has already progressed. Statins inhibit the mevalonate pathway, thus preventing the synthesis of cholesterol, geranylgeranyl pyrophosphate and farnesyl pyrophosphate. Multiple clinical studies have shown an inverse relationship between statin use and PCa risk, especially the risk for developing advanced metastatic cancer. Biochemical investigations have largely corroborated the positive effect of statins on PCa risk, showing that statins inhibited cell proliferation, induced apoptosis, and decreased cell migration and invasion in PCa cells in vitro."

The subject of cholesterol in solid tumors is interesting enough, but cholesterol is doubly important in PCa.  The old term "androgen independent" proved to be incorrect in most cases & was replaced by CRPC, but that term has proven to be incorrect too, & drugs such as Zytiga simply plug the holes in traditional castration therapy.  I have argued that statins should be a part of ADT, since (1) PCa cells can use cholesterol to manufacture androgens, & (2) PCa cells can maufacture cholesterol if there is insufficient cholesterol in circulation to satisfy uptake demands.

But, androgens aside: "The protective effect of statins was observed in the meta-analysis of numerous studies including ... stomach cancer, esophagus cancer, and hepatocellular carcinoma ..." (2015) [6]  The case for statins in PCa would exist even if the cancer were to be androgen independent.    

It's not clear what the new study adds to this picture.  But there might be clues in earlier BCa papers by Hyder [7] [8] (2014).

In [8]:  "RO degraded ERα while concomitantly inducing the anti-proliferative protein ERβ. Two other cholesterol-lowering drugs, Fluvastatin and Simvastatin, were less effective in reducing breast cancer cell viability and were found not to induce ERβ. ERβ inhibition or knockdown prevented RO-dependent loss of cell viability."

If this happens in PCa it would be a very big deal.  A pivotal early event in PCa is the loss of protective ERbeta & its replacement by growth-stimulating ERalpha.



[2]  "On the occurrence of crystals in tumours"  Copyright © 1909 The Pathological Society of Great Britain and Ireland








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