Cholesterol biosynthesis & Enzalutamide resistance

[pjoshea13]

New study below.

Looks like Simvastatin might prolong the effectiveness of Xtandi.

Some will know that I favor the use of statins to shut off certain escape paths in therapies that involve the androgen receptor axis. In particular, I favor Simvastatin, but other statins that are also highly lipiphilic might be comparable.

"Although patients can benefit from enzalutamide at the beginning of ... therapy, acquired enzalutamide resistance usually occurs within a short period."

"In the present study, we found that HMG-CoA reductase (HMGCR), a crucial enzyme in the mevalonate pathway for sterol biosynthesis, is elevated in enzalutamide-resistant prostate cancer cell lines. HMGCR knockdown could re-sensitize these cells to the drug, and HMGCR overexpression conferred resistance to it, suggesting that aberrant HMGCR expression is an important enzalutamide resistance mechanism in prostate cancer cells. Furthermore, enzalutamide-resistant prostate cancer cells were more sensitive to statins, which are HMGCR inhibitors."

"Of note, a combination of simvastatin and enzalutamide significantly inhibited the growth of enzalutamide-resistant prostate cancer cells in vitro and tumors in vivo. Mechanistically, simvastatin decreased protein levels of the androgen receptor (AR), which was further reduced in combination with enzalutamide. We observed that the decrease in AR may occur through simvastatin-mediated inhibition of the mTOR pathway, whose activation was associated with increased HMGCR and AR expression. These results indicate that simvastatin enhances the efficacy of enzalutamide-based therapy, highlighting the therapeutic potential of statins to overcome enzalutamide resistance in CRPC."

One can wait 10 years for a clinical trial, of course, but Simvastatin has a good safety record.

-Patrick

ncbi.nlm.nih.gov/pubmed/300...

J Biol Chem. 2018 Aug 8. pii: jbc.RA118.004442. doi: 10.1074/jbc.RA118.004442. [Epub ahead of print]

Inhibition of cholesterol biosynthesis overcomes enzalutamide resistance in castration-resistant prostate cancer (CRPC).

Kong Y1, Cheng L2, Mao F1, Zhang Z1, Zhang Y1, Farah E1, Bosler J1, Bai Y1, Ahmad N3, Kuang S4, Li L2, Liu X1.

Author information

1

Purdue University, United States.

2

The Ohio State University, United States.

3

1300 University Avenue, University of Wisconsin, United States.

4

Animal Sciences, Purdue University, United States.

Abstract

Enzalutamide, a nonsteroidal second-generation antiandrogen, has been recently approved for the management of castration-resistant prostate cancer (CRPC). Although patients can benefit from enzalutamide at the beginning of this therapy, acquired enzalutamide resistance usually occurs within a short period. This motivated us to investigate the mechanism involved and possible approaches for overcoming enzalutamide resistance in CRPC. In the present study, we found that HMG-CoA reductase (HMGCR), a crucial enzyme in the mevalonate pathway for sterol biosynthesis, is elevated in enzalutamide-resistant prostate cancer cell lines. HMGCR knockdown could re-sensitize these cells to the drug, and HMGCR overexpression conferred resistance to it, suggesting that aberrant HMGCR expression is an important enzalutamide resistance mechanism in prostate cancer cells. Furthermore, enzalutamide-resistant prostate cancer cells were more sensitive to statins, which are HMGCR inhibitors. Of note, a combination of simvastatin and enzalutamide significantly inhibited the growth of enzalutamide-resistant prostate cancer cells in vitro and tumors in vivo. Mechanistically, simvastatin decreased protein levels of the androgen receptor (AR), which was further reduced in combination with enzalutamide. We observed that the decrease in AR may occur through simvastatin-mediated inhibition of the mTOR pathway, whose activation was associated with increased HMGCR and AR expression. These results indicate that simvastatin enhances the efficacy of enzalutamide-based therapy, highlighting the therapeutic potential of statins to overcome enzalutamide resistance in CRPC.

KEYWORDS:

cholesterol regulation; drug resistance; hormone receptor; prostate cancer; tumor therapy

PMID: 30089652 DOI: 10.1074/jbc.RA118.004442

[cesanon]

Why simvistatin over Crestor.

Dr. Myers always had a specific preference for Crestor.

[pjoshea13 in reply to cesanon]

Rosuvastatin (Crestor) is hydrophilic. OK for lowering LDL-C, but not readily taken up by PCa cells.

Simvastatin is lipophilic.

-Patrick

[CalBear74]

Have there ever been any studies on Lupron and a statin drug(s), or any drug, that extends the effective life of Lupron? Very interesting post.

[pjoshea13 in reply to CalBear74]

No Lupron+statin PCa study on PubMed.

I would think that there is a ton of data available to anyone interested in doing a study. The Nordic countries, in particular, since they have national health databases with prescription details.

-Patrick

[CalBear74]

I was about to ask you about lovastatin and whether it was lipophilic. But I first did a search and Medscape provided this info:

"Atorvastatin, lovastatin, and simvastatin are lipophilic, whereas pravastatin, rosuvastatin, and fluvastatin are more hydrophilic. Lipophilic statins cross the blood-brain barrier more readily, which may lead to central nervous system complaints such as insomnia, although this is rare."

[vandy69]

Dr. Myers prescribed Livalo for me, after several years of Crestor.

Go figure?

Best wishes. Never Give In.

Mark, Atlanta

[pjoshea13 in reply to vandy69]

One of his reasons for becoming interested in Livalo (Pitavastatin) was that it can increase adiponectin [1]. Could be a very good thing for those with PCa.

It is the only statin that doesn't raise blood sugar.

Downside is that it is the only major statin without a cheap generic. Tried it but my liver hated it.

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/183...

[podsart in reply to vandy69]

Vandy 69

Did Dr Myers say why he switched you, he never changed me from Crestor?

[vandy69 in reply to podsart]

Not that I can recall, but at the time I was taking a boatload of meds. Livalo is fairly unknown, but my Humana Medicare drug plan covers it, as it is expensive.

Mark, Atlanta

[podsart in reply to vandy69]

Thanks

[tarhoosier]

Myers was interested in small particle cholesterol in my lipid tests. I never understood his explanation but simvastatin kept it below the measureable level at Labcorp and he was pleased.

[pjoshea13 in reply to tarhoosier]

As I recall from a vlog post, he claimed that the cholesterol [C] that was carried into PCa cells was attached to very low-density lipoprotein (VLDL) i.e. VLDL-C.

Unfortunately, the relative size of the C-carrying LDL proteins worsens in favor of VLDL while on ADT.

Solid tumors accumulate cholesterol, but this presents a particular problem for PCa, where C can be used to make androgens.

Although Myers once mentioned that PCa could also make C, if necessary, I can't recall him recommending a statin to prevent that. I believe that Simvastatin would be a better choice than Crestor to achieve that.

-Patrick

[EdBar]

If my ADT brain recalls correctly Myers was interested in keeping LDL cholesterol levels low since T starved PCA will convert it to T or DHT. He switched me from Simvistatin to Crestor because he said Simvistatin can block certain pathways used by ADT drugs - Xtandi in particular, thus reducing their effectiveness. I was originally placed on 20 mg of Crestor but now I'm down to 5mg. He made this change during our last consult just before he retired, he was concerned that it had dropped LDL too low which can affect brain function. I've got enough of that already after being on triple ADT for over 4 years.

Ed

[pjoshea13 in reply to EdBar]

Ed,

Interesting that "he said Simvistatin can block certain pathways used by ADT drugs - Xtandi in particular", considering the theme of the study that began this thread.

My concern is that men with low cholesterol will feel that they do not need a statin. Those are the men whose PCa might feel the need to manufacture it. But yes, the brain has a ton of cholesterol. Stange how America became paranoid about the tiny amount in an egg.

There is a 2012 paper that mentions Simvastatin & Crestor (Rosuvastatin):

"Statins act directly on PC-3 cells with atorvastatin, mevastatin, simvastatin (1 μM) and rosuvastatin (5 μM), but not pravastatin, significantly reducing invasion .." [1]

which suggests that one needs to take 5 times the amount of Crestor to get the same effect.

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/225...

[podsart in reply to EdBar]

I wonder if Pitavastatin (livalo) provides an answer. Apparently, it’s lipophilic but perhaps it works differently than other lipophilic statins-reduced side effects but maybe usable instead of simistatin

Perhaps one of our members who has a good grasp of pharmacology, can assess whether it would affect Xtandi used pathways