Simvastatin & Radioresistance.

[pjoshea13]

New study below [1].

Years ago, when I had salvage radiation, I was not on Simvastatin, but I was by the time a lesion at L5 was treated.

From the new paper:

"These findings reveal that simvastatin may be a potent therapeutic agent for co-treatment with radiation to overcome radioresistance in PCa cells."

Radioresistance is a recognized problem of diminishing returns. Survival escape paths have been identified & there are some natural substances that might help during treatment:

[2] Resveratrol (2012).

[3] Metformin (2014).

[4a] [4b] [4c] Genistein (2001, 2008, 2009).

Note that genistein has been found to have a biphasic effect in PCa & BCa. Avoid low doses - use only very high doses.

[5a] [5b] [5c] Curcumin (2004, 2016, 2017).

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/299...

Front Pharmacol. 2018 Jun 13;9:600. doi: 10.3389/fphar.2018.00600. eCollection 2018.

Simvastatin Sensitizes Radioresistant Prostate Cancer Cells by Compromising DNA Double-Strand Break Repair.

Chen YA1, Shih HW1, Lin YC1, Hsu HY1, Wu TF2, Tsai CH3, Wu CL4,5, Wu HY3, Hsieh JT6, Tang CH1,7, Lai CH1,3,5,8.

Author information

1

Graduate Institute of Basic Medical Science, School of Medicine, China Medical University, Taichung, Taiwan.

2

Department of Applied Cosmetology, Hung Kuang University, Taichung, Taiwan.

3

Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.

4

Department of Biochemistry, College of Medicine, Chang Gung University, Taoyuan, Taiwan.

5

Molecular Infectious Disease Research Center, Department of Neurology, Chang Gung Memorial Hospital, Linkou, Taiwan.

6

Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, United States.

7

Graduate Institute of Biomedical Sciences, School of Medicine, China Medical University, Taichung, Taiwan.

8

Department of Nursing, Asia University, Taichung, Taiwan.

Abstract

Prostate cancer (PCa) is one of the most prevalent male cancers in western world. Radiation therapy (RT) is commonly used to treat PCa patients. However, a certain proportion of patients develop radioresistant PCa cells, which results in metastatic disease. Statins, which inhibit 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, are commonly used to treat hypercholesterolemia, exhibiting beneficial effects on cardiovascular diseases and on several types of cancers, including PCa. However, the mechanistic details and crosstalk between statins and RT in PCa cells remain unknown. In this study, radioresistant DOC-2/DAB2 interactive protein (DAB2IP)-deficient PCa cells were used to evaluate whether simvastatin could enhance the effect of ionizing radiation (IR). The crucial molecules that associated with simvastatin elevated radiosensitivity in PCa cells were explored. Our results demonstrated that a combination treatment with simvastatin and IR synergistically induced apoptosis of radioresistant PCa cells. In addition, simvastatin appeared to compromise DNA double-strand breaks repair by activating the expressions of histone 2A family member X (γ-H2AX) and phospho-checkpoint kinase 1 (p-CHK1), suggesting an underlying mechanism for this radiosensitization of PCa cells. These findings reveal that simvastatin may be a potent therapeutic agent for co-treatment with radiation to overcome radioresistance in PCa cells.

KEYWORDS:

DNA double-strand break; HMG-CoA reductase; cholesterol; prostate cancer; radioresistance; simvastatin

PMID: 29950990 PMCID: PMC6008406 DOI: 10.3389/fphar.2018.00600

...

[2] ncbi.nlm.nih.gov/pubmed/224...

[3] ncbi.nlm.nih.gov/pubmed/248...

[4a] ncbi.nlm.nih.gov/pubmed/112...

[4b] ncbi.nlm.nih.gov/pubmed/184...

[4c] ncbi.nlm.nih.gov/pubmed/191...

[5a] ncbi.nlm.nih.gov/pubmed/149...

[5b] ncbi.nlm.nih.gov/pubmed/272...

[5c] ncbi.nlm.nih.gov/pubmed/283...

[cesanon]

Hmmm interestingly I once asked Dr. Myers about simvistatin, and he had a strong strong preference for Crestor over simvistatin.

[pjoshea13 in reply to cesanon]

It's clear from Dr. Myers vlog posts that he was greatly concerned about CVD in his PCa patients. His video references to statins relate to CVD rather than PCa.

Simvastatin is lipophilic & more likely to be taken up by PCa cells than Rosuvastatin (Crestor), which is hydrophilic.

I have no CVD interest in statins. No doubt, Dr. Myers had observed better lipid profiles in Crestor users, but he couldn't have known the cholesterol status of their PCa cells.

-Patrick

[cesanon in reply to pjoshea13]

HMMMM!

So, Patrick, all five of the following are useful things to be taking during, and perhaps in preparation for, radiation therapy, as they will potentiate the effect of the radiation on prostate cancer cells. Do I have that right?

1. Simvistatin

2. Resveratrol

3. Metformin

4. Genistein (Note that genistein has been found to have a biphasic effect in PCa & BCa. Avoid low doses - use only very high doses. )

5. Curcumin

[pjoshea13 in reply to cesanon]

Yes - nothing to lose.

& I would stay with then for some weeks, while the radiation continues to play out.

The same escape pathways would be used during chemo, so I would expect possible benefit there too.

-Patrick

[cesanon in reply to pjoshea13]

Patrick

1. So you think this applies only to simvastatin and not to Pravastatin or Crestor?

2. What is a low dose vs high dose of Genistein?

[pjoshea13 in reply to cesanon]

"Atorvastatin, lovastatin, and simvastatin are lipophilic, whereas pravastatin, rosuvastatin, and fluvastatin are more hydrophilic."

Atorvastatin: ncbi.nlm.nih.gov/pubmed/287...

This is the highest dose of genistein that I know of:

lifeextension.com/Vitamins-...

I always take the full dose (5 caps) when using.

-Patrick

[pjoshea13 in reply to cesanon]

A low dose of genistein would be a physiological rather than pharmaceutical dose. i.e. the maximum one could get from diet alone might be unsafe. Ten times higher might be OK. LEF cannot say so but its product was designed for cancer IMO. There is no other reason to take such a high dose.

-Patrick

[Break60 in reply to pjoshea13]

My RO, who treated Snuffy recommends the same stuff except simvastatin ( he recommends rosuvastatin (Crestor) but he hasn’t mentioned genistein.

[cesanon in reply to pjoshea13]

"The same escape pathways would be used during chemo"

Patrick, what is an escape pathway? What is escaping? How does that relate to the effect of the 5 adjuvants?

[pjoshea13 in reply to cesanon]

Captain_Dave, in response to my recent Metformin post, mentioned a new paper:

"Metformin combined with quercetin synergistically repressed prostate cancer cells via inhibition of VEGF/PI3K/Akt signaling pathway."

[1] Vascular endothelial growth factor (VEGF)

[2] Phosphoinositide 3-kinase (PI3K)

[3] Protein kinase B (Akt)

When a cell comes under attack, it responds in a number of ways that improve its chance of survival. The result is the generation of a cascade of proteins that have pro-survival functions. Various pathways in the cascade have been singled out as possible targets for therapy.

My reason for using a nitroglycerine patch to improve the oxygen supply to my cancer, is that a lack of oxygen (hypoxia) will result in HIF-1alpha (hypoxia-inducible factor-1alpha). When that happens, all hell breaks loose in terms of the defenses that are erected.

Resistance to radiation or chemotherapy is initiated very early, & it makes sense to use any agent that can block what I call escape routes. Is BigPharma looking at the problem?

-Patrick

[1] en.wikipedia.org/wiki/Vascu...

[2] en.wikipedia.org/wiki/Phosp...

[3] en.wikipedia.org/wiki/Prote...

[cesanon in reply to pjoshea13]

"My reason for using a nitroglycerine patch to improve the oxygen supply to my cancer, is that a lack of oxygen (hypoxia) will result in HIF-1alpha (hypoxia-inducible factor-1alpha). When that happens, all hell breaks loose in terms of the defenses that are erected."

What do you think about the generic 20mg viagra pills? They are very inexpensive now. Or do you think the Nitroglycerine patches are better?

[pjoshea13 in reply to cesanon]

I hadn't considered the nitroglycerine patch to be useful for erectile dysfunction, but I suppose it must be - perhaps for mild ED? I am beyond help in that respect. Alas, viagara never helped.

-Patrick

[cesanon in reply to pjoshea13]

Myers put me on low dose Viagra for prostate cancer purposes. I am still taking it. He never clearly explained why?

Do you think it might serve the same purpose as your nitroglycerine patch?

[Hidden in reply to cesanon]

I wonder if the viagra was for a different purpose -- trying to maintain the health of the penis and ward off atrophy? My HIFU surgeon had me on daily dose of Cialis for a month after that surgery.

[cesanon in reply to Hidden]

I remember Myers saying something about it affecting the surface of prostate cancer cells.

[pjoshea13 in reply to cesanon]

The nitro patch, by releasing nitric oxide constantly, serves to dilate blood vessels for an extended period.

The normal use of Viagra is for a more intense but short-term effect.

Arginine promotes vasodilatation by increasing nitric oxide, but this is short-term too.

-Patrick

[cesanon in reply to pjoshea13]

"The result is the generation of a cascade of proteins that have pro-survival functions. Various pathways in the cascade have been singled out as possible targets for therapy."

Are these what you refer to as "escape pathways"?

[Hidden in reply to cesanon]

Simvastatin horribly aggravated my GERD / reflux problem. I was OK after switching to atorvastatin, which I hope has the same benefit with regard to PC cells.

[larry_dammit]

Wow. Way over this kids head, have to be a doctor or chemist to understand this 😜😜😜😜

[cesanon in reply to larry_dammit]

Patrick, believes the following will make radiation treatment (and perhaps chemo) more effective:

1. Simvistatin

2. Resveratrol

3. Metformin

4. Genistein (Note that genistein has been found to have a biphasic effect in PCa & BCa. Avoid low doses - use only very high doses. )

5. Curcumin

Part based on research and part based on logic. None of them seem to be intrinsically dangerous. Though Genistein looks to have a lot of complicated activity and interactions and personally I don't know that I would use it.

[smroush]

Good post Patrick - very actionable.

Thank you!

[arete1105]

Has anybody checked into using hyperthermia as a co-treatment with either chemo or radiation. It is a common treatment in both German and Mexican cancer clinics. Here is how is works: they heat the area up to 42-43C and the heat has a deleterious effect on the cell wall, resulting in low-chemo(10-30% dose) and reduced RT.

I talked with the people at the Santa Monica center where they do hyperthermia and they said they work in conjunction with UCLA (Dr. Steinberg) for the chemo or RT therapy.

[Kamilekamile in reply to arete1105]

We asked our dr about hyperthermia to use along with RT. Dr said hyperthermia is ok to use for some cancers but not for Pca. Can be used for like skin cancer for the cancers of the organs more on the surface. İt is not effective for Pca because prostate is deep in the body.

İ have no idea if is true.

Best

Kamile

[arete1105 in reply to Kamilekamile]

Kamile- check this link out- germancancerbreakthrough.com/

[Kamilekamile in reply to arete1105]

İf it is easy like this why dont you try it?

[arete1105 in reply to Kamilekamile]

Good question- answer is the FDA. Here is what I found.

Germany is the center for top Hyperthermia treatment. They make the latest heat units, which the TJ clinics also use. However, both programs cost $25K-$30K. I don't have that.

I was all set up to have RT at UCLA and hyperthermia at the Santa Monica center, but then my insurance, Anthem Blue Cross, classifies it as experimental and doesn't cover the hyperthermia portion. SM told me the cost is $1900/session, but on cash basis it would be $900/ session. That also I don't have. I don't know how many sessions it would be. Now if my primary ins would be Medicare and no secondary, the it would cover 80%. But I have a secondary which is really the primary.

Now there is a center in Huntington Beach CA that offer many alternative treatments, including hyperthermia, but no chemo or RT. It is the Orange County Immune Institute, directed by Dr. Ferre. 714-842-1777. drferre.com.

They offer a $300 in person evaluation of your records before further plans. I am waiting for my final scans and scope and then the consult with the Onc before I decide what I am going to do. I should know by the end of July.

[Spaceman210 in reply to arete1105]

There is another center in OC that offers it with RT: cyberknifeoc.com/treatments...

UCSF offers it as well. It requires careful monitoring and there can be other issues.

[arete1105 in reply to Spaceman210]

Since then I have switched to Kaiser. I don't know what their options are. I will ask my Onc the next time I see him.

[Spaceman210 in reply to arete1105]

It may be just as well. My friends with Kaiser in So Cal incl for various cancer treatment have had great things to say about them. Also it looks like the doc at the SM place has changed to someone who is not an oncologist. Best wishes and Happy New Year!

[Spaceman210 in reply to Kamilekamile]

There is a form of deep hyperthermia that uses microwaves to penetrate, not without issues though, suitable in certain PCa cases according to UCSF.

[cesanon]

"hyperthermia as a co-treatment"

Seems logical. Killing the cells from multiple vectors.

But complex biological systems are strange things.

There are many possible combinations of multiple vectors you can use. Why not at least use those that have passed FDA approved clinical trials?

Is there anyone using combined radiation therapy, chemo, and androgen deprivation therapy?

[pjoshea13 in reply to cesanon]

One of the potential responses to hyperthermia that comes to mind is induction of heat shock proteins [HSPs]. e.g. HSP70 protects the androgen receptor [AR] by acting as an AR chaperone. HSPs appear in cells ar a response to a variety of insults - not just heat.

"Heat shock proteins are molecular chaperones that play important roles in the folding of misfolded proteins, and in the regulation of cellular signals and transcriptional networks.10 Heat shock proteins are overexpressed in a wide range of human cancers and are implicated in tumor cell proliferation, differentiation, invasion, metastasis, and death.11 In prostate cancer, Hsp70 and Hsp90 have cytoprotective effects, such as in the inhibition of apoptosis,12 cell cycle modulation,13 invasion and metastasis,14 and AR transcriptional activity and stability.15 Therefore, in the last decade, Hsp inhibitors have been highlighted and explored as potential targets for anticancer therapy, and clinical trials have been carried out.16

"Heat shock protein 90 inhibitors have been reported as potentially effective treatments for CRPC by depressing the expression levels of AR‐FL and AR‐V7 through different mechanisms. In particular, an Hsp90 inhibitor was shown to increase the degradation rate of AR‐FL and induced AR‐V7 mRNA downregulation in vitro.17 However, it is unknown whether Hsp70 inhibitors also reduce the expression of AR‐V7, and the specific mechanism contributing to the observed effect of Hsp70 inhibitors to decrease AR‐FL has yet to be elucidated.18"

ncbi.nlm.nih.gov/pmc/articl...

-Patrick

[cesanon in reply to pjoshea13]

hmmm

So heat shock proteins "are implicated in tumor cell proliferation". But "Heat shock protein 90 inhibitors have been reported as potentially effective treatments for CRPC "

That kind of biological system complexity is what makes prostate cancer so difficult a field for patients to navigate.

Patrick, I continue to be amazed at your mastery of all this disparate research.

Now that Dr. Myers is retired, I wish I could find a Doc that took the effort to maintain such a mastery. I have yet to find that Doc. They just don't seem to have the curiosity and the time to read and ingest all this far-flung research, to integrate into good treatment protocols.

[cesanon]

"....are you not worried about the Nay-Sayers here that will demand Double blind Studies. "

1. Why would anyone care that someone would express such a demand on a public discussion board? LOL

And by the way, I have never seen anyone express such a "demand". (I must admit that I have mocked those who have disparaged the value of double-blind studies)

2. On the other hand, I have seen people vigorously disparage the palpable benefits of double-blind studies... and exhort others to do the same. (actually, come to think of it, you are the only one I remember doing this)

3. But why on earth would anyone be "worried" about someone expressing an opinion on this forum? If someone says stupid irrational things, they get corrected by peer review.

Surely the truth eventually prevails. That is how peer review works. For example, it has worked as a fairly effective bulwark against the "Anti-Vaccination" conspiracy theorists. Just think how many people would have been killed by that movement which is premised on testimonial stories of unverifiable causation.

4. As a scientist, do you object to post-publication peer review as something to be "worried" about? Surely you don't. And if so, what would you replace it with?