I vitro evidence for effectiveness of Simvastatin Metformin combination against Enzalutamide resistant CRPC

[Graham49]

Apologies if this has already bee posted

MP79-03 DRUG REPURPOSING APPROACH FOR DEVELOPING NOVEL THERAPY FOR CASTRATION RESISTANT PROSTATE CANCER

Eswar Shankar* , Gregory MacLennan , Pingfu Fu , and Sanjay Gupta

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doi.org/10.1097/JU.00000000...

Abstract

INTRODUCTION AND OBJECTIVE:

Androgen deprivation therapy (ADT) is the prevalent first line therapy against advanced prostate cancer as an adjuvant for locally treating the high-risk disease. Malignant cells initially respond to ADT, but subsequently colonize and re-emerge as more aggressive phenotype known as castration resistant prostate cancer (CRPC). The second generation androgen receptor (AR) antagonist enzalutamide (ENZU) exhibits survival advantage in CRPC patients, however ∼30% of patients develop resistance overtime activating AR in these tumors. These resistant tumors poorly respond to chemotherapy and acquire resistance partly due to enhanced aerobic glycolysis and biomass production known as the Warburg effect. Therefore, identification of an effective low-cost therapeutic alternative with fewer side effects may lead to increased survival and greatly benefit patient quality-of-life. Drug repurposing has emerged as a new option for overcoming resistance to chemotherapy. Previous studies from our laboratory (Mol Cancer Ther. 13:2288-302, 2014) has demonstrated that synergistic combination of simvastatin (SIM), a drug for the treatment of hypercholesterolemia and metformin (MET), a glucose lowering drug inhibits CRPC growth, invasiveness and migration potential with minimal effect on normal prostate epithelial cells. Here we investigate whether combination of SIM and MET could be effective in the treatment of ENZU-resistant prostate cancer cells.

METHODS:

Human CRPC cells C4-2B-ENZU (C4-2B enzalutamide resistant) were generated by growing C4-2B cells in progressive concentration of ENZU 5-20µM to develop resistance and maintained in 5µM ENZU in the culture medium for >20 generations. 22Rv1 cells are inherently resistant to ENZU. These cells were treated with SIM and MET individually and in combination, followed by assessment of cell viability, crystal violet assay, cell cycle analysis, migration, invasion and expression of various target genes by Western blotting.

RESULTS:

C4-2B-ENZU and 22Rv1 cells were treated individually and in a combination of SIM and MET at pharmacological dose range (500nM-4µM SIM and 250µM-2mM MET). Combination treatment with 4μM SIM and 2mM MET (SIM+MET) led to significant and synergistic inhibition of cell viability, migration, invasion and cell cycle blockade in both cell lines. The individual treatments of SIM and MET exhibited little or no effect on these cells. Furthermore, SIM+MET combination decreased the expression of AR, AR-V7, p-Akt (Ser473), p-AMPKα1/α2 (Ser-485/491) and simultaneously increased p-AMPKα1 (Thr-172) and AMPKα kinase activity in these cells.

CONCLUSIONS:

Combined action of SIM and MET may be an effective regimen for treatment of ENZU-resistant tumors. This opens new therapeutic modality for castration-resistant prostate cancer patients.

Source of Funding:

VA Merit Review 1I01BX002494; Department of Defense grant W81XWH-15-1-0558, W81XWH-18-1-0618 and W81XWH-19-1-0720 to SG.

[cesces]

The link didn't work. Here is the link that I found that worked.

Abstract

INTRODUCTION AND OBJECTIVE:

Androgen deprivation therapy (ADT) is the prevalent first line therapy against advanced prostate cancer as an adjuvant for locally treating the high-risk disease. Malignant cells initially respond to ADT, but subsequently colonize and re-emerge as more aggressive phenotype known as castration resistant prostate cancer (CRPC). The second generation androgen receptor (AR) antagonist enzalutamide (ENZU) exhibits survival advantage in CRPC patients, however ∼30% of patients develop resistance overtime activating AR in these tumors. These resistant tumors poorly respond to chemotherapy and acquire resistance partly due to enhanced aerobic glycolysis and biomass production known as the Warburg effect. Therefore, identification of an effective low-cost therapeutic alternative with fewer side effects may lead to increased survival and greatly benefit patient quality-of-life. Drug repurposing has emerged as a new option for overcoming resistance to chemotherapy. Previous studies from our laboratory (Mol Cancer Ther. 13:2288-302, 2014) has demonstrated that synergistic combination of simvastatin (SIM), a drug for the treatment of hypercholesterolemia and metformin (MET), a glucose lowering drug inhibits CRPC growth, invasiveness and migration potential with minimal effect on normal prostate epithelial cells. Here we investigate whether combination of SIM and MET could be effective in the treatment of ENZU-resistant prostate cancer cells.

Https://auajournals.org/doi/abs/10....

[dhccpa]

Think it'll ever see the light of day?

[Graham49 in reply to dhccpa]

In a way its already here as part of the COC protocol. The COC prostate cancer protocol consists of Metformin, Atorvastatin (similar to Simvastatin), Mebendazole (a repurposed drug for parasitic infections) and doxycycline (a repurposed mild antibiotic with anti inflammatory properties).

There is evidence for the anti cancer properties of these drugs but clinical trials are a bit lacking. They are relatively cheap approved drugs and there is no way that a drug company would pay mega bucks for clinical trials.

[dhccpa in reply to Graham49]

Yes i am familiar with COC. I wonder if they are having any luck convincing mainstream doctors of the usefulness of their work. I haven't run into a doctor yet who has heard of them.

[Graham49 in reply to dhccpa]

I doubt that COC are particularly interested in convincing mainstream doctors of the usefulness of their work. If mainstream doctors adopted their protocol, they would be out of a job. I guess some integrative doctors might already use it plus other drugs.

[MateoBeach]

That is really cool!

[curious-mind1]

I remember Dr. Charles Myers advised my dad to take SIM + MET for these very general reasons (this was back in 2015, but I always admired Myers' intense effort to think deeply about re-purposing existing drugs).