Docetaxel chemotherapy remains a standard of care for metastatic
castration-resistant
prostate cancer (CRPC).
Docetaxel modestly increases survival, yet results in frequent occurrence of side effects and resistant disease. An alternate
chemotherapy with greater efficacy and minimal side effects is needed. Acquisition of metabolic aberrations promoting increased survival and
metastasis in CRPC cells includes constitutive activation of Akt, loss of
adenosine monophosphate-activated
protein kinase (AMPK) activity due to Ser-485/491 phosphorylation, and overexpression of
3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMG-CoAR). We report that combination of
simvastatin and
metformin, within pharmacologic dose range (500 nmol/L to 4 μmol/L
simvastatin and 250 μmol/L to 2 mmol/L
metformin), significantly and synergistically reduces C4-2B3/B4 CRPC cell viability and metastatic properties, with minimal adverse effects on normal prostate epithelial cells. Combination of
simvastatin and
metformin decreased Akt Ser-473 and Thr-308 phosphorylation and AMPKα Ser-485/491 phosphorylation; increased Thr-172 phosphorylation and AMPKα activity, as assessed by increased Ser-79 and Ser-872 phosphorylation of
acetyl-CoA carboxylase and HMG-CoAR, respectively; decreased HMG-CoAR activity; and reduced total cellular
cholesterol and its synthesis in both cell lines. Studies of C4-2B4 orthotopic NCr-nu/nu mice further demonstrated that combination of
simvastatin and
metformin (3.5-7.0 μg/g
body weight simvastatin and 175-350 μg/g
body weight metformin) daily by oral gavage over a 9-week period significantly inhibited primary ventral prostate
tumor formation,
cachexia, bone
metastasis, and biochemical failure more effectively than 24 μg/g
body weight docetaxel intraperitoneally injected every 3 weeks, 7.0 μg/g/day
simvastatin, or 350 μg/g/day
metformin treatment alone, with significantly less toxicity and mortality than
docetaxel, establishing combination of
simvastatin and
metformin as a promising chemotherapeutic alternative for metastatic CRPC.