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Publication
Synergistic simvastatin and metformin combination chemotherapy for osseous
metastatic castration-resistant prostate cancer.
Authors Babcook MA, Shukla S, Fu P, Vazquez EJ, Puchowicz MA, Molter JP, Oak CZ,
MacLennan GT, Flask CA, Lindner DJ, Parker Y, Daneshgari F, Gupta S
Submitted By Submitted Externally on 7/24/2015
Status Published
Journal Molecular cancer therapeutics
Year 2014
Date Published 10/1/2014
Volume : Pages 13 : 2288 - 2302
PubMed Reference 25122066
Abstract 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 AMPKa Ser-485/491 phosphorylation; increased
Thr-172 phosphorylation and AMPKa 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.




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