Synergistic simvastatin and metformin combination chemotherapy for osseous metastatic castration-resistant prostate cancer

Melissa A. Babcook, Sanjeev Shukla, Pingfu Fu, Edwin J. Vazquez, Michelle Puchowicz, Joseph P. Molter, Christine Z. Oak, Gregory T. MacLennan, Chris A. Flask, Daniel J. Lindner, Yvonne Parker, Firouz Daneshgari, Sanjay Gupta

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Abstract

Docetaxel chemotherapyremains a standardof care formetastatic castration-resistant prostate cancer (CRPC). Docetaxelmodestly 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.

Original languageEnglish (US)
Pages (from-to)2288-2302
Number of pages15
JournalMolecular Cancer Therapeutics
Volume13
Issue number10
DOIs
StatePublished - Aug 13 2014

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Simvastatin
Metformin
Castration
Combination Drug Therapy
docetaxel
Prostatic Neoplasms
Phosphorylation
Adenosine Monophosphate
Protein Kinases
Oxidoreductases
Body Weight
Prostate
Neoplasm Metastasis
Acetyl-CoA Carboxylase
Cachexia
Osteogenesis
Cell Survival
Epithelial Cells
Cholesterol
Drug Therapy

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Synergistic simvastatin and metformin combination chemotherapy for osseous metastatic castration-resistant prostate cancer. / Babcook, Melissa A.; Shukla, Sanjeev; Fu, Pingfu; Vazquez, Edwin J.; Puchowicz, Michelle; Molter, Joseph P.; Oak, Christine Z.; MacLennan, Gregory T.; Flask, Chris A.; Lindner, Daniel J.; Parker, Yvonne; Daneshgari, Firouz; Gupta, Sanjay.

In: Molecular Cancer Therapeutics, Vol. 13, No. 10, 13.08.2014, p. 2288-2302.

Research output: Contribution to journalArticle

Babcook, MA, Shukla, S, Fu, P, Vazquez, EJ, Puchowicz, M, Molter, JP, Oak, CZ, MacLennan, GT, Flask, CA, Lindner, DJ, Parker, Y, Daneshgari, F & Gupta, S 2014, 'Synergistic simvastatin and metformin combination chemotherapy for osseous metastatic castration-resistant prostate cancer', Molecular Cancer Therapeutics, vol. 13, no. 10, pp. 2288-2302. https://doi.org/10.1158/1535-7163.MCT-14-0451
Babcook, Melissa A. ; Shukla, Sanjeev ; Fu, Pingfu ; Vazquez, Edwin J. ; Puchowicz, Michelle ; Molter, Joseph P. ; Oak, Christine Z. ; MacLennan, Gregory T. ; Flask, Chris A. ; Lindner, Daniel J. ; Parker, Yvonne ; Daneshgari, Firouz ; Gupta, Sanjay. / Synergistic simvastatin and metformin combination chemotherapy for osseous metastatic castration-resistant prostate cancer. In: Molecular Cancer Therapeutics. 2014 ; Vol. 13, No. 10. pp. 2288-2302.
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