title: Synergistic simvastatin and metformin combination chemotherapy for osseous metastatic castration-resistant prostate cancer.
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 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.
authors.affiliation: Department of Urology, Case Western Reserve University, and The Urology Institute, University Hospitals Case Medical Center, Cleveland, Ohio. Department of Nutrition, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Babcook
authors.affiliation: Department of Urology, Case Western Reserve University, and The Urology Institute, University Hospitals Case Medical Center, Cleveland, Ohio.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Shukla
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Pingfu
authors.initials: P
authors.lastname: Fu
authors.affiliation: Mouse Metabolic Phenotyping Center, Analytical and Metabolic Core, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Edwin J
authors.initials: EJ
authors.lastname: Vazquez
authors.affiliation: Department of Nutrition, Case Western Reserve University, Cleveland, Ohio. Mouse Metabolic Phenotyping Center, Analytical and Metabolic Core, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Puchowicz
authors.affiliation: Imaging Research Core Facility, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Molter
authors.affiliation: Department of Biology, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Christine Z
authors.initials: CZ
authors.lastname: Oak
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Gregory T
authors.initials: GT
authors.lastname: MacLennan
authors.affiliation: Imaging Research Core Facility, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Chris A
authors.initials: CA
authors.lastname: Flask
authors.affiliation: Department of Cancer Biology, Cleveland Clinic Foundation, Cleveland, Ohio.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Lindner
authors.affiliation: Department of Cancer Biology, Cleveland Clinic Foundation, Cleveland, Ohio.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Parker
authors.affiliation: Department of Urology, Case Western Reserve University, and The Urology Institute, University Hospitals Case Medical Center, Cleveland, Ohio.
authors.forename: Firouz
authors.initials: F
authors.lastname: Daneshgari
authors.affiliation: Department of Urology, Case Western Reserve University, and The Urology Institute, University Hospitals Case Medical Center, Cleveland, Ohio. Department of Nutrition, Case Western Reserve University, Cleveland, Ohio. Division of General Medical Sciences, Case Comprehensive Cancer Center, Cleveland, Ohio. sanjay.gupta@case.edu.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Gupta
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D002465:Cell Movement / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D009362:Neoplasm Metastasis; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000473:pathology; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000924:Anticholesteremic Agents; D007004:Hypoglycemic Agents; D008687:Metformin; D019821:Simvastatin