title: Synergistic growth inhibition of PC3 prostate cancer cells with low-dose combinations of simvastatin and alendronate.
abstract: The mevalonate pathway plays an important role in cancer biology and has been targeted with farnesyl transferase inhibitors, although their efficacy is limited due to significant adverse effects. Statins and bisphosphonates inhibit the mevalonate pathway at different steps, thus having negative effects at various levels on cancer cells. A combination of these drugs may result in an amplified cytotoxic effect and allow for use of significantly lower doses of the drugs involved. Statins inhibit the mevalonate pathway at 3-hydroxy-3-methylglutaryl coenzyme A reductase and bisphosphonates at farnesyl pyrophosphate synthase. Our results show that low-dose combinations of simvastatin and alendronate have a synergistic cytotoxic effect on androgen-independent prostate cancer PC-3 cells, but not on androgen-dependent LNCaP or DU 145 prostate cancer cells. These two drugs cause a sequential blockade of the mevalonate pathway and significantly affect survival and apoptotic pathways by down-regulating phospho-AKT and activating c-JUN and ERK.
authors: Division of Hematology-Oncology, Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, U.S.A.
authors: Mailien
authors: M
authors: Rogers
authors: Division of Cardiology, Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, U.S.A.
authors: Sumit
authors: S
authors: Kalra
authors: Division of Hematology-Oncology, Department of Medicine, The University of Vermont, Burlington, VT, U.S.A.
authors: Julia
authors: J
authors: Moukharskaya
authors: Division of Hematology-Oncology, Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, U.S.A.
authors: Kanishka
authors: K
authors: Chakraborty
authors: Department of Radiation Oncology Ludwig-Maximilians University, Munich, Germany.
authors: Maximilian
authors: M
authors: Niyazi
authors: Division of Hematology-Oncology, Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, U.S.A.
authors: Koyamangalath
authors: K
authors: Krishnan
authors: Division of Hematology-Oncology, Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, U.S.A.
authors: Janet
authors: J
authors: Lightner
authors: Department of Pediatrics, James H Quillen College of Medicine, East Tennessee State University, Johnson City, TN, U.S.A.
authors: Marianne
authors: M
authors: Brannon
authors: Department of Pediatrics, James H Quillen College of Medicine, East Tennessee State University, Johnson City, TN, U.S.A.
authors: William L
authors: WL
authors: Stone
authors: Division of Hematology-Oncology, Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, U.S.A. Department of Pharmaceutical Sciences, Bill Gatton College of Pharmacy, East Tennessee State University, Johnson City, TN, U.S.A. palauv@mail.etsu.edu.
authors: Victoria E
authors: VE
authors: Palau
mesh_terms: D019386:Alendronate / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D019821:Simvastatin / Q000008:administration & dosage*
chemical_list: D019821:Simvastatin; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D019386:Alendronate
keywords: Synergy; alendronate; prostate cancer; simvastatin