Statin derivatives as therapeutic agents for castration-resistant prostate cancer.
Despite recent advances in modern medicine, castration-resistant prostate cancer remains an incurable disease. Subpopulations of prostate cancer cells develop castration-resistance by obtaining the complete steroidogenic ability to synthesize androgens from cholesterol. Statin derivatives, such as simvastatin, inhibit cholesterol biosynthesis and may reduce prostate cancer incidence as well as progression to advanced, metastatic phenotype. In this study, we demonstrate novel simvastatin-related molecules SVA, AM1, and AM2 suppress the tumorigenicity of prostate cancer cell lines including androgen receptor-positive LNCaP C-81 and VCaP as well as androgen receptor-negative PC-3 and DU145. This is achieved through inhibition of cell proliferation, colony formation, and migration as well as induction of S-phase cell-cycle arrest and apoptosis. While the compounds effectively block androgen receptor signaling, their mechanism of inhibition also includes suppression of the AKT pathway, in part, through disruption of the plasma membrane. SVA also possess an added effect on cell growth inhibition when combined with docetaxel. In summary, of the compounds studied, SVA is the most potent inhibitor of prostate cancer cell tumorigenicity, demonstrating its potential as a promising therapeutic agent for castration-resistant prostate cancer.
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
Matthew A
MA
Ingersoll
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
Dannah R
DR
Miller
Department of Biological Sciences, Clark Atlanta University, Atlanta, GA, USA.
October
O
Martinez
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Section of Urology, Department of Surgery, University of Nebraska Medical Center, Omaha, NE, USA.
C Brent
CB
Wakefield
College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
Kuan-Chan
KC
Hsieh
Department of Medical and Applied Chemistry, Kaohsiung Medical University Kaohsiung, Taiwan.
M Vijaya
MV
Simha
Department of Medical and Applied Chemistry, Kaohsiung Medical University Kaohsiung, Taiwan; Department of Chemistry, National Sun Yat-sen University, Taiwan.
Chai-Lin
CL
Kao
Department of Fragrance and Cosmetic Science, Kaohsiung Medical University, Taiwan; Orthopaedic Research Center, Kaohsiung Medical University, Taiwan. Electronic address: htchen@kmu.edu.tw.
Hui-Ting
HT
Chen
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
Surinder K
SK
Batra
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Section of Urology, Department of Surgery, University of Nebraska Medical Center, Omaha, NE, USA; College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA. Electronic address: mlin@unmc.edu.
Ming-Fong
MF
Lin
D000726:Androgen Antagonists / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D009361:Neoplasm Invasiveness; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011944:Receptors, Androgen / Q000187:drug effects* / Q000378:metabolism; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000031:analogs & derivatives / Q000494:pharmacology*; D043823:Taxoids / Q000494:pharmacology
C410798:AR protein, human; D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011944:Receptors, Androgen; D043823:Taxoids; D000077143:Docetaxel; D002784:Cholesterol; D019821:Simvastatin; D051057:Proto-Oncogene Proteins c-akt
AKT; Androgen receptor; Cholesterol; ErbB-2; Simvastatin
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