Comparative evaluation of the effects of statins on human stem and cancer cells in vitro.
Anticancer effects of statins were studied using karyotypically normal human embryonic stem cells (hESC) (HES3), karyotypically abnormal hESC (BG0IV), embryonal carcinoma (NTERA-2), ovarian (TOV-112D) and colorectal cancer (HT-29) cells. The cells were treated with simvastatin, pravastatin, mevastatin and lovastatin in vitro at different concentrations (1-20 mumol/l) and their effects on cell proliferation, apoptosis and stemness-related gene expression were studied. BG01V, NTERA-2 and TOV-112D contained duplications of chromosome 12 and 17. All four statins did not show any inhibition of HES3 proliferation. However, BG01V, NTERA-2, TOV-112D and HT-29 were inhibited by simvastatin, lovastatin and mevastatin. The inhibitory effects were reversed by farnesylpyrophosphate and geranylgeranylpyrophosphate. TUNEL and cell cycle assay revealed evidence of apoptosis in karyotypically abnormal cancer and stem cell types exposed to simvastatin and lovastatin. In addition, following simvastatin treatment, some of the apoptotic and stemness-related genes showed differential expression for the BG01V, NTERA-2, TOV-112D and HT-29 cells in comparison to HES3. In conclusion, the statins inhibit cell proliferation in karyotypically abnormal stem and cancer cells, probably via an increase in activity of key apoptotic genes and the suppression of stemness-related genes on chromosomes 12 and 17.
Gauthaman
Kalamegam
K
Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, Singapore 119074.
Richards
Mark
M
Wong
John
J
Bongso
Ariff
A
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D053595:Embryonic Stem Cells / Q000187:drug effects*; D005472:Fluorouracil / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008858:Microscopy, Phase-Contrast; D016133:Polymerase Chain Reaction; D013729:Terpenes / Q000494:pharmacology; D013778:Tetrazolium Salts; D013844:Thiazoles
D000964:Antimetabolites, Antineoplastic; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013729:Terpenes; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue; D005472:Fluorouracil