Statin and Bisphosphonate Induce Starvation in Fast-Growing Cancer Cell Lines

Abstract

Statins and bisphosphonates are increasingly recognized as anti-cancer drugs, especially because of their cholesterol-lowering properties. However, these drugs act differently on various types of cancers. Thus, the aim of this study was to compare the effects of statins and bisphosphonates on the metabolism (NADP+/NADPH-relation) of highly proliferative tumor cell lines from different origins (PC-3 prostate carcinoma, MDA-MB-231 breast cancer, U-2 OS osteosarcoma) versus cells with a slower proliferation rate like MG-63 osteosarcoma cells. Global gene expression analysis revealed that after 6 days of treatment with pharmacologic doses of the statin simvastatin and of the bisphosphonate ibandronate, simvastatin regulated more than twice as many genes as ibandronate, including many genes associated with cell cycle progression. Upregulation of starvation-markers and a reduction of metabolism and associated NADPH production, an increase in autophagy, and a concomitant downregulation of H3K27 methylation was most significant in the fast-growing cancer cell lines. This study provides possible explanations for clinical observations indicating a higher sensitivity of rapidly proliferating tumors to statins and bisphosphonates.

TNFRSF12A and a new prognostic model identified from methylation combined with expression profiles to predict overall survival in hepatocellular carcinoma

“…At the same time, the enrichment of methylation-driven genes in “Statin pathway”, “Vitamin K metabolism” and “Metabolism” pathways also needs our attention. It has been reported that statins and their analogues can cause changes in the methylation levels of H3K27 and other genes in rapidly proliferating tumor cell lines ( 14 ). Vitamin K as a powerful redox-system, forms a bypass between mitochondrial complexes II and III, restores oxidative phosphorylation and aerobic glycolysis and it eliminates the hypoxic environment of cancer cells and induces cell death ( 15 ).…”

Biological effects of aromatic bis[aminomethylidenebis(phosphonic)] acids in osteoclast precursors in vitro

“…This was demonstrated in both normal and cancer cells (Iguchi et al, ; Mansouri, Mirzaei, Lage, Mousavi, & Elahian, ; Okamoto et al, ; Zhao et al, ). On contrary, it has been also demonstrated that treatment with ibandronate leads to increased cell cycle arrest in S phase in U‐2 osteosarcoma cells and in G2/M phase in MG‐63 osteoblast‐like cells (Karlic et al, ). In addition, Merrel et al showed that treatment with zoledronate increased the percentage of MDA‐MB‐231 cells in G1 phase (Merrell, Wakchoure, Lehenkari, Harris, & Selander, ).…”

Simvastatin Therapy for Drug Repositioning to Reduce the Risk of Prostate Cancer Mortality in Patients With Hyperlipidemia

“…It has been demonstrated that simvastatin inhibits the proliferation, migration, and invasion of PCa cells via the up-regulation of ANXA10 and inactivation of the AKT/PI3K pathway ( Miyazawa et al, 2017 ). Simvastatin can arrest the cell cycle at G1 in PC-3 cells through the AMPK pathway ( Karlic et al, 2017 ). In addition, lovastatin was found to enhance the efficacy of PRRA-TRAIL via the promotion of tumor suppression and induction of apoptosis ( Liu et al, 2015 ).…”