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.
Highlights
As previously reported [1], evidence from both in vitro and in vivo data has demonstrated that drugs such as statins and bisphosphonates targeting the mevalonic acid pathway and the synthesis of isoprenoids and cholesterol exert, beyond their lipid-lowering effects, pleiotropic actions, including immune regulation [1,2] and cancer prevention [3,4] as well as epigenetic effects [5]
A quiescence marker resulting from this pioneering study is the downregulation of the downregulation of topoisomerase (DNA) polymerase A1 (POLA1), which we found downregulated in our study (Table 1)
Results of transcriptomic Venn-diagram analyses showing the number of genes that were either regulated with simvastatin or by ibandronate or by both drugs, which is termed as “overlap”
Summary
As previously reported [1], evidence from both in vitro and in vivo data has demonstrated that drugs such as statins and bisphosphonates targeting the mevalonic acid pathway and the synthesis of isoprenoids and cholesterol exert, beyond their lipid-lowering effects, pleiotropic actions, including immune regulation [1,2] and cancer prevention [3,4] as well as epigenetic effects [5]. The anti-tumorigenic effects of statins vary between different types of cancer: the amelioration of breast cancer prognosis was extensively reviewed [10]; survival or recurrence by statin was documented in one study with 146,326 participants [11] and other studies with 75,684 [12] or 124,669 [13] women. There is data available on the beneficial effect of bisphosphonates for the treatment of breast cancer [14]. A statin-associated reduction of mortality has been documented in more than 100,000 cases [16]. The treatment success appears to be influenced by mitochondrial DNA mutations and associated metabolic consequences [17] and non-responders to statin-therapy with persistent high serum cholesterol still have a higher cancer risk [18]
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