title: Mevalonate pathway inhibitors affect anticancer drug-induced cell death and DNA damage response of human sarcoma cells.
abstract: Lovastatin (Lov), bisphosphonates (BP) and metformin (Met) are widely used drugs, having in common that they interfere with the mevalonate pathway (MP). The MP generates isoprene moieties required for the function of regulatory GTPases controlling cell proliferation and survival. Here, we addressed the question whether MP inhibitors interfere with the anti-tumor efficacy of anticancer drugs. We comparatively analyzed the effect of equitoxic doses of Lov, BP and Met on cell viability, cell cycle progression, apoptosis and DNA damage response (DDR) of human osteo- and fibrosarcoma cells exposed to doxorubicin or cisplatin. We found that Lov, BP and Met modulated the anticancer drug sensitivity of sarcoma cells in an agent-, dose and time-dependent fashion. Mostly, the MP inhibitors increased the cytotoxicity of the anticancer drugs in an additive manner. MP modulators differed from each other regarding their impact on anticancer drug-induced DNA damage response as measured by the phosphorylation status of SAPK/JNK, Chk-1 and H2AX as well as p53 protein level. In this regard, lovastatin and metformin turned out as the most effective inhibitory drugs. The data show that MP inhibitors can affect the anti-tumor efficacy of anticancer drugs and impact the DDR of human sarcoma cells.
authors.affiliation: Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Nilsson
authors.forename: J
authors.initials: J
authors.lastname: Huelsenbeck
authors.forename: G
authors.initials: G
authors.lastname: Fritz
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects*; D004164:Diphosphonates / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D008148:Lovastatin / Q000494:pharmacology; D008687:Metformin / Q000494:pharmacology; D008798:Mevalonic Acid / Q000037:antagonists & inhibitors*; D012516:Osteosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D008687:Metformin; D008148:Lovastatin; D002945:Cisplatin; D008798:Mevalonic Acid