Mevalonate pathway inhibitors affect anticancer drug-induced cell death and DNA damage response of human sarcoma cells
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Mevalonate pathway inhibitors affect anticancer drug-induced cell death and DNA damage response of human sarcoma cells. / Nilsson, S; Huelsenbeck, J; Fritz, G.
in: CANCER LETT, Jahrgang 304, Nr. 1, 01.05.2011, S. 60-9.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Mevalonate pathway inhibitors affect anticancer drug-induced cell death and DNA damage response of human sarcoma cells
AU - Nilsson, S
AU - Huelsenbeck, J
AU - Fritz, G
N1 - Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
PY - 2011/5/1
Y1 - 2011/5/1
N2 - 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.
AB - 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.
KW - Antineoplastic Agents/pharmacology
KW - Apoptosis/drug effects
KW - Blotting, Western
KW - Bone Neoplasms/drug therapy
KW - Cell Cycle/drug effects
KW - Cell Proliferation/drug effects
KW - Cisplatin/pharmacology
KW - DNA Damage/drug effects
KW - Diphosphonates/pharmacology
KW - Doxorubicin/pharmacology
KW - Fibrosarcoma/drug therapy
KW - Humans
KW - Lovastatin/pharmacology
KW - Metformin/pharmacology
KW - Mevalonic Acid/antagonists & inhibitors
KW - Osteosarcoma/drug therapy
KW - Phosphorylation/drug effects
KW - RNA, Messenger/genetics
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Signal Transduction/drug effects
KW - Tumor Cells, Cultured
KW - Tumor Suppressor Protein p53/genetics
U2 - 10.1016/j.canlet.2010.12.022
DO - 10.1016/j.canlet.2010.12.022
M3 - SCORING: Journal article
C2 - 21356574
VL - 304
SP - 60
EP - 69
JO - CANCER LETT
JF - CANCER LETT
SN - 0304-3835
IS - 1
ER -