Potentiation of chemotherapeutic drugs by energy metabolism inhibitors 2-deoxyglucose and etomoxir.
Inhibition of energy production as a strategy for potentiation of anticancer chemotherapy was investigated using 1 glycolysis inhibitor and 1 fatty acid beta-oxidation inhibitor-2-deoxyglucose and etomoxir, respectively, both known to be clinically well tolerated. Eighteen anticancer drugs were screened for potentiation by these inhibitors. 2-deoxyglucose potentiated acute apoptosis (24 hr) induced mainly by some, but not all, genotoxic drugs, whereas etomoxir had effect only on cisplatin. By contrast, etomoxir did potentiate the overall, 48 hr effects of some genotoxic drugs, and was in addition more efficient than deoxyglucose in potentiating the overall effects of several non-genotoxic drugs. Both types of potentiation were largely lost in the absence of p53. Because cisplatin was potentiated by both energy inhibitors in both types of assay, it was investigated at additional concentrations and over longer time. Both energy inhibitors strongly potentiated non-apoptotic concentrations of cisplatin in p53-wildtype as well as in p53-deficient, cisplatin-resistant HCT-116 colon carcinoma cells. Reduced ATP levels correlated with, but were not sole determinants, the antiproliferative effects. We conclude that the long-term effects of cisplatin potentiation are important and either p53-independent or improved by a lack of p53. We also conclude that although the potentiated drugs as yet have no obvious mechanistic factor in common, the strategy holds promise with genotoxic as well non-genotoxic anticancer drugs.
Hernlund
Emma
E
Department of Oncology-Pathology, Karolinska Institute, S-171 76 Stockholm, Sweden.
Ihrlund
Linda Strandberg
LS
Department of Oncology-Pathology, Karolinska Institute, S-171 76 Stockholm, Sweden.
Khan
Omar
O
Department of Oncology-Pathology, Karolinska Institute, S-171 76 Stockholm, Sweden.|Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
Ates
Yildiz Ozlem
YO
Department of Oncology-Pathology, Karolinska Institute, S-171 76 Stockholm, Sweden.|Faculty of Engineering and Natural Sciences, Sabanci University, Tuzla, Istanbul, Turkey.
Linder
Stig
S
Department of Oncology-Pathology, Karolinska Institute, S-171 76 Stockholm, Sweden.
Panaretakis
Theocharis
T
Department of Oncology-Pathology, Karolinska Institute, S-171 76 Stockholm, Sweden.|Institut Gustave Roussy, 39 rue Camille Desmoulins, Villejuif, France.
Shoshan
Maria C
MC
Department of Oncology-Pathology, Karolinska Institute, S-171 76 Stockholm, Sweden.
D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000188:drug therapy*; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy*; D003847:Deoxyglucose / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004734:Energy Metabolism / Q000187:drug effects*; D004852:Epoxy Compounds / Q000494:pharmacology*; D045325:HCT116 Cells; D006801:Humans; D010084:Oxidation-Reduction / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors
D000970:Antineoplastic Agents; D004852:Epoxy Compounds; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; C054207:etomoxir; D002945:Cisplatin