Lactate dehydrogenase inhibitors sensitize lymphoma cells to cisplatin without enhancing the drug effects on immortalized normal lymphocytes.
Up-regulation of glycolysis, a well recognized hallmark of cancer cells, was also found to be predictive of poor chemotherapy response. This observation suggested the attempt of sensitizing cancer cells to conventional chemotherapeutic agents by inhibiting glucose metabolism. Lactate dehydrogenase (LDH) inhibition can be a way to hinder glycolysis of cancer cells without affecting the metabolism of normal tissues, which usually does not require this enzymatic activity. In this paper, we showed that two LDH inhibitors (oxamate and galloflavin) can increase the efficacy of cisplatin in cultured Burkitt's lymphoma (BL) cells and that this potentiating effect is not exerted in proliferating normal lymphocytes. This result was explained by the finding that in BL cells LDH inhibition induced reactive oxygen species (ROS) generation, which was not evidenced in proliferating normal lymphocytes. In BL cells treated with the association of cisplatin and LDH inhibitors, these ROS can be a further cause of DNA damage, to be added to that produced by cisplatin, leading to the failure of the response repair. At present LDH inhibitors suitable for clinical use are actively searched; our results can allow a better understanding of the potentiality of LDH as a possible target to develop innovative anticancer treatments.
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Italy.
Marcella
M
Manerba
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Italy.
Lorenza
L
Di Ianni
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Italy.
Luigi
L
Fiume
Department of Pharmacy and Biotechnology, University of Bologna, Italy.
Marinella
M
Roberti
Department of Pharmacy and Biotechnology, University of Bologna, Italy.
Maurizio
M
Recanatini
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Italy. Electronic address: giuseppina.distefano@unibo.it.
Giuseppina
G
Di Stefano
D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000009:adverse effects / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D049934:Isocoumarins / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009930:Organic Chemicals / Q000494:pharmacology; D009994:Osmolar Concentration; D017382:Reactive Oxygen Species / Q000819:agonists / Q000378:metabolism
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D049934:Isocoumarins; D009363:Neoplasm Proteins; D009930:Organic Chemicals; D017382:Reactive Oxygen Species; C572336:galloflavin; C048603:oxamate (repellent); D007770:L-Lactate Dehydrogenase; D002945:Cisplatin
Cancer cell metabolism; Cisplatin; Lactate dehydrogenase; Lymphoma cells