Selected flavonoids potentiate the toxicity of cisplatin in human lung adenocarcinoma cells: a role for glutathione depletion.
Adjuvant therapies that enhance the anti-tumor effects of cis-diammineplatinum(II) dichloride (cisplatin, CDDP) are actively being pursued. Growing evidence supports the involvement of mitochondrial dysfunction in the anti-cancer effect of cisplatin. We examined the potential of using selective flavonoids that are effective in depleting tumor cells of glutathione (GSH) to potentiate cisplatin-mediated cytotoxicity in human lung adenocarcinoma (A549) cells. We found that cisplatin (40 microM, 48-h treatment) disrupts the steady-state levels of mitochondrial respiratory complex I, which correlates with elevated mitochondrial reactive oxygen species (ROS) production and cytochrome c release. The flavonoids, 2',5'-dihydroxychalcone (2',5'-DHC, 20 microM) and chrysin (20 microM) potentiated the cytotoxicity of cisplatin (20 microM), which could be blocked by supplementation of the media with exogenous GSH (500 microM). Both 2',5'-DHC and chrysin were more effective than the specific inhibitor of GSH synthesis, L-buthionine sulfoximine (BSO, 20 microM), in inducing GSH depletion and potentiating the cytotoxic effect of cisplatin. These data suggest that the flavonoid-induced potentiation of cisplatin's toxicity is due, in part, to synergetic pro-oxidant effects of cisplatin by inducing mitochondrial dysfunction, and the flavonoids by depleting cellular GSH, an important antioxidant defense.
Kachadourian
Remy
R
Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206, USA.
Leitner
Heather M
HM
Day
Brian J
BJ
D000230:Adenocarcinoma / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D047188:Chalcones / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology*; D004357:Drug Synergism; D042967:Electron Transport Complex I / Q000032:analysis / Q000037:antagonists & inhibitors; D005419:Flavonoids / Q000494:pharmacology*; D005978:Glutathione / Q000172:deficiency / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D017382:Reactive Oxygen Species / Q000378:metabolism
C107497:2',5'-dihydroxychalcone; D000970:Antineoplastic Agents; D047188:Chalcones; D005419:Flavonoids; D017382:Reactive Oxygen Species; C043561:chrysin; D042967:Electron Transport Complex I; D005978:Glutathione; D002945:Cisplatin