Selected flavonoids potentiate the toxicity of cisplatin in human lung adenocarcinoma cells: A role for glutathione depletion

  • Authors:
    • Remy Kachadourian
    • Heather M. Leitner
    • Brian J. Day
  • View Affiliations

  • Published online on: Sunday, July 1, 2007
  • Pages: 161-168
  • DOI: 10.3892/ijo.31.1.161

Abstract

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 µM, 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 µM) and chrysin (20 µM) potentiated the cytotoxicity of cisplatin (20 µM), which could be blocked by supplementation of the media with exogenous GSH (500 µM). Both 2',5'-DHC and chrysin were more effective than the specific inhibitor of GSH synthesis, L-buthionine sulfoximine (BSO, 20 µM), 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.
Journal Cover

July 2007
Volume 31 Issue 1

Print ISSN: 1019-6439
Online ISSN:1791-2423

2013 Impact Factor: 2.773
Ranked #30/202 Oncology
(total number of cites)

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APA
Kachadourian, R., Leitner, H., & Day, B. (2007). Selected flavonoids potentiate the toxicity of cisplatin in human lung adenocarcinoma cells: A role for glutathione depletion. International Journal of Oncology, 31(1), 161-168.
MLA
Kachadourian, Leitner, and Brian Day. "Selected flavonoids potentiate the toxicity of cisplatin in human lung adenocarcinoma cells: A role for glutathione depletion." International Journal of Oncology International Journal of Oncology 31.1 (2007): 161-168.
Chicago
Kachadourian, Leitner, and Brian Day. "Selected flavonoids potentiate the toxicity of cisplatin in human lung adenocarcinoma cells: A role for glutathione depletion." International Journal of Oncology International Journal of Oncology 31 no. 1 (2007): 161-168.