Kachadourian R, Leitner HM, Day BJSelected flavonoids potentiate the toxicity of cisplatin in human lung adenocarcinoma cells: a role for glutathione depletion. Int J Oncol 31: 161-168

Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206, USA.
International Journal of Oncology (Impact Factor: 3.03). 08/2007; 31(1):161-8. DOI: 10.3892/ijo.31.1.161
Source: PubMed


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.

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    • "Chrysin potentiates cisplatin cytotoxicity, in part, via synergizing pro-oxidant effects of cisplatin by inducing mitochondrial dysfunction, and by depleting cellular GSH, an important antioxidant defense. Chrysin is an effective inducer of GSH depletion and potentiate the toxicity of known prooxidants such as 2- methoxyestradiol, rotenone, and curcumin through mitochondrial dysfunction in PC-3 and HL-60 cells [7]. Moreover, it is exciting to note that chrysin has been reported to show selective cytotoxicity against cancer over non-cancer cell lines. "
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    ABSTRACT: This letter illustrates the significant chemosensitizing effects of chrysin to resistance cancer cells and refers to the article on "Combination of chrysin and cisplatin promotes the apoptosis of Hep G2 cells by up-regulating p53" by Li et al., published in your journal recently. Recent studies have demonstrated that chrysin is able to sensitize or kill cancer cells which are resistant to chemotherapeutic drugs such as cisplatin, doxorubicin and adriamycin. Owing to its potential anti-cancer effects and devoid of toxicity to non-transformed cells, further research is required to completely explore its chemosensitizing effects in other cancers and also assess and evaluate its safety, before going for possible human application. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Full-text · Article · Apr 2015 · Chemico-biological interactions
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    • "This may be attributable to Asian diets that are rich in flavonoid-containing plants, which are thought to be anti-tumorigenic. Chrysin (5,7-dihydroxyflavone, ChR), a natural flavonoid present in daily diets, possesses the ability to inhibit growth and induce apoptosis in a variety of cancer cells, including cervical cancer (3), leukemia (4,5), colon carcinoma (6), esophageal adenocarcinoma (7) and lung adenocarcinoma (8). Poor oral bioavailability has been a major limitation for the successful use of dietary flavonoids as cancer chemotherapeutic agents (9,10). "
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    ABSTRACT: We previously demonstrated that 5,7-dihydroxy-8-nitrochrysin (NOC), a novel synthetic chrysin analog, preferentially inhibits HER-2/neu-overexpressing MDA-MB-453 breast cancer cell growth by inducing apoptosis; however, the precise molecular mechanism was unclear. In this study, we demonstrated that NOC significantly induces apoptosis of MDA-MB-453 cells and that this is primarily mediated through a mitochondrial death cascade. This was presented as a loss of mitochondrial membrane potential, release of cytochrome c and activation of caspase-9. NOC induces a significant increase in levels of the BH3-only protein Bim. Small interfering RNA-mediated knockdown of Bim markedly attenuated NOC-induced apoptosis. An upstream transcriptional regulator of Bim, forkhead box O3a transcription factor (FOXO3a), experienced a decrease in phosphorylation and nuclear translocation. Silencing of FOXO3a resulted in a marked attenuation in the expression of Bim, as well as protection against NOC-mediated apoptosis. Furthermore, NOC-induced activation and nuclear localization of FOXO3a was associated with reduced levels of Akt phosphorylation. These results suggest that NOC induces apoptosis in MDA-MB-453 human breast cancer cells via caspase activation and modulation of the Akt/FOXO3a pathway.
    Full-text · Article · Mar 2013 · Oncology letters
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    • "Some studies have shown that the pro-oxidant activity of some flavonoids potentiate the antitumor activity of cisplatin. The flavonoids, 2 0 ,5 0 dihydroxychalcone (2 0 ,5 0 -DHC, 20 lM), and chrysin (20 lM) potentiated the cytotoxicity of cisplatin in human lung adenocarcinoma (A549) cells and the mechanism of action was attributed to GSH depletion (Kachadourian et al. 2007). Cytotoxicity of quercetin in human leukemia cells HL-60 has been attributed to its pro-oxidant action (Sergediene et al. 1999). "
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    ABSTRACT: Cisplatin is a highly effective antitumor agent whose clinical application is limited by the inherent nephrotoxicity. The current measures of nephroprotection used in patients receiving cisplatin are not satisfactory, and studies have focused on the investigation of new possible protective strategies. Many pathways involved in cisplatin nephrotoxicity have been delineated and proposed as targets for nephroprotection, and many new potentially protective agents have been reported. The multiple pathways which lead to renal damage and renal cell death have points of convergence and share some common modulators. The most frequent event among all the described pathways is the oxidative stress that acts as both a trigger and a result. The most exploited pathways, the proposed protective strategies, the achievements obtained so far as well as conflicting data are summarized and discussed in this review, providing a general view of the knowledge accumulated with past and recent research on this subject.
    Full-text · Article · Mar 2012 · Archives of Toxicology
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