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

Abstract

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.

Chrysin overcomes TRAIL resistance of cancer cells through Mcl-1 downregulation by inhibiting STAT3 phosphorylation

“…There is increasing evidence of potential benefits of chrysin as a pharmacological agent. Diverse anticancer effects and mechanisms have been reported for chrysin, including inducing apoptosis by Akt inhibition (11), inducing cell cycle arrest through p38-MAPK activation (12), and enhancing cytotoxicity of chemotherapeutic drugs via cellular glutathione depletion (13,14). Chrysin was shown to sensitize HCT-116 human colorectal cancer cells to TNFα-induced apoptosis, by inhibiting TNFα-induced NF-κB activation and preventing expression of FLIP L anti-apoptotic protein which is an NF-κB target gene (15).…”

Induction of apoptosis by 5,7-dihydroxy-8-nitrochrysin in breast cancer cells: The role of reactive oxygen species and Akt

“…Intracellular ROS mediates multiple cellular responses, including protein kinase activation (37), cell cycle progression (38), myeloid cell differentiation (39,40) and apoptosis (41). It has been documented in several studies that depletion of intracellular GSH plays a critical role in initiating apoptosis by ChR (11,28). In the present study, we first found that the ChR derivative, NOC, promoted the accumulation of ROS products in a concentration-dependent manner in MDA-MB-453 cells (Fig.…”

“…Chrysin (5,7-dihydroxyflavone, ChR), a natural flavonoid present in our daily diet, has recently been shown to be a potent inhibitor of the enzyme aromatase (2). ChR also has anti-inflammatory (3,4), and antioxidant (5) effects, and has been found to possess the ability to inhibit growth and induce apoptosis in a variety of human cancer cells, including cervical cancer (6), leukemia (7,8), colon carcinoma (9), esophageal adenocarcinoma (10) and lung adenocarcinoma cells (11). Nevertheless, poor oral bioavailability has been a major limitation for the successful use of dietary flavonoids as cancer chemotherapeutic agents (12,13).…”

Harnessing drug resistance: Using ABC transporter proteins to target cancer cells

“…One hypothesis is that they interfere directly with the mitochondrial respiratory chain, similar to the proposed mechanism for rotenone. We recently suggested that, by forming mitochondrial DNA adducts, cisplatin might alter the assembly of the mitochondrial respiratory chain, thus leading to an increase of superoxide production [45]. It is also worth noting that one mechanism cancer cells use for adapting to oxidative stress is by elevating their intracellular concentrations of GSH [46].…”

“…In human lung adenocarcinoma (A549) cells, nontoxic concentrations of chrysin and 2′,5′-DHC (10-25 μM) were remarkably effective in both depleting GSH and potentiating the toxicity of rotenone, an agent that interferes directly with mitochondrial respiratory complex I. Chrysin and 2′,5′-DHC also potentiated the toxicity of cisplatin in A549 cells, and more efficiently than BSO [45]. The potentiation effects were blocked by adding exogenous GSH to the culture media, and likely mediated by the mitochondria.…”