Flavonoid-induced glutathione depletion: Potential implications for cancer treatment

Abstract

The ability of a number of flavonoids to induce glutathione (GSH) depletion was measured in lung (A549), myeloid (HL-60), and prostate (PC-3) human tumor cells. The hydroxychalcone (2′-HC) and the dihydroxychalcones (2′,2-, 2′,3-, 2′,4-, and 2′,5′-DHC) were the most effective in A549 and HL-60 cells, depleting more than 50% of intracellular GSH within 4 h of exposure at 25 µM. In contrast, the flavones chrysin and apigenin were the most effective in PC-3 cells, depleting 50-70% of intracellular GSH within 24 h of exposure at 25 µM. In general, these flavonoids were more effective than three classical substrates of multidrug resistance protein 1 (MK-571, indomethacin, and verapamil). Prototypic flavonoids (2′,5′-DHC and chrysin) were subsequently tested for their abilities to potentiate the toxicities of prooxidants (etoposide, rotenone, 2-methoxyestradiol, and curcumin). In A549 cells, 2′,5′-DHC potentiated the cytotoxicities of rotenone, 2-methoxyestradiol, and curcumin, but not etoposide. In HL-60 and PC-3 cells, chrysin potentiated the cytotoxicity of curcumin, cytotoxicity that was attenuated by the catalytic antioxidant manganese(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP). Assessments of mitochondrial GSH levels mitochondrial membrane potential and cytochrome c release showed that the potentiation effects induced by 2′,5′-DHC and chrysin involve mitochondrial dysfunction.

Cytocidal Effects of Polyphenolic Compounds, Alone or in Combination with, Anticancer Drugs Against Cancer Cells: Potential Future Application of the Combinatory Therapy

“…Moreover, ROS accumulation, inhibition of glutathione reductase, and depletion of GSH were observed in the apoptosis triggered by anthocyanidins in these metastatic colorectal cancer cell lines [23]. These experimental re-sults are in good agreement with previous reports on a possible role of flavonoids, as well as other phytochemicals, in modulating the glutathione (GSH) antioxidant activity, including regulation of intracellular GSH levels through targeting its synthesis, induction of multiple resistant protein 1 mediated GSH efflux, or inhibition of glutathione peroxidase enzyme activity observed in hematopoietic malignant and solid cancer cells in vitro and in vivo [19,24,44]. Furthermore, an in vitro study showed that anthocyanidins inhibit glutathione reductase (GR) in an oxygen-dependent manner, presumably via the effect of superoxide [45].…”

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

“…Glutathione (GSH) depletion as a potential strategy to sensitize cancer cells has been under investigation for over two decades (14)(15)(16)(17)(18)(19)(20)(21)(22). Indeed, GSH and glutathione peroxidase (GPx) play central roles in cellular homeostasis by controlling the levels of ROS, and cancer cells tend to exhibit higher levels of ROS (22,23).…”

“…However, limitations of this strategy include an inherent lack of specificity towards cancer cells and subsequent side effects (21). A potentially more tumor specific approach to deplete GSH is by using substrates of multidrug resistance proteins (MRPs), a family of ATP-binding cassette (ABC) proteins that are known GSH co-transporters and tend to be over-expressed in cancer cells (14)(15)(16)(17)25).…”

“…In the cell, flavonoids can produce modulatory effects through alterations of protein and lipid kinase signaling pathways (27). Moreover, a number of flavonoids may exert direct and indirect prooxidant effects by inhibiting the mitochondrial respiratory chain complexes I and II and by inducing GSH depletion through MRP1 activation (14,(28)(29)(30)(31). Most MRP1 'inhibitors' are MRP1 substrates that are competitive inhibitors of drug efflux and are co-transported with GSH, yet verapamil and some flavonoids can induce GSH depletion without being expelled from the cell (31).…”

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

“…We recently showed that, in three separate cancer cell lines, simple naturally occurring compounds such as chrysin and 2′,5′-dihydroxychalcone (2′,5′-DHC) were more effective than verapamil in depleting cytosolic GSH [73]. 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].…”