Flavonoid-induced glutathione depletion: Potential implications for cancer treatment

Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206, USA.
Free Radical Biology and Medicine (Impact Factor: 5.74). 08/2006; 41(1):65-76. DOI: 10.1016/j.freeradbiomed.2006.03.002
Source: PubMed


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 microM. 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 microM. 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.

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    • "A big advantage of volatile oils shows a very clear antimutagenic capacity which could well be linked to anticarcinogenic activity. Recent studies have demonstrated that the prooxidant activity of volatile oils or some of their constituents as also that of some polyphenols is very efficient in reducing local tumor volume or tumor cell proliferation by apoptotic and/or necrotic effects (Salim and Fukushima 2003; Yoo et al. 2005; Kachadourian and Day 2006). Our result revealed that the gamma-irradiated red chili alone decreased epithelial and goblet cell hyperplasia and preneoplastic changes in the colon and dysplastic changes, oval cell proliferation, and Kupffer cell hyperplasia in the liver. "
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    ABSTRACT: The comparative effect of raw red chili and red chili treated by gamma irradiation or microwave pasteurization with or without 5-fluorouracil on experimentally induced colon cancer in rats was investigated. Dimethylhydrazine was used to induce colon cancer which is histologically similar to and comparable with human neoplasm. Histopathological examination of dimethylhydrazine-treated rats demonstrated epithelial and goblet cell hyperplasia as well as preneoplastic changes of the rat colon expressed by loss of polarity of the nuclei and abnormal mitosis. The preneoplastic changes were developed to adenocarcinoma in 80% of cases. The liver showed different pathological pictures that included dysplastic changes, preneoplastic foci, and oval cell proliferation. We observed that red chili with or without 5-fluorouracil inhibited colon adenocarcinoma. The gamma red chili either alone or with 5-fluorouracil was the best groups. The gamma irradiated red chili alone decreased epithelial and goblet cell hyperplasia and preneoplastic changes in colon and dysplastic changes, oval cell proliferation, and Kupffer cell hyperplasia in the liver. The gamma irradiated red chili with 5-fluorouracil inhibited the preneoplastic changes in colon. It was concluded that the sanitization of red chili by gamma irradiation either alone or with 5-fluorouracil was more beneficial from the human health point of view than that by microwave.
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    • "Cancer cells present elevated GSH levels that generally increase antioxidant capacity and resistance to oxidative stress and regulate different mechanisms linked to carcinogenesis, sensitivity against cytotoxic drugs, ionizing radiation, and some cytokines, DNA synthesis, and cell proliferation (Estrela et al., 2006). There are yet a few reports on the possible role of flavonoids, as well as other phytochemicals, in modulating the glutathione antioxidant system activity, including regulation of GSH intracellular levels through targeting its synthesis (Ramos and Aller, 2008), induction of MRP-1 mediated GSH efflux (Kachadourian and Day, 2006), or inhibition of glutathione peroxidase enzyme activity (Trachootham et al., 2006). Upon grape seed extract treatment, HT29 colon cancer cells showed increased ROS production (that might result in oxidative stress in cells) and a decreased level of intracellular reduced glutathione (Kaur et al., 2011). "

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    • "In addition to their ability to prevent and alter the course of cancer progression, several naturally occurring flavonoids have been shown to protect against the adverse effects of common chemotherapy agents (Psotova et al., 2004; Perez-Tomas, 2006; Klein et al., 2007; O'Connor, 2007; Lee et al., 2008). A wide array of these compounds were screened and were shown capable of inducing significant GSH depletion in a number of cancer cell lines in the interest of using flavonoids as chemotherapy adjuncts (Kachadourian and Day, 2006). The ability of flavonoids to cause GSH efflux/depletion, their anti-tumor effects and their ability to protect against chemotherapy induced toxicities make flavonoids especially interesting in regard to development as agents. "
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    ABSTRACT: We hypothesized that flavonoid-induced glutathione (GSH) efflux through multi-drug resistance proteins (MRPs) and subsequent intracellular GSH depletion is a viable mechanism to sensitize cancer cells to chemotherapies. This concept was demonstrated using chrysin (5-25 μM) induced GSH efflux in human non-small cell lung cancer lines exposed to the chemotherapeutic agent, doxorubicin (DOX). Treatment with chrysin resulted in significant and sustained intracellular GSH depletion and the GSH enzyme network in the four cancer cell types was predictive of the severity of chrysin induced intracellular GSH depletion. Gene expression data indicated a positive correlation between basal MRP1, MRP3 and MRP5 expression and total GSH efflux before and after chrysin exposure. Co-treating the cells for 72 h with chrysin (5-30 μM) and DOX (0.025-3.0 μM) significantly enhanced the sensitivity of the cells to DOX as compared to 72-hour DOX alone treatment in all four cell lines. The maximum decrease in the IC(50) values of cells treated with DOX alone compared to co-treatment with chrysin and DOX was 43% in A549 cells, 47% in H157 and H1975 cells and 78% in H460 cells. Chrysin worked synergistically with DOX to induce cancer cell death. This approach could allow for use of lower concentrations and/or sensitize cancer cells to drugs that are typically resistant to therapy.
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