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In this study, we used porcine aortic endothelial cells (PAECs) as an in vitro system to investigate the role of intracellular GSH status in arsenite-induced vascular endothelial damage. Exposure of PAECs to l-buthionine sulfoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase (gamma-GCS), markedly enhanced the arsenite-induced cytotoxicity. The data implied that intracellular GSH might play an important role in protection of PAECs from arsenite-induced cytotoxicity. Low concentrations of arsenite exposure increased intracellular GSH concentrations, whereas high concentrations of arsenite exposure decreased intracellular GSH concentrations. We further modulated intracellular GSH concentration by using GSH modulators. N-Acetyl cysteine (NAC) and l-cystine (oxidized l-cysteine), by up-regulating intracellular GSH concentrations, were shown to protect PAECs from arsenite-induced cytotoxicity. On the other hand, BSO and monosodium glutamate (MSG), which down-regulated the intracellular GSH concentrations, further potentiated arsenite-induced cytotoxicity. Moreover, exposure of PAECs to NAC alleviated the arsenite-induced JNK/AP-1 activation and apoptosis, whereas exposure of PAECs to BSO enhanced the arsenite-induced JNK/AP-1 activation and apoptosis. These results indicated that an increase in GSH content represented one of the detoxification mechanisms responding to arsenite exposure and probably played critical roles in the regulation of stress-response signaling molecules as well as in protection of PAECs from arsenite attack.

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The development of resistance to platinum drugs in cancer cells severely reduces the efficacy of these drugs. Thus, the discovery of novel drugs or combined strategies to overcome drug resistance is imperative. In addition to our previous finding that combined D-penicillamine with platinum drugs exerts synergistic cytotoxicity, we recently identified a novel therapeutic strategy by combining an iron chelating agent desferal with platinum drugs to overcome platinum resistance in an oxaliplatin-resistant human cervical cancer cell line, S3. Further study demonstrated that the level of platinum–DNA adduct formation positively correlated with cell death in combination of desferal with platinums than that of each drug alone in S3 cells. Decrement of human copper transporter 1 (hCtr1) and transferrin receptor 1 (TfR1) expression involved in the development of platinum resistance in S3 cells. Moreover, desferal promoted the expression of hCtr1 through the upregulation of Sp1. The overexpression of Sp1 increased the expression of NF-κB and translocated it into the nucleus to bind to the TfR1 promoter region, which subsequently increased the expression of TfR1. Importantly, the cotreatment of oxaliplatin with desferal significantly potentiated the oxaliplatin-elicited antitumoral effect in the oxaliplatin-resistant xenograft animal model without any toxic effect observed. Taken together, these results demonstrated that the combination of desferal with oxaliplatin can overcome oxaliplatin resistance through the regulation of hCtr1 and TfR1, and may have beneficial effect for treatment of patient with oxaliplatin-refractory tumors.