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Patients with advanced urothelial carcinoma (UC) generally have poor prognoses due to therapeutic resistance. Furthermore, there are limited treatment options for advanced UC. Therefore, novel or effective chemotherapeutic agents are needed to improve patient survival. The present study was conducted to investigate the effect of temozolomide (TMZ) on UC cells so as to identify a potential method to overcome therapeutic resistance. TMZ is an alkylating agent with a target different from that of other anticancer drugs used to treat UC, such as cisplatin. TMZ enhanced the autophagic response and senescence, which was mediated via the p53 and p21 pathways. Inhibiting the autophagic response using chloroquine synergistically augmented the cytotoxic effect of TMZ on UC cells. TMZ significantly reduced the invasiveness of UC cells. Notably, the abundance of side population fraction was also significantly reduced following TMZ treatment. Considering that side population fraction is known to confer therapeutic resistance, it is noteworthy that the TMZ treatment markedly decreased side population fraction. Altogether, TMZ may have the potential to be applied as a part of an alternative treatment strategy to reduce the malignancy of UC cells. [ABSTRACT FROM AUTHOR]

Tumor hypoxia is known to promote the acquisition of more aggressive phenotypes in human transitional cell carcinoma (TCC), including drug resistance. Accumulating evidence suggests that mitochondria play a central role in the chemoresistance of TCC. However, the role of mitochondria in the hypoxia-induced drug resistance in TCC remains elusive. The present study investigated the function of mitochondria in the drug resistance using a TCC cell line under hypoxic conditions. In vitro hypoxia (0.1% O 2 , 48 h) was achieved by incubating TCC cells in air chamber. Mitochondrial events involving hypoxia-induced drug resistance were assessed. Hypoxia significantly reduced the cisplatin-induced apoptosis of TCC cells. Additionally, hypoxia substantially decreased the level of mitochondrial reactive oxygen species (ROS) generated by cisplatin treatment. Analogously, elimination of mitochondrial ROS significantly rescued cells from cisplatin-induced apoptosis. Hypoxia enhanced mitochondrial hyperpolarization, which was not related to ATP production or the reversal of ATP synthase activity. The mitochondrial DNA (mtDNA) amplification efficiency data illustrated that hypoxia significantly prevented oxidative damage to the mitogenome. Moreover, transmission electron microscopy revealed that cisplatin-induced disruption of the mitochondrial ultrastructure was abated under hypoxic conditions. Notably, depletion of mtDNA by ethidium bromide abrogated hypoxia-induced resistance to cisplatin. Taken together, the present study demonstrated that TCC cells exposed to hypoxic conditions rendered mitochondria less sensitive to oxidative stress induced by cisplatin treatment, leading to enhanced drug resistance. [ABSTRACT FROM AUTHOR]