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• W2058388635 abstract "Therapeutically induced autophagic cell death has been proven to be effective in cases of solid tumors. The dual phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor NVP-BEZ235 possesses antitumor activity against solid tumors. Inhibition of mTOR has been shown to elicit autophagy. In this study, we examined the antiproliferation and autophagic activities of NVP-BEZ235 in parental and cisplatin-resistant urothelial carcinoma (UC) cells. Two UC cell lines, NTUB1 and a cisplatin-resistant subline N/P(14), were applied to examine the cytotoxic effect of NVP-BEZ-235. The cell death mechanism was also evaluated. NVP-BEZ235 was effective in inhibiting the growth of UC cells including parental and cisplatin-resistant cells on flow cytometry assay and Western blot. Although NVP-BEZ235 did not induce LC3-II conversion, it did elicit acidic vesicular organelle (AVO) development on flow cytometry. On Western blot, NVP-BEZ235 decreased p62 and phospho-Rb expressions in a concentration-dependent manner. GFP-LC3 conversion and the appearance of cleaved-GFP following NVP-BEZ235 treatment were demonstrated on Western blot. In addition, lysosomotropic inhibition of autophagy by chloroquine (CQ), an agent that is currently in clinical use and a known antagonist of autophagy, resulted in proliferation of UC cells. Thus, inhibition of autophagic flux by CQ appears to be a survival mechanism that counteracts the anticancer effects of NVP-BEZ235. We demonstrated that NVP-BEZ235 inhibits UC cell proliferation by activating autophagic flux and cell cycle arrest, but does not induce apoptotic cell death. Our findings suggest that the anticancer efficacy of NVP-BEZ235 is due to autophagic flux and co-treatment with CQ counteracts the cytotoxic effect." @default.
• W2058388635 created "2016-06-24" @default.
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• W2058388635 date "2013-07-01" @default.
• W2058388635 modified "2023-10-09" @default.
• W2058388635 title "Dual inhibitor of phosphoinositide 3-kinase/mammalian target of rapamycin NVP-BEZ235 effectively inhibits cisplatin-resistant urothelial cancer cell growth through autophagic flux" @default.
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• W2058388635 doi "https://doi.org/10.1016/j.toxlet.2013.04.021" @default.
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