Journal
PLOS ONE
Volume 10, Issue 4, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0122712
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Funding
- Ministry of Science and Technology of the People's Republic of China [2011CB944104]
- National Natural Science Foundation of China [81172009, 81372168]
- Doctoral Fund of Ministry of Education of China [20110091120028]
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Vitamin E intake has been implicated in reduction of bladder cancer risk. However, the mechanisms remain elusive. Here we reported that d-tocotrienol (delta-T3), one of vitamin E isomers, possessed the most potent cytotoxic capacity against human bladder cancer cells, compared with other Vitamin E isomers. delta-T3 inhibited cancer cell proliferation and colonogenicity through induction of G1 phase arrest and apoptosis. Western blotting assay revealed that delta-T3 increased the expression levels of cell cycle inhibitors (p21, p27), proapoptotic protein (Bax) and suppressed expression levels of cell cycle protein (Cyclin D1), anti-apoptotic proteins (Bcl-2, Bcl-xL and Mcl-1), resulting in the Caspase-3 activation and cleavage of PARP. Moreover, the delta-T3 treatment inhibited ETK phosphorylation level and induced SHP-1 expression, which was correlated with downregulation of STAT3 activation. In line with this, delta-T3 reduced the STAT3 protein level in nuclear fraction, as well as its transcription activity. Knockdown of SHP-1 partially reversed delta-T3-induced cell growth arrest. Importantly, low dose of delta-T3 sensitized Gemcitabine-induced cytotoxic effects on human bladder cancer cells. Overall, our findings demonstrated, for the first time, the cytotoxic effects of delta-T3 on bladder cancer cells and suggest that delta-T3 might be a promising chemosensitization reagent for Gemcitabine in bladder cancer treatment.
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