TY - JOUR
T1 - From fighting depression to conquering tumors
T2 - A novel tricyclic thiazepine compound as a tubulin polymerization inhibitor
AU - Mu, Y.
AU - Liu, Y.
AU - Xiang, J.
AU - Zhang, Q.
AU - Zhai, S.
AU - Russo, D. P.
AU - Zhu, H.
AU - Bai, X.
AU - Yan, B.
N1 - Funding Information:
Acknowledgements. This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB14030401) and Natural Science Foundation of Shandong Province (ZR2014BM026 and ZR2013BQ026).
Publisher Copyright:
© 2016, Macmillan Publishers Limited. All rights reserved.
PY - 2016
Y1 - 2016
N2 - A novel tricyclic thiazepine derivative, 6-(p-tolyl)benzo[f] pyrido[2,3-b][1,4] thiazepine 11,11-dioxide (TBPT), exhibits potent inhibitory effects in two non-small-cell lung cancer cell lines, H460 and its drug-resistant variant, H460TaxR, while exhibiting much less toxic effects on normal human fibroblasts. After five injections of TBPT at a dose of 60 mg/kg, it inhibits H460TaxR tumor growth in xenografted mouse models by 66.7% without causing observable toxicity to normal tissues. Based on gene perturbation data and a series of investigations, we reveal that TBPT is not a P-glycoprotein substrate and it inhibits microtubule formation by targeting tubulin, thereby causing cell cycle arrest at the G2/M stage and eventually inducing apoptosis. This redeployment of antidepressant compound scaffold for anticancer applications provides a promising future for conquering drug-resistant tumors with fewer side effects.
AB - A novel tricyclic thiazepine derivative, 6-(p-tolyl)benzo[f] pyrido[2,3-b][1,4] thiazepine 11,11-dioxide (TBPT), exhibits potent inhibitory effects in two non-small-cell lung cancer cell lines, H460 and its drug-resistant variant, H460TaxR, while exhibiting much less toxic effects on normal human fibroblasts. After five injections of TBPT at a dose of 60 mg/kg, it inhibits H460TaxR tumor growth in xenografted mouse models by 66.7% without causing observable toxicity to normal tissues. Based on gene perturbation data and a series of investigations, we reveal that TBPT is not a P-glycoprotein substrate and it inhibits microtubule formation by targeting tubulin, thereby causing cell cycle arrest at the G2/M stage and eventually inducing apoptosis. This redeployment of antidepressant compound scaffold for anticancer applications provides a promising future for conquering drug-resistant tumors with fewer side effects.
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U2 - 10.1038/cddis.2016.53
DO - 10.1038/cddis.2016.53
M3 - Article
C2 - 26986511
AN - SCOPUS:85018879939
SN - 2041-4889
VL - 7
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 3
M1 - e2143
ER -