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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, H460 TaxR , while exhibiting much less toxic effects on normal human fibroblasts. After five injections of TBPT at a dose of 60 mg/kg, it inhibits H460 TaxR  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 anti-depressant compound scaffold for anticancer applications provides a promising future for conquering drug-resistant tumors with fewer side effects.

From fighting depression to conquering tumors: a novel tricyclic thiazepine compound as a tubulin polymerization inhibitor