A novel combination of withaferin A and sorafenib shows synergistic efficacy against both papillary and anaplastic thyroid cancers

摘要: Abstract Background Sorafenib (SO), a multikinase-targeted inhibitor in clinical trials for papillary and anaplastic cancers, shows limited efficacy with moderate toxicity. Withaferin A (WA), natural withanolide, potent preclinical anticancer activity thyroid cancers through multiple cytotoxic mechanisms including heat-shock protein inhibition. We hypothesized that combination therapy (WA + SO) would have synergistic effect against carcinoma cells at lower sorafenib doses. Methods Human (BCPAP) (SW1736) cancer cell lines were evaluated after treatment SO, WA, or their different Proliferation was measured by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium trypan blue exclusion; apoptosis cell-cycle arrest flow cytometry. Western analysis confirmed (Poly ADP ribose polymerase [PARP] caspase-3 cleavage) Raf Experiments repeated triplicate statistically significance set P value of less than .05. Results The concentration drug which 50% the are inhibited (IC 50 ) BCPAP 6.3 μmol/L .155 .055 WA IC SO), whereas SW1736 7.6 2.5 1.4 SO). Combination decreased viability to 19% (from individually). Apoptosis levels on cytometry increased significantly from 0% 2% (SO alone) 89% (combo , levels. Cell-cycle modulation significant (35% increase G2 SO 70% 75% WA; Conclusions withaferin showed vitro induction apoptosis. This achieved overall doses sorafenib, indicating potential strategy decrease toxicity future translational studies.