RESEARCH ARTICLE A Novel Microtubule-Disrupting Agent Induces Endoplasmic Reticular Stress-

Here, we present evidence of a novel microtubule-disrupting agent, N-deacetyl-N-(chro-mone-2-carbonyl)-thiocolchicine (TCD), exhibiting potent antitumor activity (with IC50 val-ues in the nanomolar range) against hepatocellular carcinoma cell lines. Cell cycle analysis revealed that TCD induced G2/M cell-cycle arrest in a dose- and time-dependent manner in both Hep-J5 and Mahlavu HCC cell lines. TCD also induced a decrease in mitochondrial membrane potential (ΔΨm) and caused DNA damage. Mechanistically, TCD activated pro-tein kinase RNA-like endoplasmic reticular kinase and several transcription factors, includ-ing activating transcription factor (ATF) 6, ATF4, ATF3, and the CCAAT-enhancer binding protein homologous protein. These data clearly demonstrate that the antitumor activity of TCD is mechanistically linked to its capacity to trigger both intrinsic and extrinsic apoptotic cell death via endoplasmic reticular stress pathway. The potent antitumor activity of TCD was similarly demonstrated in a hepatocellular carcinoma xenograft model, where 5 and 10 mg/kg doses of TCD significantly arrested Hep-J5 and Mahlavu tumor growth. Our find-ing suggests that TCD is a promising therapeutic agent against hepatocellular carcinoma; further translational assessment of its clinical usage is warranted