title: Preclinical study of cinobufagin as a promising anti-colorectal cancer agent.
abstract: Here, we assessed the anti-colorectal cancer (CRC) cell activity of cinobufagin (CBG). We found that CBG exerted potent cytotoxic and anti-proliferative activity against CRC lines (HCT-116 and HT-29) and primary human CRC cells. Meanwhile, it activated apoptosis, and disrupted cell-cycle progression in the cells. At the signaling level, CBG treatment in CRC cells provoked endoplasmic reticulum stress (ER stress), the latter was evidenced by caspase-12 activation, CHOP expression, as well as PERK and IRE1 phosphorylations. Contrarily, the ER stress inhibitor salubrinal, the caspase-12 inhibitor and CHOP shRNA remarkably attenuated CBG-induced CRC cell death and apoptosis. Further, CBG in-activated mammalian target or rapamycin complex 1 (mTORC1), which appeared responsible for proliferation inhibition in CRC cells. Introduction of a constitutively-active S6K1 ("ca-S6K1") restored proliferation of CBG-treated CRC cells. Finally, CBG intraperitoneal injection suppressed HCT-116 xenograft tumor growth in the nude mice. CHOP upregulation and mTORC1 in-activation were also noticed in CBG-treated HCT-116 tumors. The results of this preclinical study suggest that CBG could be tested as promising anti-CRC agent.
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.|Department of General Surgery, Suzhou Municipal Hospital, Suzhou, China.
authors.forename: Xing-Sheng
authors.initials: XS
authors.lastname: Lu
authors.affiliation: Department of Hepatobiliary Surgery, The Third Hospital Affiliated to Soochow University, Changzhou City, Jiangsu, China.
authors.forename: Yin-Biao
authors.initials: YB
authors.lastname: Qiao
authors.affiliation: Institute of Neuroscience, Soochow University, Suzhou, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary Surgery, The Third Hospital Affiliated to Soochow University, Changzhou City, Jiangsu, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
authors.affiliation: Department of Medical Oncology, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, China.
authors.forename: Min-Bin
authors.initials: MB
authors.lastname: Chen
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Chun-Gen
authors.initials: CG
authors.lastname: Xing
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002018:Bufanolides / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002018:Bufanolides; D000076222:Mechanistic Target of Rapamycin Complex 1; C002471:cinobufagin
keywords: ER stress; cinobufagin (CBG); colorectal cancer (CRC); mTOR and apoptosis