title: Pre-clinical characterization of PKC412, a multi-kinase inhibitor, against colorectal cancer cells.
abstract: The potential effect of PKC412, a small molecular multi-kinase inhibitor, in colorectal cancer (CRC) cells was evaluated here. We showed that PKC412 was cytotoxic and anti-proliferative against CRC cell lines (HT-29, HCT-116, HT-15 and DLD-1) and primary CRC cells. PKC412 provoked caspase-dependent apoptotic death, and induced G2-M arrest in the CRC cells. AKT activation was inhibited by PKC412 in CRC cells. Reversely, expression of constitutively-active AKT1 (CA-AKT1) decreased the PKC412's cytotoxicity against HT-29 cells. We propose that Bcl-2 could be a primary resistance factor of PKC412. ABT-737, a Bcl-2 inhibitor, or Bcl-2 siRNA knockdown, dramatically potentiated PKC412's lethality against CRC cells. Forced Bcl-2 over-expression, on the other hand, attenuated PKC412's cytotoxicity. Significantly, PKC412 oral administration suppressed AKT activation and inhibited HT-29 tumor growth in nude mice. Mice survival was also improved with PKC412 administration. These results indicate that PKC412 may have potential value for CRC treatment.
authors: Department of Geriatric Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.|Department of Oncology, Yancheng Fist People's Hospital, Yancheng, China.
authors: Jian-Ping
authors: JP
authors: Li
authors: Department of Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.|Department of Surgery, Yancheng Fist People's Hospital, Yancheng, China.
authors: Zhi-Jun
authors: ZJ
authors: Huang
authors: Department of Hepatobiliary Surgery, Suzhou Municipal Hospital, Suzhou, China.
authors: Xing-Sheng
authors: XS
authors: Lu
authors: Department of Geriatric Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors: Yi-Chan
authors: YC
authors: Zhou
authors: Department of Geriatric Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors: Yun
authors: Y
authors: Shao
authors: Department of Geriatric Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors: Xiao-Pu
authors: XP
authors: He
authors: Department of Oncology, Yancheng Fist People's Hospital, Yancheng, China.
authors: Su-Rong
authors: SR
authors: Chen
authors: Department of Oncology, Yancheng Fist People's Hospital, Yancheng, China.
authors: Dong-Dong
authors: DD
authors: Wang
authors: Department of Neurosurgery, Yancheng Pavilion Lake District People's Hospital, Yancheng, China.
authors: Li-Sen
authors: LS
authors: Qin
authors: Department of Geriatric Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors: Wei-Hao
authors: WH
authors: Sun
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019311:Staurosporine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D019311:Staurosporine; C059539:midostaurin
keywords: AKT; Bcl-2; PKC412; colorectal cancer (CRC); receptor tyrosine kinases