title: AT7867 Inhibits Human Colorectal Cancer Cells via AKT-Dependent and AKT-Independent Mechanisms.
abstract: AKT is often hyper-activated in human colorectal cancers (CRC). This current study evaluated the potential anti-CRC activity by AT7867, a novel AKT and p70S6K1 (S6K1) dual inhibitor. We showed that AT7867 inhibited survival and proliferation of established (HT-29, HCT116 and DLD-1 lines) and primary human CRC cells. Meanwhile, it provoked caspase-dependent apoptosis in the CRC cells. Molecularly, AT7867 blocked AKT-S6K1 activation in CRC cells. Restoring AKT-S6K1 activation, via expression of a constitutively-active AKT1 ("ca-AKT1"), only partially attenuated AT7867-induced HT-29 cell death. Further studies demonstrated that AT7867 inhibited sphingosine kinase 1 (SphK1) activity to promote pro-apoptotic ceramide production in HT-29 cells. Such effects by AT7867 were independent of AKT inhibition. AT7867-indued ceramide production and subsequent HT-29 cell apoptosis were attenuated by co-treatment of sphingosine-1-phosphate (S1P), but were potentiated with the glucosylceramide synthase (GCS) inhibitor PDMP. In vivo, intraperitoneal injection of AT7867 inhibited HT-29 xenograft tumor growth in nude mice. AKT activation was also inhibited in AT7867-treated HT-29 tumors. Together, the preclinical results suggest that AT7867 inhibits CRC cells via AKT-dependent and -independent mechanisms.
authors.affiliation: Department of General Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.|Department of General Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Shihu
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Zhengming
authors.initials: Z
authors.lastname: Deng
authors.affiliation: Orthopedic Department, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Yao
authors.affiliation: Department of General Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Huang
authors.affiliation: Department of General Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Shibing
authors.initials: S
authors.lastname: Cao
authors.affiliation: Department of General Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Xiangcheng
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000099157:Sphingosine Kinase
chemical_list: D017853:Phosphotransferases (Alcohol Group Acceptor); D010880:Piperidines; D051057:Proto-Oncogene Proteins c-akt; D011720:Pyrazoles; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D000099157:Sphingosine Kinase; C551535:AT 7867; C494918:AKT1 protein, human; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1