CC-223 blocks mTORC1/C2 activation and inhibits human hepatocellular carcinoma cells in vitro and in vivo.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related human mortalities. Over-activation of mammalian target of rapamycin (mTOR) is important for HCC tumorigenesis and progression. The current study assessed the potential anti-HCC activity by a novel mTOR kinase inhibitor, CC-223. We demonstrate that CC-223, at nM concentrations, induced profound cytotoxic and anti-proliferative activities against established HCC cell lines (HepG2, KYN-2 and Huh-7) and primary human HCC cells. Meanwhile, CC-223 activated caspase-3/-9 and apoptosis in the above HCC cells. CC-223 concurrently blocked mTORC1 and mTORC2 activation, and its cytotoxicity against HCC cells was much more potent than the traditional mTORC1 inhibitors (RAD001 and rapamycin). Further studies demonstrated that CC-223 disrupted mitochondrial function, and induced mitochondrial permeability transition pore (mPTP) opening and reactive oxygen species (ROS) production. On the other hand, ROS scavengers and mPTP blockers (cyclosporin A or sanglifehrin A) largely attenuated CC-223-induced HepG2 cell apoptosis. In vivo studies showed that oral administration of CC-223 dramatically inhibited growth of HepG2 xenografts in severe combined immuno-deficient (SCID) mice. mTORC1/2 activation was also blocked in xenografts with CC-223 administration. Together, CC-223 simultaneously blocks mTORC1/2 and efficiently inhibits human HCC cells.
Emergency Department, Minhang Hospital, Fudan University, Shanghai, China.
Zichen
Z
Xie
Emergency Department, Minhang Hospital, Fudan University, Shanghai, China.
Jiqin
J
Wang
Emergency Department, Minhang Hospital, Fudan University, Shanghai, China.
Mei
M
Liu
Emergency Department, Minhang Hospital, Fudan University, Shanghai, China.
Deshan
D
Chen
Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Chao
C
Qiu
Emergency Department, Minhang Hospital, Fudan University, Shanghai, China.
Keyu
http://orcid.org/0000-0002-9451-9019
K
Sun
D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
C000601736:CC-223; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D017382:Reactive Oxygen Species; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D053148:Caspase 3; D053453:Caspase 9