title: The anti-hepatocellular carcinoma cell activity by a novel mTOR kinase inhibitor CZ415.
abstract: Dysregulation of mammalian target of rapamycin (mTOR) in hepatocellular carcinoma (HCC) represents a valuable treatment target. Recent studies have developed a highly-selective and potent mTOR kinase inhibitor, CZ415. Here, we showed that nM concentrations of CZ415 efficiently inhibited survival and induced apoptosis in HCC cell lines (HepG2 and Huh-7) and primary-cultured human HCC cells. Meanwhile, CZ415 inhibited proliferation of HCC cells, more potently than mTORC1 inhibitors (rapamycin and RAD001). CZ415 was yet non-cytotoxic to the L02 human hepatocytes. Mechanistic studies showed that CZ415 disrupted assembly of mTOR complex 1 (mTORC1) and mTORC2 in HepG2 cells. Meanwhile, activation of mTORC1 (p-S6K1) and mTORC2 (p-AKT, Ser-473) was almost blocked by CZ415. In vivo studies revealed that oral administration of CZ415 significantly suppressed HepG2 xenograft tumor growth in severe combined immuno-deficient (SCID) mice. Activation of mTORC1/2 was also largely inhibited in CZ415-treated HepG2 tumor tissue. Together, these results show that CZ415 blocks mTORC1/2 activation and efficiently inhibits HCC cell growth in vitro and in vivo.
authors.affiliation: Department of Gastrointestinal Pancreatic Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou medical College, Hangzhou, China; Research Center of Blood Transfusion Medicine, Education Ministry Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou medical College, Hangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Research Center of Blood Transfusion Medicine, Education Ministry Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou medical College, Hangzhou, China.
authors.forename: Bingyu
authors.initials: B
authors.lastname: Chen
authors.affiliation: Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou medical College, Hangzhou, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Research Center of Blood Transfusion Medicine, Education Ministry Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou medical College, Hangzhou, China.
authors.forename: Kaiqiang
authors.initials: K
authors.lastname: Li
authors.affiliation: Research Center of Blood Transfusion Medicine, Education Ministry Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou medical College, Hangzhou, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Hao
authors.affiliation: Research Center of Blood Transfusion Medicine, Education Ministry Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou medical College, Hangzhou, China.
authors.forename: Luxi
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Research Center of Blood Transfusion Medicine, Education Ministry Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou medical College, Hangzhou, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou medical College, Hangzhou, China.
authors.forename: Xiaozhou
authors.initials: X
authors.lastname: Mou
authors.affiliation: Department of Gastrointestinal Pancreatic Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou medical College, Hangzhou, China. Electronic address: drxxklzjsry@163.com.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Xu
authors.affiliation: Research Center of Blood Transfusion Medicine, Education Ministry Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou medical College, Hangzhou, China; Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou medical College, Hangzhou, China. Electronic address: drzwklzjsry@163.com.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003499:Cyclic S-Oxides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C000621007:CZ415 compound; D003499:Cyclic S-Oxides; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Apoptosis; CZ415; Hepatocellular carcinoma; Mammalian target of rapamycin (mTOR)