The anti-hepatocellular carcinoma cell activity by a novel mTOR kinase inhibitor CZ415

Journal Article · Sat Jun 03 04:00:00 EDT 2017 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2017.03.156· OSTI ID:22697040

Zhang, Wei ^[1]; Chen, Bingyu ^[2]; Zhang, Yu ^[3]; Li, Kaiqiang; Hao, Ke; Jiang, Luxi; Wang, Ying ^[2]; Mou, Xiaozhou ^[3]; Xu, Xiaodong ^[1]; Wang, Zhen ^[2]

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1. Department of Gastrointestinal Pancreatic Surgery, Zhejiang Provincial People's Hospital, People’s Hospital of Hangzhou medical College, Hangzhou (China)
2. 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)
3. Clinical Research Institute, Zhejiang Provincial People's Hospital, People’s Hospital of Hangzhou medical College, Hangzhou (China)

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. - Highlights: • CZ415 is anti-survival and pro-apoptotic to hepatocellular carcinoma (HCC) cells. • CZ415 inhibits HCC cell proliferation, more efficiently than mTORC1 inhibitors. • CZ415 blocks assembly and activation of both mTORC1 and mTORC2 in HCC cells. • CZ415 oral administration inhibits HepG2 tumor growth in SCID mice. • mTORC1/2 activation in HepG2 tumor is inhibited with CZ415 administration.

• OSTI ID: 22697040
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 3 Vol. 487; ISSN BBRCA9; ISSN 0006-291X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
CARCINOMAS
CELL PROLIFERATION
IN VIVO
INHIBITION
LIVER CELLS
ORAL ADMINISTRATION
PHOSPHOTRANSFERASES
PLANT GROWTH