AZD8055 Exerts Antitumor Effects on Colon Cancer Cells by Inhibiting mTOR and Cell-cycle Progression

Yun Chen; Cheng-Hung Lee; Bor-Yuan Tseng; Ya-Hui Tsai; Huang-Wen Tsai; Chao-Ling Yao; Sheng-Hong Tseng

doi:10.21873/anticanres.12369

AZD8055 Exerts Antitumor Effects on Colon Cancer Cells by Inhibiting mTOR and Cell-cycle Progression

Anticancer Res. 2018 Mar;38(3):1445-1454. doi: 10.21873/anticanres.12369.

Authors

Yun Chen^{1

2}, Cheng-Hung Lee^{3

4}, Bor-Yuan Tseng¹, Ya-Hui Tsai^{1

2

5}, Huang-Wen Tsai¹, Chao-Ling Yao^{6

3}, Sheng-Hong Tseng⁷

Affiliations

¹ Department of Surgery, Far Eastern Memorial Hospital, New Taipei, Taiwan, R.O.C.
² Department of Chemical Engineering and Materials Science, Yuan Ze University, Taoyuan, Taiwan, R.O.C.
³ Graduate School of Biotechnology and Bioengineering, Yuan Ze University, Taoyuan, Taiwan, R.O.C.
⁴ Department of General Surgery, Buddhist Dalin Tzu Chi Hospital, Chia-Yi and School of Medicine, Tzu Chi University, Hualien, Taiwan, R.O.C.
⁵ Department of Materials and Textiles, Oriental Institute of Technology, New Taipei, Taiwan, R.O.C.
⁶ Department of Chemical Engineering and Materials Science, Yuan Ze University, Taoyuan, Taiwan, R.O.C. d897601@alumni.nthu.edu.tw yao@saturn.yzu.edu.tw shenghongtseng@gmail.com.
⁷ Department of Surgery, National Taiwan University Hospital, and National Taiwan University College of Medicine, Taipei, Taiwan, R.O.C. d897601@alumni.nthu.edu.tw yao@saturn.yzu.edu.tw shenghongtseng@gmail.com.

PMID: 29491070
DOI: 10.21873/anticanres.12369

Abstract

Background/aim: AZD8055 is an inhibitor of mammalian target of rapamycin (mTOR) that can suppress both mTOR complex 1 (mTORC1) and mTORC2. This study investigated the antitumor effects of AZD8055 on colon cancer.

Materials and methods: The effects of AZD8055 on proliferation, apoptosis, and cell cycle of colon cancer cells, and tumor growth in a mouse colon cancer model were studied.

Results: AZD8055 significantly inhibited proliferation and induced apoptosis of colon cancer cells (p<0.05). The phosphorylation of both AKT and S6 kinase 1 (S6K1) was suppressed by AZD8055. AZD8055 also induced G₀/G₁ cell-cycle arrest, reduced cyclin D1 and increased p27 expression, and suppressed the levels of phospho-cyclin-dependent kinase 2 and phospho-retinoblastoma. Compared to the control, oral administration of AZD8055 significantly suppressed tumor growth in mice (p<0.05).

Conclusion: AZD8055 induces cytotoxicity, apoptosis, and cell-cycle arrest of colon cancer cells, and exerts an antitumor effect in mice. It also inhibits the mTOR signaling pathway and mTOR-dependent cell-cycle progression.

Keywords: AZD8055; apoptosis; cell cycle; colon cancer; mTOR.

MeSH terms

Animals
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Colonic Neoplasms / drug therapy*
Colonic Neoplasms / metabolism
Colonic Neoplasms / pathology
G1 Phase Cell Cycle Checkpoints / drug effects*
HCT116 Cells
Humans
Male
Mice, Inbred BALB C
Morpholines / administration & dosage
Morpholines / pharmacology*
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / metabolism
Neoplasms, Experimental / pathology
Signal Transduction / drug effects
TOR Serine-Threonine Kinases / antagonists & inhibitors*
TOR Serine-Threonine Kinases / metabolism
Tumor Burden / drug effects

Substances

Morpholines
(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol
TOR Serine-Threonine Kinases