title: Autophagy inhibition enhances colorectal cancer apoptosis induced by dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235.
abstract: Phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway performs a central role in tumorigenesis and is constitutively activated in many malignancies. As a novel dual PI3K/mTOR inhibitor currently undergoing evaluation in a phase I/II clinical trial, NVP-BEZ235 indicates a significant antitumor efficacy in diverse solid tumors, including colorectal cancer (CRC). Autophagy is a catabolic process that maintains cellular homeostasis and reduces diverse stresses through lysosomal recycling of the unnecessary and damaged cell components. This process is also observed to antagonize the antitumor efficacy of PI3K/mTOR inhibitor agents such as NVP-BEZ235, via apoptosis inhibition. In the present study, we investigated anti-proliferative and apoptosis-inducing ability of NVP-BEZ235 in SW480 cells and the crosstalk between autophagy and apoptosis in SW480 cells treated with NVP-BEZ235 in combination with an autophagy inhibitor. The results revealed that, NVP-BEZ235 effectively inhibit the growth of SW480 cells by targeting the PI3K/mTOR signaling pathway and induced apoptosis. The inhibition of autophagy with 3-methyladenine or chloroquine inhibitors in combination with NVP-BEZ235 in SW480 cells enhanced the apoptotic rate as componets to NVP-BEZ235 alone. In conclusion, the findings provide a rationale for chemotherapy targeting the PI3K/mTOR signaling pathway presenting a potential therapeutic strategy to enhance the efficacy of dual PI3K/mTOR inhibitor NVP-BEZ235 in combination with an autophagy inhibitor in CRC treatment and treatment of other tumors.
authors.affiliation: Department of Pathology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Yang
authors.affiliation: College of Pharmacy, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
authors.forename: Bingxuan
authors.initials: B
authors.lastname: Niu
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Libo
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453100, P.R. China.
authors.forename: Meiling
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453100, P.R. China.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Kang
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453100, P.R. China.
authors.forename: Luonan
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453100, P.R. China.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Department of Pathology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
authors.forename: Jiateng
authors.initials: J
authors.lastname: Zhong
keywords: NVP-BEZ235; apoptosis; autophagy; colorectal cancer; phosphatidylinositol 3-kinase/mammalian target of rapamycin