Autophagy inhibition enhances colorectal cancer apoptosis induced by dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235

Yang,Xiaoyu; Niu,Bingxuan; Wang,Libo; Chen,Meiling; Kang,Xiaochun; Wang,Luonan; Ji,Yinghua; Zhong,Jiateng

doi:10.3892/ol.2016.4590

Autophagy inhibition enhances colorectal cancer apoptosis induced by dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235

Authors:
- Xiaoyu Yang
- Bingxuan Niu
- Libo Wang
- Meiling Chen
- Xiaochun Kang
- Luonan Wang
- Yinghua Ji
- Jiateng Zhong
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Affiliations: Department of Pathology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China, College of Pharmacy, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China, Department of Gastroenterology, The First Affiliated Hospital of Jilin University, Changchun, Jilin 130021, P.R. China, Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453100, P.R. China
Published online on: May 17, 2016 https://doi.org/10.3892/ol.2016.4590
Pages: 102-106
Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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