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Autophagy inhibition enhances colorectal cancer apoptosis induced by dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235
- Source :
- Oncology Letters
- Publication Year :
- 2016
- Publisher :
- Spandidos Publications, 2016.
-
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.
- Subjects :
- 0301 basic medicine
autophagy
Cancer Research
Kinase
phosphatidylinositol 3-kinase/mammalian target of rapamycin
Autophagy
RPTOR
apoptosis
virus diseases
Cellular homeostasis
colorectal cancer
Articles
Cell cycle
Pharmacology
Biology
NVP-BEZ235
03 medical and health sciences
030104 developmental biology
0302 clinical medicine
Oncology
immune system diseases
Apoptosis
030220 oncology & carcinogenesis
Signal transduction
PI3K/AKT/mTOR pathway
Subjects
Details
- ISSN :
- 17921082 and 17921074
- Volume :
- 12
- Database :
- OpenAIRE
- Journal :
- Oncology Letters
- Accession number :
- edsair.doi.dedup.....4fd16969ccddfe16bfa9e578aeb9844f