NVP-BEZ-235 enhances radiosensitization via blockade of the PI3K/mTOR pathway in cisplatin-resistant non-small cell lung carcinoma.
Kwang Woon Kim1,*, Carey J. Myers3,*, Dae Kwang Jung2, and Bo Lu3
1 Department of Pediatric Surgery, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN.
2 Department of Hematology/Oncology, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN.
3 Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA.
* These authors contributed equally to this work
Correspondence:
Bo Lu, email:
Correspondence:
Kwang Woon Kim, email:
Keywords: mTOR, NSCLC, autophagy, cisplatin resistance, radiosensitization
Received: June 13, 2014 Accepted: August 10, 2014 Published: August 11, 2014
Abstract
Introduction: Most drug resistant cancer cells also develop resistance to radiation therapy. In this study, we hypothesized that the dual inhibitor of phosphatidylinositol-3 kinase/mammalian target of rapamycin, NVP-BEZ-235, could potentially enhance radiosensitization in cisplatin-resistance (CDDP-R) non-small cell lung cancer (NSCLC) cells by disabling autophagy as a mechanism of self-preservation.
Methods: We used both in vitro and in vivo approaches, including clonogenic assays, Western blotting, molecular analyses of autophagy and apoptosis, a xenograft model of tumor growth, and immunohistochemical analysis.
Results: Basal p-Akt, p-mTOR and p-S6R proteins were enhanced in CDDP-R NSCLC cells. CDDP-R-resistant NSCLC cells are less radiation sensitive in comparison to parental cells (DER=0.82, p=0.02); BEZ-235 enhanced the radiosensitivity (DER=1.2, p=0.01). In addition, combining BEZ-235/RT showed a dramatic tumor growth delay in a mouse xenograft model. Immunohistochemistry showed that combination therapy yielded 50% decrease in caspase-3 activity. Moreover, cell proliferation was reduced by 87.8% and vascular density by 86.1%. These results were associated with a downregulation of PI3K/mTOR signaling pathway and an increase in autophagy.
Conclusions: These findings may be utilized as a novel strategy to enhance the efficacy of radiation therapy in drug-selected non-small cell lung cancer exhibiting radioresistance.
