Abstract
Pancreatic cancer has the lowest 5-year survival rate of all major cancers despite decades of effort to design and implement novel, more effective treatment options. In this study, we tested whether the dual phosphoinositide 3-kinase/mechanistic target of rapamycin inhibitor BEZ235 (BEZ) potentiates the antitumor effects of doxorubicin (DOX) against pancreatic cancer. Cotreatment of BEZ235 with DOX resulted in dose-dependent inhibition of the phosphoinositide 3-kinase/mechanistic target of rapamycin survival pathway, which corresponded with an increase in poly ADP ribose polymerase cleavage. Moreover, BEZ cotreatment significantly improved the effects of DOX toward both cell viability and cell death in part through reduced Bcl-2 expression and increased expression of the shorter, more cytotoxic forms of BIM. BEZ also facilitated intracellular accumulation of DOX, which led to enhanced DNA damage and reactive oxygen species generation. Furthermore, BEZ in combination with gemcitabine reduced MiaPaca2 cell proliferation but failed to increase reactive oxygen species generation or BIM expression, resulting in reduced necrosis and apoptosis. Treatment with BEZ and DOX in mice bearing tumor xenographs significantly repressed tumor growth as compared with BEZ, DOX, or gemcitabine. Additionally, in contrast to the enhanced expression seen in MiaPaca2 cells, BEZ and DOX cotreatment reduced BIM expression in H9C2 cardiomyocytes. Also, the Bcl-2/Bax ratio was increased, which was associated with a reduction in cell death. In vivo echocardiography showed decreased cardiac function with DOX treatment, which was not improved by combination treatment with BEZ. Thus, we propose that combining BEZ with DOX would be a better option for patients than current standard of care by providing a more effective tumor response without the associated increase in toxicity.
Footnotes
- Received March 23, 2015.
- Accepted June 16, 2015.
This work was supported by the National Institutes of Health [Grant R37-HL51045] and the American Heart Association [Grant PT109079].
This work was previously presented as a meeting abstract as follows: Durrant D, Das A, Kukreja RC (2014) BEZ235, a selective PI3k/mTOR inhibitor, enhances the therapeutic efficacy of doxorubicin in pancreatic cancer, in Basic Clin Pharmacol Toxicol; 2014 July 13–18; World Congress on Basic and Clinical Pharmacology, Cape Town, South Africa.; Durrant D, Das A, Kukreja RC (2014) BEZ235, a selective PI3k/mTOR inhibitor, enhances the therapeutic efficacy of doxorubicin in pancreatic cancer. FASEB J. 28, Supplement 655.7.
- Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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