RT Journal Article
SR Electronic
T1 Targeted Inhibition of Phosphoinositide 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Sensitizes Pancreatic Cancer Cells to Doxorubicin without Exacerbating Cardiac Toxicity
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.115.099143
DO 10.1124/mol.115.099143
A1 David E Durrant
A1 Anindita Das
A1 Samya Dyer
A1 Seyedmehrad Tavallai
A1 Paul Dent
A1 Rakesh C. Kukreja
YR 2015
UL http://molpharm.aspetjournals.org/content/early/2015/06/22/mol.115.099143.abstract
AB Pancreatic cancer has the lowest five-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 PI3K/mTOR inhibitor BEZ235 (BEZ) potentiates the anti-tumor effects of doxorubicin (DOX) against pancreatic cancer. Co-treatment of BEZ235 with DOX resulted in dose-dependent inhibition of the PI3K/mTOR survival pathway which corresponded with an increase in PARP cleavage. Moreover, BEZ co-treatment significantly improved the effects of DOX towards 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 ROS generation. Furthermore, BEZ in combination with gemcitabine (Gem) reduced MiaPaca2 cell proliferation but failed to increase ROS 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 to BEZ, DOX or Gem. Additionally, in contrast to the enhanced expression seen in MiaPaca2 cells, BEZ and DOX co-treatment reduced BIM expression in H9C2 cardiomyocytes. Also, Bcl-2/Bax ratio was increased which was associated with 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 more effective tumor response without the associated increase in toxicity.