Targeted Inhibition of Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Sensitizes Pancreatic Cancer Cells to Doxorubicin without Exacerbating Cardiac Toxicity

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.

A Cellular Automata Model of Oncolytic Virotherapy in Pancreatic Cancer

“…Over 50 days, our numerical results regarding the increase in tumor volume show a consistency with the experimental work (Durrant et al. 2015 ).…”

“…( 6 )), where ; b A comparison of numerical results with experimental results referring to (Durrant et al. 2015 ), where control and gem in the legend denote tumor growth without drug and with gemcitabine drug, respectively. In the simulation with curve 1, and are equal and 0.94, respectively.…”

“…5 b shows experimental results of tumor growth curve from the work by Durrant et al. ( 2015 ), where pancreatic cancer cells are inoculated into immunodeficient mice, where the inoculation site is subcutaneous. Implanted cancer cells are allowed to grow during two weeks before the initiation of gemcitabine drug treatment ( ) and its growth curve is indicated by the blue curve in Fig.…”

Doxorubicin Induces Endotheliotoxicity and Mitochondrial Dysfunction via ROS/eNOS/NO Pathway

“…As a series of critical pathophysiological events of cardiovascular complications, endothelial dysfunction may cause hemorrhage, infarction, atherosclerosis, restenosis (Soultati et al, 2012;Wojcik et al, 2015). Studies have shown that Dox could downregulate CX40 (Idris-Khodja et al, 2013), MnSOD expression and activity (Koka et al, 2010;Santos-Alves et al, 2019), regulate Bcl-2/Bax ratio (Durrant et al, 2015;You et al, 2019), promote the shift from topoisomerase II a to II b (Deng et al, 2014;Damiani et al, 2018), disturb microRNA, DNA methylation or protein acetylation (Nordgren et al, 2017;Ferreira et al, 2017), affect PARP-2/SIRT (Szántó et al, 2011), VEGF pathway (Chiusa et al, 2012), and interfere with tight junction formation between cardiac microvascular endothelial cells leading to increased permeability (Wilkinson et al, 2016). In the study, we proved in vivo that, after injected Dox with the classical protocol, the mice showed the LDH and CK activities in serum increased significantly (Figures 2A, B), the inflammatory changes were observed by histopathology ( Figure 2C), which was noticeable as brown TUNEL-positive cells in microscopy ( Figure 2D).…”

GDC-0449 improves the antitumor activity of nano-doxorubicin in pancreatic cancer in a fibroblast-enriched microenvironment

“…The main side effect of Dox is cardiotoxicity, which can be drastically reduced by encapsulation in a polyethylene glycol (PEG)-coated liposome or by other nano-formulations 18 . However, Dox has low response rates in pancreatic cancer when used as a single agent because of acquired resistance 19 and limited penetration 19 – 21 . In the present study, the potential therapeutic strategy of a combination of nano-sized PEG-PCL-Dox micelles and GDC-0449 was investigated in pancreatic cancer in vitro and in vivo .…”