Abstract 2596: Inhibition of PI3K-mTOR pathway using combination of chloroquine and aspirin regimen leads to apoptosis in pancreatic cancer cells.

Abstract

Abstract Pancreatic cancer ranks as the fourth most deadly form of cancer in the United States with approximately 37,000 deaths each year. The present study aims to evaluate the combinatorial chemopreventive effects of low doses of chloroquine (CQ) and aspirin (ASP) alone and in combination CQA (CQ+ASP) on three pancreatic cancer cell lines, MIA PaCa-2, Panc-1 and BxPC-3. Results demonstrated that low doses of CQ (6.25μM) and ASP (1mM) alone did not reduce cell viability, whereas combination CQA reduced cell viability by ∼80% (P<0.001). CQA combination blocked cell cycle progression at G0/G1 checkpoint. The CQA treatment for 24 h inhibited the NF-κB p50 DNA binding activity by ∼45% (P<0.01) in MIA PaCa-2 and BxPC-3 cells, but no NF-κB inhibition observed in Panc-1 cells. Mechanistic studies revealed that treatment with CQA combination increased the expression of LC3-II protein, indicates inhibition of autophagy. In order to verify the involvement of PI3K and mTOR pathway in CQA-induced apoptosis, we used PI3K inhibitor (3-MA) and mTOR inhibitor (Rapamycin) and analyzed by cell viability assay. The inhibition of PI3K by 3-MA pretreatment enhanced the cell growth inhibition of CQA treatment, whereas the inhibition of m-TOR by rapamycin pretreatment attenuated CQA induced reduction in cell viability. Overall, our results for the first time, illustrate that low dose CQA combinations impart synergistic suppressive activity than chemopreventive agents alone, thus confirming the importance of novel combination chemoprevention strategies against pancreatic cancer. Citation Format: Arvind Thakkar, B. Karthik Grandhi, Jeffrey Wang, Sunil Prabhu. Inhibition of PI3K-mTOR pathway using combination of chloroquine and aspirin regimen leads to apoptosis in pancreatic cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2596. doi:10.1158/1538-7445.AM2013-2596