Pancreatic cancer ranks as the fourth most deadly form of cancer in the United States with approximately 37,000 deaths each year. Due to poor prognosis, attention has recently focused on the chemoprevention of this disease rather than on diagnosis and treatment. The present study aims to evaluate the combinatorial chemopreventive effects of low doses of aspirin (ASP), curcumin (CUR), sulforaphane (SFN) alone and in combination ACS (ASP+CUR+SFN) on two pancreatic cancer cell lines, MIA PaCa-2 and Panc-1. Results demonstrated that low doses of ASP (1mM), CUR (10μM) and SFN (5μM) alone did not reduce cell viability, whereas combination ACS reduced cell viability by ∼70% (P<0.001). ACS treatment also induced cell apoptosis by ∼60% accompanied by activation of caspase- 3 and Poly (ADP-ribose) polymerase (PARP) proteins. The NF-κB DNA binding activity was inhibited by ∼45% (P<0.01) and ∼75% (P<0.001) in MIA PaCa-2 and Panc-1 cells respectively. The reduction in NF-κB activity was accompanied by down-regulation of phospho IκBα and phospho Akt proteins. Mechanistic studies revealed that ACS promoted reduction in cell viability, associated with increased expression of phospho extracellular signal-regulated kinase 1/2 (ERK1/2), phospho c-Jun, phospho p38 MAPK and phospho p53 proteins. Furthermore, to evaluate the significance of activation of ERK1/2 pathway on ACS induced reduction in cell viability and NF-κB, the cells were pretreated with U0126 (ERK1/2 inhibitor). The inhibition of ERK1/2 by U0126 pretreatment abolished the effect of ACS on cell viability and NF-κB DNA binding activity. Overall, our results for the first time, illustrate that low dose ACS 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, Dhruvitkumar Sutaria, Karthik Grandhi, Ying Huang, Jeffrey Wang, Sunil Prabhu. Activation of ERK1/2 using combination of aspirin, curcumin, and sulforaphane regimen leads to NF-κB inhibition and apoptosis in pancreatic cancer cells. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A65.