Studies on the mechanism of action of frondoside A in pancreatic cancer

Abstract

J. Al Shemaili , K. Parekh , S.A. Thomas , D.L. Kelly , X.-Z. Ding , S. Attoub , S.P. Collin , T.E. Adrian . Department of Physiology, Faculty of Medicine, UAE University, Al Ain, United Arab Emirates 2 Eppley Cancer Center, University of Nebraska, Omaha, NE, USA Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Coastside BioResources, Stonington, ME, USA Frondoside A is a novel anticancer triterpenoid compound isolated from the Atlantic sea cucumber Cucumaria frondosa. Frondoside A causes inhibition of growth, invasion, metastases and angiogenesis and induces apoptosis in a number of different cancer types including pancreatic cancer. Frondoside A potentiates the effects of gemcitabine in pancreatic cancer in vitro and in vivo. The present study was designed to identify the mechanism of action of frondoside A. The effect of frondoside A on gene expressionwas investigated in S2013 pancreatic cancer cells treated with 2mM Frondoside A for 6 h using a human oligonucleotide expression array library. There were marked changes in expression of several genes involved in growth regulation. Expression of genes showing the greatest changes were confirmed by real-time RT-PCR and time-courses of gene expressionwere investigated in seven cancer cell lines. Downregulated genes included E2F1, cyclin A2, cdc20, cdc21, cdc45 and cdc47. Upregulated genes included fatty acid binding protein 3 (FABP3), macrophage inhibitory cytokine 1 (MIC-1), p21WAF-1, repressor of E1A, dual-specificity phosphatase and death-associated protein kinase-1. Attention was focused on MIC-1 which mediates apoptosis induction in response to NSAIDS and FABP3, which is known to have potent tumor suppressor activity in breast cancer. Knockdown of either MIC-1 or FABP3 using specific siRNA in AsPC-1 cells reversed the growth inhibitory effects of frondoside A. These findings suggest that both FABP3 and MIC-1 are involved in the growth inhibitory effects of frondoside A in pancreatic cancer. Since this mechanism appears unique, it explains the synergistic anti-cancer effects seen when combined with gemcitabine.