Abstract LB-424: Plumbagin, a medicinal plant-derived napthoquinone, inhibits the growth of pancreatic cancer cells in in vitro and in vivo xenograft mouse model systems via targeting NFkB and STAT3 signaling network

Abstract

Abstract Pancreatic cancer (PaC) is one of the most fatal of all cancers and is ranked as the fourth most common cause of cancer related deaths among both men and women in the United States. It is estimated that 42,407 cases of PaC will be diagnosed in the United States alone in 2009 and 35,240 cancer related deaths are projected. Chemotherapy and radiation therapy are the widely practical major treatment modalities for the disease. Systemic toxicity caused by high doses of current chemotherapeutic drugs in PaC patients is of great concern, as it limits their use in patients. Chemotherapy through natural agents has proved successful for the prevention of a variety of cancer types. Plumbagin (PL) is a quinoid constituent isolated from the root of Plumbago zeylanica L. The root of this plant has been used in Indian system of medicine for more than 2500 years for the treatment of various ailments. A recent study demonstrates that PL treatment induces apoptosis of PaC cells. In this study, we investigated the chemopreventive potential of PL and its associated mechanism against PaC. To test the effect of PL in vitro condition, we have used PaC PANC1 and BxPC3 cells which were treated with PL treatment (5, 10, 15, or 20 M) for 24 h. We observed that PL treatment to PaC cells resulted in dose and time-dependent decrease in cell viability. The IC50 of PL in PANC1 and BxPC3 cells was observed 10 M after 24 h treatment. PL treatment at 15 M arrested cell cycle in G0/G1 phase in PANC1 (82.11%) and BxPC3 (68.93%) cells after 24 h post-treatment. To determine whether PL treatment inhibits the cell invasion of PaC cells, we performed in vitro chemoinvasion assay. PL treatment at doses of 15 and 20 M depicted 55% and 70 % inhibition of PANC1 cells invasion. To establish molecular mechanism associated with PL chemoprevention, we used western blot analysis to show that PL treatment inhibits the phosphorylation of pNFkBSer552, pStat3Ser727, and pSTAT3Tyr705 in PaC cells. PL treatment also inhibited DNA-binding of Stat3 and NF-kB in PaC cells as assessed by electro mobility shift assay. We further evaluated the effect of PL on NF-kB and Stat3 downstream target genes in PaC cells. Results demonstrated that PL treatment of PaC cells inhibited the expression of cyclin D1 and VEGF. To establish the chemopreventive potential of PL in PaC, we ectopically implanted 2.5×106 PaC PANC1 in SCID mice. Three days after implantation, PL treatment (2mg/kg body weight, i.p. five days a week) was given up to 9 weeks. Control mice were treated with PBS. PL treatment showed significant (P<0.01) inhibition in tumor growth (50%), and tumor weight (50%), when compared with control animals. Taken together, these results indicate that PL is an effective natural agent which could be use against PaC chemoprevention and treatment (Support: R&D Funds, Department of Human Oncology, and UW Madison, WI). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-424.