Abstract A86: Piperlongumine enhances the efficacy of gemcitabine in pancreatic cancer cells in vitro and in vivo
Authors: Mohammad Jiyan , Dhillon Harsharan , Reindl Katie 
Published: December 2016

Reactive oxygen species (ROS)-inducing agents have been identified as possible treatments for various cancers, including pancreatic cancer. Cancer cells have high levels of ROS compared to healthy cells due to excessive metabolic activity. This phenomenon makes ROS a viable target for cancer treatment. We investigated the effect of a known ROS inducer, piperlongumine (PL), a bioactive agent found in long peppers, alone and in combination with a chemotherapeutic agent (gemcitabine; Gem) on pancreatic cancer cells in vitro and in vivo. The pancreatic cancer cell line (MIA PaCa-2) was treated with PL, gemcitabine, or a combination of the agents to evaluate the effect of PL on enhancing the efficacy of gemcitabine. Cell survival was assessed by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and propidium iodide (PI) staining, and Matrigel, and wound healing assays were performed. Our in vitro results show (MTT assay); 1uM of PL causes a 90% reduction in cell viability, 1nM of gemcitabine causes a 86% reduction, and the combination of PL (1uM) + gemcitabine (1nM) causes a 66.7% reduction compared to control (normalized to 100%). The PI staining (cell membrane integrity) control was 81% viable, 2.5uM PL treatment was 39.4% viable, 100nM gemcitabine treatment was 69.4% viable, and the combination PL (2.5uM) + gemcitabine (100nM) treatment was 36% viable. For the Matrigel and wound healing assays we observed a significant reduction number of cells and wound distance for wells treated with PL+ gemcitabine compared to the control and individual treatments. We evaluated the therapeutic advantage of combining PL and gemcitabine in nude mice bearing orthotopically implanted MIA PaCa-2 cells. Doses of 5 mg/kg of PL and 25 mg/kg gemcitabine were selected for intraperitoneal administration three times a week. The treatment efficacy was determined by considering the mean pancreatic tumor weight and volume immediately following euthanization. Administration of PL caused a 36% and 67% reduction in tumor weight and volume, respectively. Gemcitabine alone caused a 50% reduction in tumor weight and a 64% reduction in tumor volume. However, the combination of PL and gemcitabine showed a significant decrease (p&lt;0.01) in tumor weight and volume relative to DMSO alone, PL alone, and gemcitabine-alone treated mice. No macroscopic evidence of spreading to other visceral organs was evident for any experimental groups. Our results (in vitro and in vivo) suggest that PL has a potential to be used in combination with gemcitabine to more effectively treat pancreatic cancer.

Citation Format: Jiyan Mohammad, Harsharan Dhillon, Katie Reindl.{Authors}. Piperlongumine enhances the efficacy of gemcitabine in pancreatic cancer cells in vitro and in vivo. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A86.