Oncotarget

Research Papers:

Piperlongumine potentiates the effects of gemcitabine in in vitro and in vivo human pancreatic cancer models

Jiyan Mohammad, Harsharan Dhillon, Shireen Chikara, Sujan Mamidi, Avinash Sreedasyam, Kishore Chittem, Megan Orr, John C. Wilkinson and Katie M. Reindl _

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Oncotarget. 2018; 9:10457-10469. https://doi.org/10.18632/oncotarget.23623

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Abstract

Jiyan Mohammad1, Harsharan Dhillon1, Shireen Chikara1, Sujan Mamidi2, Avinash Sreedasyam2, Kishore Chittem3, Megan Orr4, John C. Wilkinson5 and Katie M. Reindl1

1Department of Biological Sciences, North Dakota State University, Fargo, ND 51808, USA

2Genome Sequencing Center, HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA

3Department of Plant Pathology, North Dakota State University, Fargo, ND 51808, USA

4Department of Statistics, North Dakota State University, Fargo, ND 51808, USA

5Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND 51808, USA

Correspondence to:

Katie M. Reindl, email: katie.reindl@ndsu.edu

Keywords: apoptosis; cell cycle regulation; complementary and alternative therapy; reactive oxygen species; RNA-Seq

Received: September 13, 2017    Accepted: December 15, 2017    Published: December 23, 2017

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers due to a late diagnosis and poor response to available treatments. There is a need to identify complementary treatment strategies that will enhance the efficacy and reduce the toxicity of currently used therapeutic approaches. We investigated the ability of a known ROS inducer, piperlongumine (PL), to complement the modest anti-cancer effects of the approved chemotherapeutic agent gemcitabine (GEM) in PDAC cells in vitro and in vivo. PDAC cells treated with PL + GEM showed reduced cell viability, clonogenic survival, and growth on Matrigel compared to control and individually-treated cells. Nude mice bearing orthotopically implanted MIA PaCa-2 cells treated with both PL (5 mg/kg) and GEM (25 mg/kg) had significantly lower tumor weight and volume compared to control and single agent-treated mice. RNA sequencing (RNA-Seq) revealed that PL + GEM resulted in significant changes in p53-responsive genes that play a role in cell death, cell cycle, oxidative stress, and DNA repair pathways. Cell culture assays confirmed PL + GEM results in elevated ROS levels, arrests the cell cycle in the G0/G1 phase, and induces PDAC cell death. We propose a mechanism for the complementary anti-tumor effects of PL and GEM in PDAC cells through elevation of ROS and transcription of cell cycle arrest and cell death-associated genes. Collectively, our results suggest that PL has potential to be combined with GEM to more effectively treat PDAC.


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