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Oncotarget. 2017 Dec 23;9(12):10457-10469. doi: 10.18632/oncotarget.23623. eCollection 2018 Feb 13.

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

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Department of Biological Sciences, North Dakota State University, Fargo, ND 51808, USA.
Genome Sequencing Center, HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
Department of Plant Pathology, North Dakota State University, Fargo, ND 51808, USA.
Department of Statistics, North Dakota State University, Fargo, ND 51808, USA.
Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND 51808, USA.


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.


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

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