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, Katie M. Reindl

Research output: Contribution to journalArticle

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)10457-10469
Number of pages13
JournalOncotarget
Volume9
Issue number12
DOIs
StatePublished - 2018

Keywords

  • Apoptosis
  • Cell cycle regulation
  • Complementary and alternative therapy
  • RNA-Seq
  • Reactive oxygen species

ASJC Scopus subject areas

  • Oncology

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    Mohammad, J., Dhillon, H., Chikara, S., Mamidi, S., Sreedasyam, A., Chittem, K., Orr, M., Wilkinson, J. C., & Reindl, K. M. (2018). Piperlongumine potentiates the effects of gemcitabine in in vitro and in vivo human pancreatic cancer models. Oncotarget, 9(12), 10457-10469. https://doi.org/10.18632/oncotarget.23623