TY - JOUR
T1 - Piperlongumine potentiates the effects of gemcitabine in in vitro and in vivo human pancreatic cancer models
AU - Mohammad, Jiyan
AU - Dhillon, Harsharan
AU - Chikara, Shireen
AU - Mamidi, Sujan
AU - Sreedasyam, Avinash
AU - Chittem, Kishore
AU - Orr, Megan
AU - Wilkinson, John C.
AU - Reindl, Katie M.
N1 - Funding Information:
Funding for this project was made possible by NIH Grant Numbers 1P20GM109024, P30GM103332, and 1U54GM115458-01 (to KMR) from the National Institute of General Medicine (NIGMS) and NIH Grant Number 1R15CA206067 (to JCW) from the National Cancer Institute (NCI). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
Publisher Copyright:
© Mohammad et al.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Cell cycle regulation
KW - Complementary and alternative therapy
KW - RNA-Seq
KW - Reactive oxygen species
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U2 - 10.18632/oncotarget.23623
DO - 10.18632/oncotarget.23623
M3 - Article
C2 - 29535819
AN - SCOPUS:85041943656
SN - 1949-2553
VL - 9
SP - 10457
EP - 10469
JO - Oncotarget
JF - Oncotarget
IS - 12
ER -