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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the third most common cause of cancer death in the United States with a 5-year relative survival rate of only 8% [1]
We investigated the ability of a known reactive oxygen species (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
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
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the third most common cause of cancer death in the United States with a 5-year relative survival rate of only 8% [1]. To increase GEM’s www.impactjournals.com/oncotarget efficacy, adjuvant therapies such as 5-fluorouracil, nabpaclitaxel, or cisplatin are often used [4] These agents target other mechanisms used by cancer cells to grow and divide. We postulate that using PL in combination with GEM will enhance PDAC cell death by raising ROS to a level that induces cell death The rationale for this therapeutic approach is that highly metabolic tumor cells have heightened basal oxidative stress and are susceptible to cell death when additional oxidative stress is induced [12]. We identified the underlying mechanisms for the enhanced anti-tumor effects of PL + GEM in PDAC cells which include elevation of ROS and differential expression genes including cell cycle and apoptosis-associated genes
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