Piperlongumine and Immune Cytokine TRAIL Synergize to Promote Tumor Death

Sci Rep. 2015 May 18;5:9987. doi: 10.1038/srep09987.


Malignant transformation results in increased levels of reactive oxygen species (ROS). Adaption to this toxic stress allows cancer cells to proliferate. Recently, piperlongumine (PL), a natural alkaloid, was identified to exhibit novel anticancer effects by targeting ROS signaling. PL induces apoptosis specifically in cancer cells by downregulating several anti-apoptotic proteins. Notably, the same anti-apoptotic proteins were previously found to reduce tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in cancer cells. Therefore, we reasoned that PL would synergize with TRAIL to stimulate potent apoptosis in cancer cells. We demonstrate for the first time that PL and TRAIL exhibit a synergistic anti-cancer effect in cancer cell lines of various origins. PL resulted in the upregulation of TRAIL receptor DR5, which potentiated TRAIL-induced apoptosis in cancer cells. Furthermore, such upregulation was found to be dependent on ROS and the activation of JNK and p38 kinases. Treatment with combined PL and TRAIL demonstrated significant anti-proliferative effects in a triple-negative breast cancer MDA-MB-231 xenograft model. This work provides a novel therapeutic approach for inducing cancer cell death. Combination of PL and TRAIL may suggest a novel paradigm for treatment of primary and metastatic tumors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cell Death / drug effects*
  • Cell Line, Tumor
  • Dioxolanes / administration & dosage
  • Dioxolanes / pharmacology*
  • Disease Models, Animal
  • Drug Synergism
  • Female
  • Humans
  • Mitogen-Activated Protein Kinases / metabolism
  • Reactive Oxygen Species / metabolism
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / agonists
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
  • Signal Transduction / drug effects
  • TNF-Related Apoptosis-Inducing Ligand / administration & dosage
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology*
  • Triple Negative Breast Neoplasms / drug therapy
  • Triple Negative Breast Neoplasms / metabolism
  • Triple Negative Breast Neoplasms / pathology
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Dioxolanes
  • Reactive Oxygen Species
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNF-Related Apoptosis-Inducing Ligand
  • Mitogen-Activated Protein Kinases
  • piperlonguminine