Piperlongumine induces G2/M phase arrest and apoptosis in cholangiocarcinoma cells through the ROS-JNK-ERK signaling pathway

Apoptosis. 2017 Nov;22(11):1473-1484. doi: 10.1007/s10495-017-1422-y.

Abstract

Cholangiocarcinoma (CCA) is an aggressive, metastatic bile duct cancer. CCA is difficult to diagnose, and responds poorly to current radio- and chemo-therapy. Piperlongumine (PL) is a naturally-occurring small molecule selectively toxic to cancer cells by targeting reactive oxygen species (ROS). In this study, we demonstrated the potential anticancer activity of PL in CCA. PL markedly induced death in CCA cell lines in a dose- and time-dependent manner through the activation of caspase-3 and PARP. PL also stimulated ROS accumulation in CCA. Co-exposure of PL with the ROS scavenger N-acetyl-L-cysteine or GSH completely blocked PL-induced apoptosis in CCA cell lines. Increased p21 via the p53-independent pathway in PL-treated CCA cells led to G2/M phase arrest and cell apoptosis. In addition, the study showed that PL trigger CCA cell lines death through JNK-ERK activation. Furthermore, the different antioxidant capacity of CCA cell lines also indicates the susceptibility of the cells to PL treatment. Our findings reveal that PL exhibits anti-tumor activity and has potential to be used as a chemotherapeutic agent against CCA.

Keywords: Anti-tumor activity; Cell apoptosis; Cholangiocarcinoma; Piperlongumine; Reactive oxygen species.

MeSH terms

  • Acetylcysteine / pharmacology
  • Antineoplastic Agents, Phytogenic / antagonists & inhibitors
  • Antineoplastic Agents, Phytogenic / isolation & purification
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects
  • Bile Ducts / drug effects
  • Bile Ducts / metabolism
  • Bile Ducts / pathology
  • Caspase 3 / genetics
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Dioxolanes / antagonists & inhibitors
  • Dioxolanes / isolation & purification
  • Dioxolanes / pharmacology*
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • G2 Phase Cell Cycle Checkpoints / drug effects*
  • G2 Phase Cell Cycle Checkpoints / genetics
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Glutathione / pharmacology
  • Humans
  • MAP Kinase Signaling System / drug effects
  • Piper / chemistry*
  • Poly(ADP-ribose) Polymerases / genetics
  • Poly(ADP-ribose) Polymerases / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Reactive Oxygen Species / agonists*
  • Reactive Oxygen Species / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • bcl-2-Associated X Protein / agonists
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism

Substances

  • Antineoplastic Agents, Phytogenic
  • BAX protein, human
  • BCL2 protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Dioxolanes
  • Proto-Oncogene Proteins c-bcl-2
  • Reactive Oxygen Species
  • Tumor Suppressor Protein p53
  • bcl-2-Associated X Protein
  • Poly(ADP-ribose) Polymerases
  • CASP3 protein, human
  • Caspase 3
  • Glutathione
  • piperlongumine
  • Acetylcysteine