Piperine, an alkaloid from black pepper, inhibits growth of human colon cancer cells via G1 arrest and apoptosis triggered by endoplasmic reticulum stress

Mol Carcinog. 2015 Oct;54(10):1070-85. doi: 10.1002/mc.22176. Epub 2014 May 13.


Piperine, a piperidine alkaloid present in black pepper, inhibits the growth of cancer cells, although the mechanism of action is not well understood. In this study, we show that piperine (75-150 µM) inhibited the growth of several colon cancer cell lines but had little effect on the growth of normal fibroblasts and epithelial cells. Piperine inhibited HT-29 colon carcinoma cell proliferation by causing G1 phase cell cycle arrest that was associated with decreased expression of cyclins D1 and D3 and their activating partner cyclin-dependent kinases 4 and 6, as well as reduced phosphorylation of the retinoblastoma protein and up-regulation of p21/WAF1 and p27/KIP1 expression. In addition, piperine caused hydroxyl radical production and apoptosis that was partially dependent on the production of reactive oxygen species. Piperine-treated HT-29 cells showed loss of mitochondrial membrane integrity and cleavage of poly (ADP-ribose) polymerase-1, as well as caspase activation and reduced apoptosis in the presence of the pan-caspase inhibitor zVAD-FMK. Increased expression of the endoplasmic reticulum stress-associated proteins inositol-requiring 1α protein, C/EBP homologous protein, and binding immunoglobulin protein, and activation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, as well as decreased phosphorylation of Akt and reduced survivin expression were also observed in piperine-treated HT-29 cells. Furthermore, piperine inhibited colony formation by HT-29 cells, as well as the growth of HT-29 spheroids. Cell cycle arrest and endoplasmic reticulum stress-associated apoptosis following piperine treatment of HT-29 cells provides the first evidence that piperine may be useful in the treatment of colon cancer.

Keywords: caspase; cell cycle; cytotoxicity; phytochemical; stress-associated protein kinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids / pharmacology*
  • Apoptosis / drug effects*
  • Benzodioxoles / pharmacology*
  • Cell Cycle Checkpoints / drug effects*
  • Cell Proliferation / drug effects*
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / metabolism
  • Cyclin-Dependent Kinases / metabolism
  • Cyclins / metabolism
  • Endoplasmic Reticulum Stress / drug effects
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • G1 Phase / drug effects*
  • HT29 Cells
  • Humans
  • Inhibitor of Apoptosis Proteins / metabolism
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Piper nigrum / chemistry
  • Piperidines / pharmacology*
  • Polyunsaturated Alkamides / pharmacology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-jun / metabolism
  • Reactive Oxygen Species / metabolism
  • Survivin
  • Up-Regulation / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Alkaloids
  • BIRC5 protein, human
  • Benzodioxoles
  • Cyclins
  • Inhibitor of Apoptosis Proteins
  • Piperidines
  • Polyunsaturated Alkamides
  • Proto-Oncogene Proteins c-jun
  • Reactive Oxygen Species
  • Survivin
  • Proto-Oncogene Proteins c-akt
  • Cyclin-Dependent Kinases
  • p38 Mitogen-Activated Protein Kinases
  • piperine