Anti-cancer effects of Piper nigrum via inducing multiple molecular signaling in vivo and in vitro

J Ethnopharmacol. 2016 Jul 21;188:87-95. doi: 10.1016/j.jep.2016.04.047. Epub 2016 May 4.


Ethnopharmacological relevance: Piper nigrum is widely used as a folk medicine including usage for pain relief, fevers, as well as an anti-cancer agent. However the crude extract of piperine free P. nigrum (PFPE), which inhibits breast cancer, and its mechanisms are still being kept secret. This research aims to elucidate the anti-cancer effects of PFPE and its mechanisms.

Materials and methods: Anti-cancer effects of PFPE were investigated in N-nitroso-N-methylurea (NMU)-induced mammary tumorigenesis rats and breast cancer cell lines MCF-7 and ZR-75-1. Furthermore, the cancer prevention effects of PFPE were investigated in rats. Western blotting was employed to study protein levels induced by PFPE.

Results: PFPE was found to up-regulate p53, and down-regulate estrogen receptor (ER), E-cadherin (E-cad), matrix metalloproteinase 9 (MMP-9), matrix metalloproteinase 2 (MMP-2), c-Myc, and vascular endothelial growth factor (VEGF) levels in breast cancer rats. Moreover, PFPE decreased protein levels of E-cad, c-Myc, and VEGF in MCF-7 cells. These results suggest that PFPE can enhance breast cancer cell response to phytochemicals, then induce cell cycle arrest, and inhibit cancer cell proliferation resulting in tumor size decrease in the PFPE treated group. It further suggests that PFPE may suppress tumor cell invasion, migration, and angiogenesis. In addition, PFPE possessed cancer prevention effects through generation of reactive oxygen species (ROS) to higher cancer cell cellular stress.

Conclusions: PFPE may possess anti-cancer and cancer prevention effects; hence, it deserves further investigation as a novel candidate for breast cancer treatment.

Keywords: Anti-cancer; Breast cancer; MCF-7; Piper nigrum; ZR-75-1.

MeSH terms

  • Angiogenic Proteins / metabolism
  • Animals
  • Anticarcinogenic Agents / isolation & purification
  • Anticarcinogenic Agents / pharmacology*
  • Antineoplastic Agents / isolation & purification
  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Cycle Checkpoints / drug effects
  • Cell Cycle Proteins / metabolism
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Female
  • Humans
  • MCF-7 Cells
  • Mammary Neoplasms, Experimental / chemically induced
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology
  • Mammary Neoplasms, Experimental / prevention & control*
  • Methylnitrosourea
  • Neoplasm Invasiveness
  • Neovascularization, Pathologic
  • Oxidative Stress / drug effects
  • Phytotherapy
  • Piper nigrum / chemistry*
  • Plant Extracts / isolation & purification
  • Plant Extracts / pharmacology*
  • Plants, Medicinal
  • Proton Magnetic Resonance Spectroscopy
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects*
  • Time Factors


  • Angiogenic Proteins
  • Anticarcinogenic Agents
  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Plant Extracts
  • Reactive Oxygen Species
  • Methylnitrosourea