Bromelain Inhibits COX-2 Expression by Blocking the Activation of MAPK Regulated NF-kappa B Against Skin Tumor-Initiation Triggering Mitochondrial Death Pathway

Cancer Lett. 2009 Sep 18;282(2):167-76. doi: 10.1016/j.canlet.2009.03.003. Epub 2009 Mar 31.

Abstract

Chemoprevention impels the pursuit for either single targeted or cocktail of multi-targeted agents. Bromelain, potential agent in this regard, is a pharmacologically active compound, present in stems and fruits of pineapple (Ananas cosmosus), endowed with anti-inflammatory, anti-invasive and anti-metastatic properties. Herein, we report the anti tumor-initiating effects of bromelain in 2-stage mouse skin tumorigenesis model. Pre-treatment of bromelain resulted in reduction in cumulative number of tumors (CNT) and average number of tumors per mouse. Preventive effect was also comprehended in terms of reduction in tumor volume up to a tune of approximately 65%. Components of the cell signaling pathways, connecting proteins involved in cell death were targeted. Bromelain treatment resulted in upregulation of p53 and Bax and subsequent activation of caspase 3 and caspase 9 with concomitant decrease in Bcl-2. A marked inhibition in cyclooxygenase-2 (Cox-2) expression and inactivation of nuclear factor-kappa B (NF-kappaB) was recorded, as phosphorylation and consequent degradation of I kappa B alpha was blocked by bromelain. Also, bromelain treatment curtailed extracellular signal regulated protein kinase (ERK1/2), p38 mitogen-activated protein kinase (MAPK) and Akt activity. The basis of anti tumor-initiating activity of bromelain was revealed by its time dependent reduction in DNA nick formation and increase in percentage prevention. Thus, modulation of inappropriate cell signaling cascades driven by bromelain is a coherent approach in achieving chemoprevention.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 9,10-Dimethyl-1,2-benzanthracene
  • Animals
  • Anticarcinogenic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Bromelains / pharmacology*
  • Cyclooxygenase 2 Inhibitors / pharmacology*
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors*
  • Female
  • Mice
  • Mitochondria / drug effects
  • NF-kappa B / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / physiology
  • Proto-Oncogene Proteins c-bcl-2 / analysis
  • Signal Transduction / drug effects*
  • Skin Neoplasms / prevention & control*
  • Tetradecanoylphorbol Acetate
  • Tumor Suppressor Protein p53 / analysis
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*

Substances

  • Anticarcinogenic Agents
  • Cyclooxygenase 2 Inhibitors
  • NF-kappa B
  • Proto-Oncogene Proteins c-bcl-2
  • Tumor Suppressor Protein p53
  • 9,10-Dimethyl-1,2-benzanthracene
  • Bromelains
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Tetradecanoylphorbol Acetate