Carnosol, a dietary diterpene, displays growth inhibitory effects in human prostate cancer PC3 cells leading to G2-phase cell cycle arrest and targets the 5'-AMP-activated protein kinase (AMPK) pathway

Pharm Res. 2008 Sep;25(9):2125-34. doi: 10.1007/s11095-008-9552-0. Epub 2008 Feb 21.

Abstract

Purpose: This study examines the anti-cancer effect of carnosol in human prostate cancer PC3 cells and its role in modulating multiple signaling pathways associated with carcinogenesis.

Methods: PC3 cells were treated with carnosol and were evaluated using a flow cytometry, a protein array and Western blot analysis to identify signaling pathways targeted by carnosol.

Results: Using an MTT assay we found that carnosol (10-70 microM) decreases cell viability in a time and dose-dependent manner. Further analysis using flow cytometry as well as biochemical analysis identified G2-phase cell cycle arrest. To establish a more precise mechanism, we performed a protein array that evaluated 638 proteins involved in cell signaling pathways. The protein array identified 5'-AMP-activated protein kinase (AMPK), a serine/threonine protein kinase involved in the regulation of cellular energy balance as a potential target. Further downstream effects consistent with cancer inhibition included the modulation of the mTOR/HSP70S6k/4E-BP1 pathway. Additionally, we found that carnosol targeted the PI3K/Akt pathway in a dose dependent manner.

Conclusions: These results suggest that carnosol targets multiple signaling pathways that include the AMPK pathway. The ability of carnosol to inhibit prostate cancer in vitro suggests carnosol may be a novel agent for the management of PCa.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases
  • Abietanes / pharmacology*
  • Anticarcinogenic Agents / pharmacology*
  • Apoptosis Regulatory Proteins / metabolism
  • Blotting, Western
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Flow Cytometry
  • G2 Phase / drug effects*
  • Humans
  • Male
  • Multienzyme Complexes / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Prostatic Neoplasms / enzymology
  • Prostatic Neoplasms / pathology*
  • Prostatic Neoplasms / prevention & control
  • Protein Array Analysis
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects*
  • Time Factors

Substances

  • Abietanes
  • Anticarcinogenic Agents
  • Apoptosis Regulatory Proteins
  • Cell Cycle Proteins
  • Multienzyme Complexes
  • carnosol
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • AMP-Activated Protein Kinases