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

• Published in: Pharmaceutical research 2008-09, Vol.25 (9), p.2125-2134
• Main Authors: Johnson, Jeremy J., Syed, Deeba N., Heren, Chenelle R., Suh, Yewseok, Adhami, Vaqar M., Mukhtar, Hasan
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; AMP-activated protein kinase; AMP-Activated Protein Kinases; Anticarcinogenic Agents - pharmacology; Apoptosis Regulatory Proteins - metabolism; Biochemical analysis; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Blotting, Western; Carcinogenesis; Cell cycle; Cell Cycle Proteins - metabolism; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Cell signaling; Cell Survival - drug effects; Cell viability; Diterpenes, Abietane - pharmacology; Dose-Response Relationship, Drug; Energy balance; Flow Cytometry; G2 Phase - drug effects; Humans; Kinases; Male; Medical Law; Multienzyme Complexes - metabolism; Pharmacology; Pharmacology/Toxicology; Pharmacy; Phosphatidylinositol 3-Kinases - metabolism; Phytochemicals; Prostate cancer; Prostatic Neoplasms - enzymology; Prostatic Neoplasms - pathology; Prostatic Neoplasms - prevention & control; Protein Array Analysis; Protein arrays; Protein-Serine-Threonine Kinases - metabolism; Protein-serine/threonine kinase; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Research Paper; Signal transduction; Signal Transduction - drug effects; Time Factors; TOR protein
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-008-9552-0

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 μM) decreases cell viability in a time and dose-dependent manner. Further analysis using flow cytometry as well as biochemical analysis identified G 2 -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.