Protoapigenone, a novel flavonoid, induces apoptosis in human prostate cancer cells through activation of p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase 1/2.

Abstract

In this study, we investigated the anticancer effect of protoapigenone on human prostate cancer cells. Protoapigenone inhibited cell growth through arresting cancer cells at S and G(2)/M phases as well as inducing apoptosis. Blockade of cell cycle by protoapigenone was associated with an increase in the levels of inactivated phospho (p)-Cdc25C (Ser216) and a decrease in the levels of activated p-cyclin B1 (Ser147), cyclin B1, and cyclin-dependent kinase (Cdk) 2. Protoapigenone triggered apoptosis by increasing the levels of cleaved poly(ADP-ribose) polymerase and caspase-3. In addition, activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK)1/2 was a critical mediator in protoapigenone-induced cell death. Inhibition of the expression of p38 MAPK and JNK1/2 by pharmacological inhibitors or specific small interfering RNA reversed the protoapigenone-induced apoptosis through decreasing the level of cleaved caspase-3. In contrast, p38 MAPK, but not JNK1/2, was involved in the protoapigenone-mediated S and G(2)/M arrest by modulating the levels of Cdk2 and p-Cdc25C (Ser216). Moreover, in vivo xenograft study showed that protoapigenone had a significant inhibition of prostate tumor growth without major side effects on the mice we tested. This inhibition was associated with induction of apoptosis and activation of p38 MAPK and JNK1/2 in protoapigenone-treated tumor tissues. In conclusion, our results demonstrated protoapigenone suppressed prostate cancer cell growth through the activation of p38 MAPK and JNK1/2, with the potential to be developed as a chemotherapeutic agent for prostate cancer.

• Authors: Hsueh-Ling Chang, Yang-Chang Wu, Jinu-Huang Su, Yao-Tsung Yeh, Shyng-Shiou F Yuan
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 325 Issue 3 Pg. 841-9 (Jun 2008) ISSN: 1521-0103 [Electronic] United States
• PMID: 18337475 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cyclohexanones
• Flavones
• protoapigenone
• Mitogen-Activated Protein Kinase 9
• Mitogen-Activated Protein Kinase 8
• p38 Mitogen-Activated Protein Kinases

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cyclohexanones (pharmacology, therapeutic use)
• Flavones (pharmacology, therapeutic use)
• Humans
• Male
• Mice
• Mice, Nude
• Mitogen-Activated Protein Kinase 8 (metabolism)
• Mitogen-Activated Protein Kinase 9 (metabolism)
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays
• p38 Mitogen-Activated Protein Kinases (metabolism)