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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on March 12, 2008; DOI: 10.1124/jpet.107.135442

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Received for publication December 20, 2007.
Revised March 10, 2008.
Accepted for publication March 11, 2008.

Protoapigenone, a novel flavonoid, induces apoptosis in human prostate cancer cells through activation of p38 MAPK and JNK1/2

Hsueh-Ling Chang 1, Yang-Chang Wu 1, Jinu-Huang Su 2, Yao-Tsung Yeh 3, Shyng-Shiou Yuan 4*

1 Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan 2 Department of Obstetrics and Gynecology, Kaohsiung Medical University, Kaohsiung, Taiwan 3 Department of Medical Technology, Fooyin University, Kaohsiung, Taiwan 4 Department of Medical Research and Obstetrics and Gynecology, E-DA Hospital, I-Shou University, Kaoh

* Address correspondence to: E-mail: yuanssf{at}ms33.hinet.net

Abstract

In this study, we investigated the anti-cancer effect of protoapigenone on human prostate cancer cells. Protoapigenone inhibited cell growth through arresting cancer cells at S and G2/M phases as well as inducing apoptosis. Blockade of cell cycle by protoapigenone was associated with an increase in the levels of inactivated p-Cdc25C (Ser216), and a decrease in the levels of activated p-Cyclin B1 (Ser147), Cyclin B1 and Cdk2. Protoapigenone triggered apoptosis by increasing the levels of cleaved PARP and caspase-3. In addition, activation of p38 MAPK and JNK1/2 was a critical mediator in protoapigenone-induced cell death. Inhibition of the expression of p38 MAPK and JNK1/2 by pharmacological inhibitors or specific siRNA reversed the protoapigenone-induced apoptosis through decreasing the level of cleaved caspase-3. On the other hand, p38 MAPK, but not JNK1/2, was involved in the protoapigenone-mediated S and G2/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.


Key words: Apoptosis, JNK1/2, Prostate cancer, Protoapigenone, T. torresiana, p38 MAPK




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