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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

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

Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan (H.-L.C., Y.-C.W.); Department of Medical Research and Obstetrics and Gynecology, E-DA Hospital, I-Shou University, Kaohsiung, Taiwan (H.-L.C., S.-S.F.Y.); Department of Obstetrics and Gynecology, Kaohsiung Medical University, Kaohsiung, Taiwan (J.-H.S.); Department of Medical Technology, Fooyin University, Kaohsiung, Taiwan (Y.-T.Y.); and Department of Biological Science and Technology, I-Shou University, Kaohsiung, Taiwan (S.-S.F.Y.)

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 G₂/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 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.

Address correspondence to: Dr. Shyng-Shiou F. Yuan, Department of Medical Research, E-DA Hospital, I-Shou University, 6, E-DA Rd., Jiau-Shu Tsuen, Yan-Chau Shiang, Kaohsiung County, Taiwan 824, Republic of China. E-mail: yuanssf{at}ms33.hinet.net