(8<i>R</i>)-3β,8-Dihydroxypolypoda-13<i>E</i>,17<i>E</i>,21-triene Induces Cell Cycle Arrest and Apoptosis in Treatment-Resistant Prostate Cancer Cells

Abstract

Mastic, a resinous exudate from Pistacia lentiscus, has been reported to exhibit selective cytotoxicity against different cancer cell lines. There are, however, no data published correlating distinct mastic-derived compounds with the postulated cytotoxic activity. A polypodane-type bicyclic triterpenoid, (8R)-3β,8-dihydroxypolypoda-13E,17E,21-triene (1), was isolated from P. lentiscus oleogum resin. In androgen-independent PC-3 prostate cancer cells, 1 potently inhibited the expression of cyclins D1 and E, but had no effect on the expression of the cyclin kinase inhibitor p21(Waf1/Cip1). Inhibition of the expression of cell cycle-regulating cyclins resulted in cell cycle arrest in the G₀/G₁ phase, reduction in the number of cells in the S phase, and the triggering of apoptosis, as detected by increased expression of phosphatidylserine on the cell surface and by formation of DNA laddering. In addition, 1 suppressed the formation of prostate cancer colonies in soft agar and inhibited proliferation, angiogenesis, and the growth of prostate tumors xenografted onto chick chorioallantoic membranes without overt systemic toxicity. Taken together, these data show that 1 triggers apoptosis in chemoresistant, androgen-independent human prostate cancer cells in vitro and in vivo. Thus, 1 may serve as a lead compound for targeting so far incurable androgen-insensitive prostate cancers.