Wedelolactone, a medicinal plant-derived coumestan, induces caspase-dependent             apoptosis in prostate cancer cells via downregulation of PKCε without inhibiting             Akt.
Emerging studies indicate that metabolism of arachidonic acid through the             5-lipoxygenase (5-Lox) pathway plays a critical role in the survival of prostate             cancer cells raising the possibility that 5-Lox can be targeted for an effective             therapy of prostate cancer. Wedelolactone (WDL), a medicinal plant-derived natural             compound, is known to inhibit 5-Lox activity in neutrophils. However, its effect             on apoptosis in prostate cancer cells has not been addressed. Thus, we tested             the effects of WDL on human prostate cancer cells in vitro. We observed that WDL             kills both androgen-sensitive as well as androgen-independent prostate cancer             cells in a dose-dependent manner by dramatically inducing apoptosis. We also found             that WDL-induced apoptosis in prostate cancer cells is dependent on c-Jun N-terminal             Kinase (c-JNK) and caspase-3. Interestingly, WDL triggers apoptosis in prostate             cancer cells via downregulation of protein kinase Cε (PKCε), but without inhibition             of Akt. WDL does not affect the viability of normal prostate epithelial cells             (PrEC) at doses that kill prostate cancer cells, and WDL-induced apoptosis is             effectively prevented by 5-oxoETE, a metabolite of 5-Lox (but not by 15-oxoETE,             a metabolite of 15-Lox), suggesting that the apoptosis-inducing effect of WDL             in prostate cancer cells is mediated via inhibition of 5-Lox activity. These findings             indicate that WDL selectivity induces caspase-dependent apoptosis in prostate             cancer cells via a novel mechanism involving inhibition of PKCε without affecting             Akt and suggest that WDL may emerge as a novel therapeutic agent against clinical             prostate cancer in human.
Vattikuti Urology Institute, Henry Ford Health System, Detroit, MI 48202, USA.
Sivalokanathan
S
Sarveswaran
Subhash C
SC
Gautam
Jagadananda
J
Ghosh
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003374:Coumarins / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism*; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
D000970:Antineoplastic Agents; D003374:Coumarins; C051122:wedelolactone; D051057:Proto-Oncogene Proteins c-akt; D051744:Protein Kinase C-epsilon; D048670:MAP Kinase Kinase 4; D020169:Caspases