Wedelolactone, a medicinal plant-derived coumestan, induces caspase-dependent apoptosis in prostate cancer cells via downregulation of PKCε without inhibiting Akt

Abstract

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.

Wedelolactone protects human bronchial epithelial cell injury against cigarette smoke extract-induced oxidant stress and inflammation responses through Nrf2 pathway

“…1) is isolated from Eclipta prostrata L. It has been previously reported to inhibit the growth of various cancer cells, such as prostate cancer cells [13], breast cancer cells [14], and pituitary adenoma cells [15]. In previous studies, we found E. prostrata L. extract, can protect NHBE cell against CSE-induced activation.…”

Protein Kinase C (PKC) Isozymes and Cancer

“…These drugs include wedelolactone, a medicinal plant-derived coumestan [448]; a second-generation selenium compound, methylseleninic acid [449]; a specific inhibitor of 5-LOX activity, MK591 [450]; and plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) [451]. One study, however, has suggested that prostate cancer cells overexpressing PKC exhibit sensitivity to bryostatin 1-induced cell death [423].…”

Assessment of Augmented Immune Surveillance and Tumor Cell Death by Cytoplasmic Stabilization of p53 as a Chemopreventive Strategy of 3 Promising Medicinal Herbs in Murine 2-Stage Skin Carcinogenesis

“…56 Alpha-cadinol (an alcohol) found in variety of plants, including C officinalis, can induce cytotoxicity in cancer cells of different origins. 57 In summary, the genesis of tumors is not mere hyperproliferation but a process perturbed by a plethora of individual events that include inflammation, altered cell survival, and progression of cell cycle.…”