Panaxydol induces apoptosis through an increased intracellular calcium level, activation of JNK and p38 MAPK and NADPH oxidase-dependent generation of reactive oxygen species

Abstract

Panaxydol, a polyacetylenic compound derived from Panax ginseng roots, has been shown to inhibit the growth of cancer cells. In this study, we demonstrated that panaxydol induced apoptosis preferentially in transformed cells with a minimal effect on non-transformed cells. Furthermore, panaxydol was shown to induce apoptosis through an increase in intracellular Ca(2+) concentration ([Ca(2+)](i)), activation of JNK and p38 MAPK, and generation of reactive oxygen species (ROS) initially by NADPH oxidase and then by mitochondria. Panaxydol-induced apoptosis was caspase-dependent and occurred through a mitochondrial pathway. ROS generation by NADPH oxidase was critical for panaxydol-induced apoptosis. Mitochondrial ROS production was also required, however, it appeared to be secondary to the ROS generation by NADPH oxidase. Activation of NADPH oxidase was demonstrated by the membrane translocation of regulatory p47(phox) and p67(phox) subunits and shown to be necessary for ROS generation by panaxydol treatment. Panaxydol triggered a rapid and sustained increase of [Ca(2+)](i), which resulted in activation of JNK and p38 MAPK. JNK and p38 MAPK play a key role in activation of NADPH oxidase, since inhibition of their expression or activity abrogated membrane translocation of p47(phox) and p67(phox) subunits and ROS generation. In summary, these data indicate that panaxydol induces apoptosis preferentially in cancer cells, and the signaling mechanisms involve a [Ca(2+)](i) increase, JNK and p38 MAPK activation, and ROS generation through NADPH oxidase and mitochondria.

Panaxydol, a component of Panax ginseng, induces apoptosis in cancer cells through EGFR activation and ER stress and inhibits tumor growth in mouse models

“…1b). As an increase in [Ca 21 ]c triggered activation of NADPH oxidase and apoptosis as previously shown, 5 the effect of U73122 on panaxydol-induced cytoplasmic ROS generation and apoptosis was examined. As expected, U73122 blocked both cytoplasmic ROS generation and apoptosis ( Fig.…”

“…5 We initially examined whether the increase in [Ca 21 ]c was due to ER Ca 21 release. In MCF-7 cells, both 2-APB, an IP 3 R inhibitor, and dantrolene, a ryanodine receptor (RyR) inhibitor, blocked the panaxydol-induced increase in [Ca 21 ]c ( ]c (Fig.…”

“…other events. In fact, ROS generation by NADPH oxidase, which occurred 10-15 min after panaxydol treatment, 5 To address the molecular mechanism linking cytoplasmic oxidative stress and elevated [Ca 21 ]m, we evaluated whether ER stress was involved. Initially, ER stress markers were analyzed in MCF-7 cells treated with 20 lg/ml panaxydol.…”

“…[1][2][3][4] It has been shown that panaxydol (heptadeca-1-en-4,6-diyn-9,10-epoxy-3-ol), one of the C17 polyacetylenic compounds of P. ginseng, induces G1 cell cycle arrest or apoptosis in cancer cells depending on the concentration. 4,5 We also previously reported that the mechanisms of panaxydol-induced apoptosis involve a rapid increase in the cytoplasmic Ca 21 concentration ([Ca 21 ]c), activating NADPH oxidase via p38/JNK. NADPH oxidase activation induces oxidative stress and triggers mitochondria-dependent apoptosis.…”

Two Novel Curcumin Analogues Induced Reactive Oxygen Species Generation and Mitochondrial-Related Apoptosis in Human Breast Cancer MCF - 7 Cells

“…A number of studies have implicated ROS generated in the mitochondria as key players in the induction of apoptosis [12]. ROS generation increased markedly (by 72.12% and 88.15%) in MCF -7 cells treated with F3 and LE, as compared with control cells (Figures 2c and 2d).…”