Guggulsterone-Induced Apoptosis in Human Prostate Cancer Cells Is Caused by Reactive Oxygen Intermediate–Dependent Activation of c-Jun NH2-Terminal Kinase

Abstract

Guggulsterone, a constituent of Indian Ayurvedic medicinal plant Commiphora mukul, causes apoptosis in cancer cells but the sequence of events leading to cell death is poorly understood. We now show that guggulsterone-induced cell death in human prostate cancer cells is caused by reactive oxygen intermediate (ROI)-dependent activation of c-Jun NH 2 -terminal kinase (JNK). Exposure of PC-3 and LNCaP cells to apoptosis inducing concentrations of guggulsterone resulted in activation of JNK and p38 mitogen-activated protein kinase (p38 MAPK) in both cell lines and activation of extracellular signal-regulated kinase 1/2 (ERK1/2) in LNCaP cells. The guggulsterone-induced apoptosis in PC-3/LNCaP cells was partially but statistically significantly attenuated by pharmacologic inhibition (SP600125) as well as genetic suppression of JNK activation. On the other hand, pharmacologic inhibition of p38 MAPK activation in PC-3 or LNCaP cells (SB202190) and ERK1/2 activation in LNCaP cells (PD98059) did not protect against guggulsterone-induced cell death. The guggulsterone treatment caused generation of ROI in prostate cancer cells but not in a normal prostate epithelial cell line (PrEC), which was also resistant to guggulsteronemediated JNK activation. The guggulsterone-induced JNK activation as well as cell death in prostate cancer cells was significantly attenuated by overexpression of catalase and superoxide dismutase. In addition, guggulsterone treatment resulted in a decrease in protein level and promoter activity of androgen receptor in LNCaP cells. In conclusion, the present study reveals that the guggulsterone-induced cell death in human prostate cancer cells is regulated by ROI-dependent activation of JNK and guggulsterone inhibits promoter activity of androgen receptor. [Cancer Res 2007;67(15):7439-49]

Guggulsterone inhibits human cholangiocarcinoma Sk-ChA-1 and Mz-ChA-1 cell growth by inducing caspase-dependent apoptosis and downregulation of survivin and Bcl-2 expression

“…In addition, typical DNA fragmentation, a hallmark of apoptosis, was also observed subsequent to the cells being treated with 60 µmol/l Z-guggulsterone for 48 and 72 h. Flow cytometry revealed that Z-guggulsterone induced apoptosis in cholangiocarcinoma Sk-ChA-1 and Mz-ChA-1 cells in a time-and dose-dependent manner. Consistently, the present findings were supported by previous studies that identified similar effects of guggulsterone in other types of cancer cells (13)(14)(15)(16).…”

“…As the main substrate of caspases, the alteration in the expression of cleaved PARP also supports this conclusion. Consistent with the present results, several other studies have reported that caspase-dependent apoptosis induced by guggulsterone also occurred in prostate and colon cancer cells (13,16). Additional studies investigating the possibility that guggulsterone triggers apoptosis through caspase-independent pathways are required in the future, as the caspase inhibitors used in the present study did not completely abolish guggulsterone-induced apoptosis.…”

“…Previous studies have reported that guggulsterone possesses anticancer potential due to the anti-proliferative and apoptosis-inducing effects exerted by this agent on a panel of human cancers, including leukemia, breast carcinoma, prostate cancer, colorectal cancer, pancreatic carcinoma and esophageal cancer (13)(14)(15)(16)(17)(18).…”

The plant sterol guggulsterone attenuates inflammation and immune dysfunction in murine models of inflammatory bowel disease

“…Previous works [41][42][43] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Mencarelli et al, 19…”

Mechanisms of Superoxide Signaling in Epigenetic Processes: Relation to Aging and Cancer

“…This is typical for prostate cells [17][18][19][20][21][22][23][24][25], pancreatic cancer cells [26][27][28][29][30][31][32][33], melanoma cells [34][35], breast cancer cells [36][37][38][39], and other cancer cells [40][41][42][43][44][45][46][47][48][49][50]. It is important that the elevated ROS formation in cancer cells can have both surviving and hindering effects.…”