Ponicidin, an ent-kaurane diterpenoid derived from a constituent of the herbal supplement PC-SPES, Rabdosia rubescens, induces apoptosis by activation of caspase-3 and mitochondrial events in lung cancer cells in vitro.
Ponicidin, an ent-kaurane diterpenoid derived from a constituent of the herbal supplement PC-SPES, Rabdosia rubescens, is recently reported to have anti-tumor effects on a large variety of cancers. In this study, we demonstrate that ponicidin exhibits cytotoxicity, induces apoptosis, disrupts the mitochondrial membrane potential, and triggers the activation of caspase-3, -8 and -9 in lung cancer A549 and GLC-82 cells. Ponicidin treatment of lung cancer cells caused downregulation of anti-apoptotic protein Bcl-2 and survivin as well as upregulaton of pro-apoptotic protein Bax in a time dependent manner when apoptosis ocurred. Ponicidin induced activation of caspase-3 can be blocked by a caspase-3-specific inhibitor z-DEVD-FMK Furthermore, the caspase-8-specific inhibitor z-IETD-FMK could block the ponicidin-induced activation of caspase-3, PARP cleavage, and prevented the release of cytochrome c from mitochondria into the cytoplasm. This indicate that activated caspase-8 initiates the release of cytochrome c during ponicidin-induced apoptosis. We therefore conclude that ponicidin has significant apoptosis-inducing effects by activation of caspase-3 -8, and -9 as well as downregulation of anti-apoptotic protein Bcl-2, survivin and upregulation of pro-apoptotic protein Bax, with caspase-8 acting as an upstream activator. The data offer a potential mechanism for ponicidin-induced apoptosis in lung cancer cells, suggesting that ponicidin may severve as an effective reagent for the treatment of lung cancer, and that in vivo anti-cancer effects as well as its potential clinical effectiveness need further investigation.
Department of Hematology and Oncology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China.
Jia Jun
JJ
Liu
Ren Wei
RW
Huang
Dong Jun
DJ
Lin
Jun
J
Peng
Maohong
M
Zhang
Xianglin
X
Pan
Ming
M
Hou
Xiang Yuan
XY
Wu
Qu
Q
Lin
Feng
F
Chen
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000494:pharmacology*; D004365:Drugs, Chinese Herbal / Q000737:chemistry*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D051034:Inhibitor of Apoptosis Proteins; D037602:Isodon / Q000737:chemistry; D008175:Lung Neoplasms / Q000188:drug therapy*; D008564:Membrane Potentials / Q000187:drug effects; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000187:drug effects / Q000378:metabolism; D008517:Phytotherapy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin
C107489:BIRC5 protein, human; D004224:Diterpenes; D004365:Drugs, Chinese Herbal; D004791:Enzyme Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D000077022:Survivin; C114209:herbal preparation PC-SPES; C090365:ponicidin; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases