Induction of apoptosis in human lung carcinoma cells by the water extract of Panax notoginseng is associated with the activation of caspase-3 through downregulation of Akt.
The root of Panax notoginseng is highly valued and commonly used in Oriental medicine. Although recent experimental data have revealed the proapoptotic potency of P. notoginseng extracts, the underlying molecular mechanisms of this apoptotic activity have not yet been studied in detail. In the present study, the effects of the water extract of P. notoginseng (WEPN) on the growth of human lung carcinoma cells were investigated. It was found that the exposure of A549 and NIC-H460 cells to WEPN resulted in growth inhibition and the induction of apoptosis in a dose-dependent manner. The WEPN treatment induced the upregulation of pro-apoptotic Bax, downregulation of anti-apoptotic Bcl-2 expression and loss of mitochondrial membrane potential (MMP), which was associated with the proteolytic activation of caspases and the concomitant degradation of poly(ADP ribose) polymerase (PARP) protein. However, the caspase-3-specific inhibitor z-DEVD-fmk blocked PARP degradation and increased the survival rate of WEPN-treated cells. Moreover, the activity of Akt was downregulated in WEPN-treated cells and the phosphatidylinositol-3 kinase (PI3K)/Akt inhibitor LY294002 sensitized the cells to WEPN-induced apoptosis through enhancing the activation of caspase-3 and loss of MMP. The results indicated that the major regulators of WEPN-induced apoptosis in human lung carcinoma cells are the Bcl-2 family and caspase-3, which are associated with mitochondrial dysfunction and dephosphorylation of the Akt signaling pathway.
Park
Seung Chan
SC
Department of East-West Cancer Center, College of Oriental Medicine, Daejeon University, Daejeon 301-724, Korea.
Yoo
Hwa Seung
HS
Park
Cheol
C
Cho
Chong Kwan
CK
Kim
Gi-Young
GY
Kim
Wun-Jae
WJ
Lee
Yeon-Weol
YW
Choi
Yung Hyun
YH
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D004789:Enzyme Activation; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D009025:Morpholines / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; C494826:BAX protein, human; D002867:Chromones; D015853:Cysteine Proteinase Inhibitors; D004365:Drugs, Chinese Herbal; D009025:Morpholines; D009842:Oligopeptides; C519374:Panax notoginseng extract; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D011065:Poly(ADP-ribose) Polymerases; D051057:Proto-Oncogene Proteins c-akt; C505407:CASP3 protein, human; D053148:Caspase 3