Apoptotic and anti-metastatic effects of the whole skin of Venenum bufonis             in A549 human lung cancer cells.
In the present study, the effects of the whole skin of Venenum bufonis on             apoptotic and anti-invasive activity in A549 human lung cancer cells were investigated.             Treatment with extract of the whole skin of V. bufonis (SVB) resulted in a significant             decrease in cell growth of A549 cells, depending on dosage, which was associated             with apoptosis induction, as proved by chromatin condensation and accumulation             of apoptotic fraction. SVB treatment induced expression of death receptor-related             proteins, such as death receptor 4, which further triggered activation of caspase-8             and cleavage of Bid. In addition, the increase in apoptosis by SVB treatment was             correlated with dysfunction of mitochondria, activation of caspase-9 and -3, downregulation             of IAP family proteins, such as XIAP, cIAP-1 and cIAP-2, and concomitant degradation             of activated caspase-3-specific target proteins, such as poly (ADP-ribose) polymerase             and β-catenin proteins. However, z-DEVD-fmk, a caspase-3-specific inhibitor, blocked             SVB-induced apoptosis and increased the survival rate of SVB-treated cells, indicating             that activation of caspase-3 plays a key role in SVB-induced apoptosis. In addition,             within concentrations that were not cytotoxic to A549 cells, SVB induced marked             inhibition of cell motility and invasiveness. Activities of matrix metalloproteinase             (MMP)-2 and MMP-9 in AGS cells were dose-dependently inhibited by treatment with             SVB, and this was also correlated with a decrease in expression of their mRNA             and proteins, and upregulation of tissue inhibitors of metalloproteinase (TIMP)-1             and TIMP-2 mRNA expression. Further studies are needed; however, the results indicated             that SVB induces apoptosis of A549 cells through a signaling cascade of death             receptor-mediated extrinsic as well as mitochondria-mediated intrinsic caspase             pathways. Our data also demonstrated that MMPs are critical targets of SVB-induced             anti-invasiveness in A549 cells.
Department of East-West Cancer Center, College of Oriental Medicine,                     Daejeon University, Daejeon 301-724, Republic of Korea.
Jeong-Seok
JS
Park
Dong Yeok
DY
Shin
Yeon-Weol
YW
Lee
Chong-Kwan
CK
Cho
Gi Young
GY
Kim
Wun-Jae
WJ
Kim
Hwa-Seung
HS
Yoo
Yung Hyun
YH
Choi
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002018:Bufanolides / Q000737:chemistry*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D006801:Humans; D007527:Isoenzymes; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D012867:Skin / Q000737:chemistry; D014020:Tissue Extracts / Q000494:pharmacology*
D002018:Bufanolides; D007527:Isoenzymes; D014020:Tissue Extracts; C095591:chan su; D020169:Caspases