Apoptotic and anti-metastatic effects of the whole skin of Venenum bufonis in A549 human lung cancer cells

Abstract

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.

Boehmenan, a Lignan From the Chinese Medicinal Plant Clematis armandii, Inhibits A431 Cell Growth via Blocking p70S6/S6 Kinase Pathway

“… 6 Mitochondrial dysfunction triggers intracellular ROS production and ΔΨ m loss, which further causes degradation of caspase-9 and caspase-3 and subsequent cleavage of specific cellular death substrates (eg, PARP), ultimately leads to cell apoptosis. 24 In the present study, boehmenan treatment significantly induced production of intracellular ROS, loss of ΔΨ m , degradation of caspase-9, and cleavage of caspase-3 and PARP. In addition, our results also demonstrated that boehmenan time- and concentration-dependently decreased the anti-apoptotic factor Bcl-2 expression.…”

Cinobufagin Induces Cell Cycle Arrest at the G2/M Phase and Promotes Apoptosis in Malignant Melanoma Cells

“…Previously, Venenum Bufonis and Venenum Bufonis extracts were mainly used as a cardiac stimulant and tumor analgesic (28). In recent years, a large number of studies have shown that the extract of Venenum Bufonis can inhibit the proliferation of some tumor cells (29). As one of the active components of Venenum Bufonis, cinobufagin has also entered garnered interest from researchers, as it has been reported that cinobufagin can effectively inhibit the proliferation of lung cancer cells (30), liver cancer cells (17), prostate cancer cells (31), and osteosarcoma cells (32) in vitro .…”

TIMP-1 Inhibits Apoptosis in Lung Adenocarcinoma Cells via Interaction with Bcl-2

“…This study was undertaken to define the role of TIMP-1 in lung adenocarcinoma cell line. Although TIMP-1 is emerging as an important prognostic marker in clinical findings and several studies have documented the prognostic value of TIMP-1 in lung cancers [ 16 , 33 , 34 ], the antiapoptotic role of TIMP-1 has not been robustly addressed in lung adenocarcinoma cell lines, with the majority of studies having been carried out using the A549 cell line with conflicting results [ 35 , 36 ].…”