Anti-tumor activity of CrTX in human lung adenocarcinoma cell line A549.

Abstract

AIM:

To assess the cytotoxic effect of crotoxin (CrTX), a potent neurotoxin extracted from the venom of the pit viper Crotalus durissus terrificus, in human lung adenocarcinoma A549 cells and investigated the underlying mechanisms.

METHODS:

A549 cells were treated with gradient concentrations of CrTX, and the cell cycle and apoptosis were analyzed using a flow cytometric assay. The changes of cellular effectors p53, caspase-3 and cleaved caspase-3, total P38MAPK and pP38MAPK were investigated using Western blot assays. A549 xenograft model was used to examine the inhibition of CrTX on tumor growth in vivo.

RESULTS:

Treatment of A549 cells with CrTX (25-200 μg/mL) for 48 h significantly inhibited the cell growth in a dose-dependent manner (IC(50)=78 μg/mL). Treatment with CrTX (25 μg/mL) for 24 h caused G1 arrest and induced cell apoptosis. CrTX (25 μg/mL) significantly increased the expression of wt p53, cleaved caspase-3 and phospho-P38MAPK. Pretreatment with the specific P38MAPK inhibitor SB203580 (5 μmol/L) significantly reduced CrTX-induced apoptosis and cleaved caspase-3 level, but G(1) arrest remained unchanged and highly expressed p53 sustained. Intraperitoneal injection of CrTX (10 μg/kg, twice a week for 4 weeks) significantly inhibited A549 tumor xenograft growth, and decreased MVD and VEGF levels.

CONCLUSION:

CrTX produced significant anti-tumor effects by inducing cell apoptosis probably due to activation of P38MAPK and caspase-3, and by cell cycle arrest mediated by increased wt p53 expression. In addition, CrTX displayed anti-angiogenic effects in vivo.

• Authors: Bin Ye, Yan Xie, Zheng-hong Qin, Jun-chao Wu, Rong Han, Jing-kang He
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 32 Issue 11 Pg. 1397-401 (Nov 2011) ISSN: 1745-7254 [Electronic] United States
• PMID: 21946324 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Tumor Suppressor Protein p53
• Crotoxin
• p38 Mitogen-Activated Protein Kinases
• Caspase 3

Topics

• Adenocarcinoma (drug therapy, genetics, metabolism)
• Adenocarcinoma of Lung
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Caspase 3 (genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Crotalus
• Crotoxin (pharmacology, therapeutic use)
• Female
• G1 Phase (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lung (drug effects, metabolism)
• Lung Neoplasms (drug therapy, genetics, metabolism)
• Mice
• Mice, Inbred BALB C
• Tumor Suppressor Protein p53 (genetics, metabolism)
• p38 Mitogen-Activated Protein Kinases (genetics, metabolism)