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Crotoxin (CrTX), a neurotoxin, is isolated from the venom of South Americanrattlesnakes and has potent antitumor activity. Here, we investigated the antitumoreffect of CrTX on the SK-MES-1 human lung squamous cell carcinoma cell line thathas acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors.CrTX caused G1 arrest and p-JNK protein upregulation that resulted in apoptosisof SK-MES-1 cells. SP600125, a specific inhibitor of p-JNK, could rescue SK-MES-1cells from CrTX-induced apoptosis. CrTX and gefinitib (Iressa) both inhibitedthe viability and proliferation of SK-MES-1 cells in a dose- and time-dependentmanner. The combination of CrTX and Iressa significantly enhanced the antitumoractivity of Iressa. In vivo studies revealed that CrTX caused increased damageto blood vessels and reduced tumor size when combined with Iressa. The presentstudy showed that the JNK signal transduction pathway mediated the anti-apoptoticeffect of CrTX, and furthermore, CrTX could enhance the antitumor effect of tyrosinekinase inhibitors in cells with acquired resistance.

Crotoxin enhances the antitumor activity of gefinitib (Iressa) in SK-MES-1 human lung squamous carcinoma cells