Crotoxin enhances the antitumor activity of gefinitib (Iressa) in SK-MES-1             human lung squamous carcinoma cells.
Crotoxin (CrTX), a neurotoxin, is isolated from the venom of South American             rattlesnakes and has potent antitumor activity. Here, we investigated the antitumor             effect of CrTX on the SK-MES-1 human lung squamous cell carcinoma cell line that             has acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors.             CrTX caused G1 arrest and p-JNK protein upregulation that resulted in apoptosis             of SK-MES-1 cells. SP600125, a specific inhibitor of p-JNK, could rescue SK-MES-1             cells from CrTX-induced apoptosis. CrTX and gefinitib (Iressa) both inhibited             the viability and proliferation of SK-MES-1 cells in a dose- and time-dependent             manner. The combination of CrTX and Iressa significantly enhanced the antitumor             activity of Iressa. In vivo studies revealed that CrTX caused increased damage             to blood vessels and reduced tumor size when combined with Iressa. The present             study showed that the JNK signal transduction pathway mediated the anti-apoptotic             effect of CrTX, and furthermore, CrTX could enhance the antitumor effect of tyrosine             kinase inhibitors in cells with acquired resistance.
Department of Cardiothoracic Surgery, the First Affiliated Hospital of Soochow University, and Department of Pharmacology, School of Pharmaceutical Science, Soochow University, Suzhou 215006, PR China.
Jun-Hua
JH
Wang
Yan
Y
Xie
Jun-Chao
JC
Wu
Rong
R
Han
Paul F
PF
Reid
Zheng-Hong
ZH
Qin
Jing-Kang
JK
He
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003439:Crotoxin / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011799:Quinazolines; D003439:Crotoxin; D066246:ErbB Receptors; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; D000077156:Gefitinib