Sensitization of HER-2/neu-overexpressing non-small cell lung cancer cells to chemotherapeutic drugs by tyrosine kinase inhibitor emodin.
Overexpression of the HER-2/neu proto-oncogene which encodes tyrosine kinase receptor p185neu, has been observed frequently in many human cancers, including non-small cell lung cancer (NSCLC), and is correlated with poor patient survival in these cancers. In addition, HER-2/neu overexpression in NSCLC is known to induce chemoresistance. Recently, we demonstrated that emodin, a tyrosine kinase inhibitor, suppresses HER-2/neu tyrosine kinase activity in HER-2/neu-overexpressing breast cancer cells and preferentially represses proliferation of these cells. The work described here was carried out to examine (1) whether the tyrosine kinase activity of p185neu is required for resistance to chemotherapeutic drugs of HER-2/neu-overexpressing NSCLC cells and (2) whether the tyrosine kinase inhibitor emodin can sensitize these cells to chemotherapeutic drugs. We found that emodin decreased tyrosine phosphorylation of HER-2/neu and preferentially suppressed proliferation of HER-2/neu-overexpressing NSCLC cells. Furthermore, the combination of emodin with cisplatin, doxorubicin or etoposide (VP16) synergistically inhibited the proliferation of HER-2/neu-overexpressing lung cancer cells, whereas low doses of emodin, cisplatin, doxorubicin, or VP16 alone had only minimal antiproliferative effects on these cells. These results indicate that tyrosine kinase activity is required for the chemoresistant phenotype of HER-2/neu-overexpressing NSCLC cells and that tyrosine kinase inhibitors such as emodin can sensitize these cells to chemotherapeutic drugs. The results may have important implications in chemotherapy for HER-2/neu-overexpressing cancers.
Zhang
L
L
Department of Tumor Biology, University of Texas MD Anderson Cancer Center, Houston 77030, USA.
Hung
M C
MC
D000970:Antineoplastic Agents / Q000633:toxicity*; D002289:Carcinoma, Non-Small-Cell Lung; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity; D004347:Drug Interactions; D004642:Emodin / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000633:toxicity; D015870:Gene Expression; D018734:Genes, erbB-2; D006801:Humans; D008175:Lung Neoplasms; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D011994:Recombinant Proteins / Q000096:biosynthesis; D014162:Transfection; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002945:Cisplatin; D004317:Doxorubicin; D004642:Emodin; D004791:Enzyme Inhibitors; D005047:Etoposide; D011505:Protein-Tyrosine Kinases; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins; C000715470:MAS1 protein, human