title: The role of BIM-EL and BCL2-α on the efficacy of erlotinib and gefitinib in lung cancer.
abstract: Tyrosine kinase inhibitors (TKI), erlotinib and gefitinib are small molecule inhibitors which are used for the treatment of lung cancer. But, the development of drug resistance has been reported as one of the major setbacks in oncology. This study focused on the mechanisms leading to secondary resistance by assessing the gene expression of BCL2 family proteins which are associated with the intrinsic apoptotic signaling pathway. 8 genes were investigated in erlotinib and gefitinib treated cells by real time PCR and protein analysis by western blotting. The cells were exposed to the test drugs 48h prior to RNA or protein isolation. It was observed that BIM-EL, a pro-apoptotic protein was up-regulated in cells sensitive to the drugs but not in the resistant cells. On the other hand BCL2-α, an anti-apoptotic protein was up-regulated in the resistant cells and not in the sensitive cells. BCL2-α revealed a counter-regulation effect on BIM-EL and this effect is probably one of the causes of secondary resistance to erlotinib and gefitinib.
authors.affiliation: Fraunhofer-Institut für Zelltherapie und Immunologie, Leipzig, Germany; Institut für Pharmazie, Universität Leipzig, Leipzig, Germany. Electronic address: jacinta.simasi@izi.fraunhofer.de.
authors.forename: Jacinta
authors.initials: J
authors.lastname: Simasi
authors.affiliation: Fraunhofer-Institut für Zelltherapie und Immunologie, Leipzig, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Oelkrug
authors.affiliation: Fraunhofer-Institut für Zelltherapie und Immunologie, Leipzig, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schubert
authors.affiliation: Institut für Pharmazie, Universität Leipzig, Leipzig, Germany.
authors.forename: Karen
authors.initials: K
authors.lastname: Nieber
authors.affiliation: Klinik für Lungen - und Bronchialmedizin, Klinikum Kassel, Kassel Medical School, Germany.
authors.forename: Adrian
authors.initials: A
authors.lastname: Gillissen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology*; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C579095:MCL1 protein, human; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011799:Quinazolines; D012333:RNA, Messenger; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib
keywords: Apoptosis regulators; BCL2 proteins; Lung cancer; Resistance; Tyrosine kinase inhibitors