title: Gefitinib enhances oxaliplatin-induced apoptosis mediated by Src and PKC-modulated gap junction function.
abstract: Chemotherapeutic drug-induced apoptosis is enhanced by gap junction intercellular communication (GJIC) in a variety of tumor cells. Oxaliplatin and gefitinib are the most widely used chemotherapeutic drugs. However, the synergistic influence remains unknown in testicular cancer chemotherapy. The aim of the present study was to investigate the apoptosis induced by oxaliplatin combined with gefitinib and the potential mechanisms in I-10 testicular cancer cells. The results showed that gefitinib significantly enhanced oxaliplatin-induced apoptosis. Furthermore, the ratio of Bcl-2/Bax and the cleavage of caspase-3 and -9 were increased by gefitinib during oxaliplatin-induced apoptosis. The oxaliplatin-induced apoptosis was enhanced through the upregulation of gap junction (GJ) channels composed of connexin 43 (Cx43) by gefitinib. The mechanism of GJIC enhancement involved the suppression by gefitinib of the expression levels of Src and PKC, which phosphorylate Cx43 and reduce GJIC. PP2 (Src inhibitor) and GF109203X (PKC inhibitor) also enhanced GJIC function. Our findings demonstrated that gefitinib enhanced oxaliplatin-induced apoptosis in I-10 cells and gefitinib upregulated the GJIC by inhibiting Src and PKC-modulated Cx43 phosphorylation.
authors.affiliation: Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China.
authors.forename: Jian-Feng
authors.initials: JF
authors.lastname: Wu
authors.affiliation: Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Ji
authors.affiliation: Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China.
authors.forename: Shu-Ying
authors.initials: SY
authors.lastname: Dong
authors.affiliation: Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China.
authors.forename: Bei-Bei
authors.initials: BB
authors.lastname: Li
authors.affiliation: Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China.
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Yu
authors.affiliation: Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China.
authors.forename: Dan-Dan
authors.initials: DD
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Liang
authors.initials: L
authors.lastname: Tao
authors.affiliation: Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China.
authors.forename: Xu-Hui
authors.initials: XH
authors.lastname: Tong
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D018031:Connexin 43 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D017629:Gap Junctions / Q000201:enzymology*; D000077156:Gefitinib; D006801:Humans; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C494826:BAX protein, human; C000595707:BCL2 protein, human; D018031:Connexin 43; D009944:Organoplatinum Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D011799:Quinazolines; D051028:bcl-2-Associated X Protein; D000077150:Oxaliplatin; D019061:src-Family Kinases; D011493:Protein Kinase C; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D000077156:Gefitinib