title: Enhancement of vinorelbine-induced cytotoxicity and apoptosis by clomipramine and lithium chloride in human neuroblastoma cancer cell line SH-SY5Y.
abstract: The aim of this work is to investigate whether clomipramine (CIM) and lithium chloride (LiCl) potentiate the cytotoxicity of vinorelbine (VNR) on SH-SY5Y human neuroblastoma cells in vitro and whether midkine (MK) can be a resistance factor for these treatments. Four groups of experiments were performed for 96 h using both monolayer and spheroid cultures of SH-SY5Y cells: (1) control group, (2) singly applied VNR, CIM, and LiCl, (3) VNR with CIM, and (4) VNR with LiCl. Their effects on monolayer and spheroid cultures were determined by evaluating cell proliferation, bromodeoxyuridine labeling index (BrdU-LI), apoptosis, cyclic adenosine monophosphate (cAMP) and midkine levels, colony-forming efficiency, spheroid size, and ultrastructure. In comparison with the control group, single and combination drug treatments significantly reduced the proliferation index (PI) for 96 h. The most potent reduction of PI was observed with VNR in combination with CIM and LiCl for all time intervals. VNR with CIM and LiCl seemed to be ineffective in reducing BrdU-LI of both monolayer cell and spheroid cultures, spheroid size, and cAMP level. VNR with LiCl increased apoptosis at 24 h, however VNR with CIM increased apoptosis at 96 h. VNR was the most potent drug in inhibiting colony-forming efficiency. The combination of VNR with CIM was the most potent in reducing midkine levels among all groups. Interestingly, the combination of VNR with LiCl led to both nuclear membrane breakdown and disappearance of the cellular membranes inside the spheroids. Both CIM and LiCl seemed to potentiate VNR-induced cytotoxicity, and MK was not a resistance factor for VNR, LiCl, and CIM.
authors.affiliation: Department of Histology and Embryology, Faculty of Medicine, Istanbul University, Istanbul, Turkey. bilira@istanbul.edu.tr
authors.forename: Ayhan
authors.initials: A
authors.lastname: Bilir
authors.forename: Mine
authors.initials: M
authors.lastname: Erguven
authors.forename: Nuray
authors.initials: N
authors.lastname: Yazihan
authors.forename: Esin
authors.initials: E
authors.lastname: Aktas
authors.forename: Gulperi
authors.initials: G
authors.lastname: Oktem
authors.forename: Akin
authors.initials: A
authors.lastname: Sabanci
mesh_terms: D000928:Antidepressive Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001973:Bromodeoxyuridine / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002997:Clomipramine / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology*; D046529:Microscopy, Electron, Transmission / Q000379:methods; D000078792:Midkine; D014411:Neoplastic Stem Cells / Q000187:drug effects; D009447:Neuroblastoma / Q000473:pathology / Q000648:ultrastructure; D013997:Time Factors; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077235:Vinorelbine
chemical_list: D000928:Antidepressive Agents; D000972:Antineoplastic Agents, Phytogenic; D016207:Cytokines; D000078792:Midkine; D014747:Vinblastine; D000242:Cyclic AMP; D001973:Bromodeoxyuridine; D018021:Lithium Chloride; D002997:Clomipramine; D000077235:Vinorelbine
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