The aim of this work is to investigate whether clomipramine (CIM) and lithiumchloride (LiCl) potentiate the cytotoxicity of vinorelbine (VNR) on SH-SY5Y humanneuroblastoma cells in vitro and whether midkine (MK) can be a resistance factor for these treatments. Four groups of experiments were performed for 96 h usingboth 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. Theireffects on monolayer and spheroid cultures were determined by evaluating cellproliferation, bromodeoxyuridine labeling index (BrdU-LI), apoptosis, cyclicadenosine monophosphate (cAMP) and midkine levels, colony-forming efficiency,spheroid size, and ultrastructure. In comparison with the control group, singleand combination drug treatments significantly reduced the proliferation index(PI) for 96 h. The most potent reduction of PI was observed with VNR incombination with CIM and LiCl for all time intervals. VNR with CIM and LiClseemed 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 drugin inhibiting colony-forming efficiency. The combination of VNR with CIM was the most potent in reducing midkine levels among all groups. Interestingly, thecombination of VNR with LiCl led to both nuclear membrane breakdown anddisappearance of the cellular membranes inside the spheroids. Both CIM and LiClseemed to potentiate VNR-induced cytotoxicity, and MK was not a resistance factorfor VNR, LiCl, and CIM.PMID: 20467784 [PubMed - as supplied by publisher]