Hammouda MB Riahi-Chebbi I Souid S Othman H Aloui Z Srairi-Abid N Karoui H Gasmi A Magnenat EM Wells TNC Clemetson KJ Rodríguez-López JN Essafi-Benkhadir K 2018 BACKGROUND The resistance of melanoma cells to cisplatin restricts its clinical use. Therefore, the search for novel tumor inhibitors and effective combination treatments that sensitize tumor cells to this drug are still needed. We purified macrovipecetin, a novel heterodimeric C-type lectin, from Macrovipera lebetina snake venom and investigated its anti-tumoral effect on its own or combined with cisplatin, in human melanoma cells. METHODS Biochemical characterization, in vitro cells assays such as viability, apoptosis, adhesion, migration, invasion, Western blotting and in silico analysis were used in this study. RESULTS Macrovipecetin decreased melanoma cell viability 100 times more than cisplatin. Interestingly, when combined with the drug, macrovipecetin enhanced the sensitivity of SK-MEL-28 cells by augmenting their apoptosis through increased expression of the apoptosis inducing factor (AIF) and activation of ERK1/2, p38, AKT and NF-κB. Moreover, macrovipecetin alone or combined with cisplatin induced the expression of TRADD, p53, Bax, Bim and Bad and down-regulated the Bcl-2 expression and ROS levels in SK-MEL-28 cells. Interestingly, these treatments impaired SK-MEL-28 cell adhesion, migration and invasion through modulating the function and expression of αvβ3 integrin along with regulating E-cadherin, vimentin, β-catenin, c-Src and RhoA expression. In silico study suggested that only the α chain of macrovipecetin interacts with a region overlapping the RGD motif binding site on this integrin. CONCLUSIONS We validated the antitumor effect of macrovipecetin when combined, or not, with cisplatin on SK-MEL-28 cells. GENERAL SIGNIFICANCE The presented work proposes the potential use of macrovipecetin and cisplatin in combination as an effective anti-melanoma treatment. https://sonar.ch/global/documents/278667 eng info:eu-repo/semantics/altIdentifier/doi/10.1016/j.bbagen.2017.11.019 info:eu-repo/semantics/altIdentifier/pmid/29196192 Biochimica et biophysica acta. General subjects. - 2018 Anti-tumoral effect Cisplatin efficacy Macrovipecetin Mechanistic characterization Melanoma Snaclec Amino Acid Sequence Animals Antineoplastic Agents Antineoplastic Agents, Alkylating Apoptosis Apoptosis Regulatory Proteins Cell Adhesion Cell Adhesion Molecules Cell Line, Tumor Cell Movement Cisplatin Drug Resistance, Neoplasm Drug Screening Assays, Antitumor Drug Synergism Gene Expression Regulation, Neoplastic Humans Integrin alphaVbeta3 Lectins, C-Type Melanoma Models, Molecular Molecular Docking Simulation Neoplasm Invasiveness Neoplasm Proteins Protein Conformation Protein Interaction Domains and Motifs Protein Interaction Mapping Sequence Alignment Sequence Homology, Amino Acid Viper Venoms Viperidae Macrovipecetin, a C-type lectin from Macrovipera lebetina venom, inhibits proliferation migration and invasion of SK-MEL-28 human melanoma cells and enhances their sensitivity to cisplatin. http://purl.org/coar/resource_type/c_6501