The Sensitization of Melatonin in Osteosarcoma Cells by Suppression of Anti-Apoptotic Proteins

Investigation of anti-cancer agents with desirable selective toxicity is critical for cancer therapy. The use of natural adjuvants can be a promising option in reducing the toxicity of the anti-cancer agent. The aim of this study was to investigate the potential application of melatonin (MLT) as a natural adjuvant molecule along with doxorubicin (DOX) to induce cytotoxicity in osteosarcoma (OS) cells.

Human OS cell lines included Saos-2, MG-63, and Human Bone Marrow Mesenchymal Stem Cells (hBM-MSCs) were treated with free DOX, free MLT, DOX-loaded NPs (DOX-NPs), MLT-loaded NPs (MLT-NPs), combination of DOX and MLT (DOX-MLT) and combination of DOX and MLT-loaded NPs (DOX-MLT-NPs) in separated cell culture. Cell proliferation of experiments were evaluated by MTT assay after 24 h. Total protein levels were determined by enzyme immunoassay ELISA.

Herein, we found the combination of MLT with DOX, especially formulated in nanoform, is resulted in a significant reduction in the protein levels of both X-linked Inhibitor of Apoptosis (XIAP) and Survivin (p<0.0001). Indeed, there was a significant decrease in the expression of XIAP and Survivin when MLT is combined with DOX compared to the individual treatments.

Our findings indicated the synergism of the antitumor effect could be due to the down-regulation of XIAP and Survivin in the levels of protein.