Combination therapy with TiO2 nanoparticles and cisplatin enhances chemotherapy response in murine melanoma models

Abstract

Background Despite recent progressions in the treatment of melanoma, the response to conventional therapies and the long-term survival in melanoma patients still remain poor. Recently, the use of nanoparticles (NPs) has been highlighted for promoting the chemotherapeutic effects of cytotoxic drugs in melanoma. The aim of this study is to mechanistically evaluate the potential of titanium dioxide (TiO₂) nanoparticles (NPs) for enhancing chemotherapy effects in in vitro and in vivo models of murine melanoma. Methods The F10 melanoma cells were exposed to different concentrations of TiO₂ NPs and/or cisplatin, then cell growth, cell viability, and cell death were evaluated. In parallel, C57BL/6 syngeneic melanoma mice were treated by TiO₂ NPs and/or cisplatin, and then drug responses, tumor size and mice’s organs were studied pathologically. Autophagy was examined by evaluating the formation of autophagosomes and gene expression levels of autophagy markers (ATG5 and ATG6) by fluorescent microscopy and qPCR, respectively. Results Nontoxic concentrations of TiO₂ NPs (50 µg/ml) promote anti-proliferative and cytotoxic effects of cisplatin in F10 melanoma cells, which is mediated through the induction of autophagy and necrotic cell death. Whereas TiO₂ NPs have no cytotoxic or metastatic effects in melanoma mice, its combination with cisplatin enhances drug responses (up to 50%), leading to higher inhibition of tumor growth compared with each monotherapy. Conclusion The combination of TiO₂ NP with cisplatin enhances chemotherapy response in both in vitro and in vivo melanoma models. In addition, autophagy plays an essential role during sensitizing melanoma cells to chemotherapy.