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

Clin Transl Oncol. 2021 Apr;23(4):738-749. doi: 10.1007/s12094-020-02463-y. Epub 2020 Jul 30.


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.

Keywords: Autophagy; Cisplatin; Melanoma; Nanoparticles; Titanium dioxide.

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / therapeutic use*
  • Autophagosomes
  • Autophagy / drug effects*
  • Autophagy / genetics
  • Autophagy-Related Protein 5 / genetics
  • Beclin-1 / genetics
  • Cell Death / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cisplatin / administration & dosage
  • Cisplatin / therapeutic use*
  • Drug Combinations
  • Drug Synergism
  • Kidney / drug effects
  • Liver / drug effects
  • Male
  • Melanoma, Experimental / drug therapy*
  • Melanoma, Experimental / pathology
  • Mice
  • Mice, Inbred C57BL
  • Nanoparticles / administration & dosage
  • Nanoparticles / therapeutic use*
  • Nanoparticles / ultrastructure
  • Necroptosis / drug effects
  • Particle Size
  • Random Allocation
  • Spleen / drug effects
  • Titanium / administration & dosage
  • Titanium / therapeutic use*
  • Tumor Burden / drug effects


  • Antineoplastic Agents
  • Atg5 protein, mouse
  • Autophagy-Related Protein 5
  • Beclin-1
  • Drug Combinations
  • titanium dioxide
  • Titanium
  • Cisplatin