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Arsenic sulfide (As 4 S 4 ) is a mineral drug that can be administrated orally and has been applied in the treatment of myeloid leukemia. The aim of this work is to investigate the therapeutic effect of As 4 S 4  in highly metastatic triple-negative breast cancer (TNBC) animal model, as As 4 S 4  has not been applied in the treatment of breast cancer yet. To overcome the poor solubility of original As 4 S 4 , a formulation of hydrophilic As 4 S 4  nanoparticles (e-As 4 S 4 ) developed previously was applied to mouse breast cancer cells as well as the tumor-bearing mice. It was shown that e-As 4 S 4  was much more cytotoxic than r-As 4 S 4 , strongly inhibiting the proliferation of the cells and scavenging intracellular reactive oxygen species (ROS). The oral administration of e-As 4 S 4  significantly increased the accumulation of arsenic in the tumor tissue and eliminated ROS in tumor tissues. Besides, e-As 4 S 4  could also inhibit the activation of hypoxia-inducible factor-1α (HIF-1α) and NLRP3 inflammasomes. Consequently, the angiogenesis was reduced, the metastasis to lung and liver was inhibited and the survival of tumor-bearing mice was prolonged. In conclusion, e-As 4 S 4  holds great potential for an alternative therapeutics in the treatment of breast cancer, due to its unique function of correcting the aggressive microenvironment.

Inhibition of Murine Breast Cancer Metastases by Hydrophilic As4S4 Nanoparticles Is Associated With Decreased ROS and HIF-1α Downregulation