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

Abstract

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.

As4S4 Exhibits Good Killing Effect on Multiple Myeloma Cells Via Repressing SOCS1 Methylation-Mediated JAK2/STAT3 Signaling Pathway

“…19,20 Furthermore, a study shows that As 4 S 4 reduces cell proliferation through scavenging intracellular ROS and downregulating hypoxia-inducible factor-1α in breast cancer cells. 21 These studies reveal that As 4 S 4 may serve as a promising option in the treatment of various solid tumors.…”

NLRP3 Inflammasome From Bench to Bedside: New Perspectives for Triple Negative Breast Cancer

“…Arsenic accumulation in tumor tissues was observed to cause down-regulation of ROS levels and a significant reduction in hypoxia-inducible factors-1α (HIF-1α) expression, leading to the inhibition of NLRP3 expression. This recent study showed that tumor metastases to the lungs and liver declined and survival of the TNBC mice was prolonged (104).…”

“…Finally, a new study applied nanoparticles of hydrophilic arsenic sulfide (e-As4S4) to a TNBC murine model to investigate its impact in this type of tumor (104). A bioavailable form of arsenic sulfide, e-As4S4 has already been shown to have a therapeutic effect in leukemia (105,106).…”

Multi-faced roles of reactive oxygen species in anti-tumor T cell immune responses and combination immunotherapy

“…As 4 S 4 is a mineral medicine usually used as one component of some formulations in the treatment of hematological malignancies [125]. When fabricated to hydrophilic nanocrystals, it can be internalized by the leukemia cells [126,127] and murine breast cancer tumor cells [128], effectively eliminating the intracellular ROS through direct scavenging ROS and inhibiting the cellular respiration [126,128,129], leading to the suppression of inflammatory microenvironment in the TNBC mouse model, resulting in prolonged survival [128].…”