Abstract
Arsenic sulfide (As4S4) 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 As4S4 in highly metastatic triple-negative breast cancer (TNBC) animal model, as As4S4 has not been applied in the treatment of breast cancer yet. To overcome the poor solubility of original As4S4, a formulation of hydrophilic As4S4 nanoparticles (e-As4S4) developed previously was applied to mouse breast cancer cells as well as the tumor-bearing mice. It was shown that e-As4S4 was much more cytotoxic than r-As4S4, strongly inhibiting the proliferation of the cells and scavenging intracellular reactive oxygen species (ROS). The oral administration of e-As4S4 significantly increased the accumulation of arsenic in the tumor tissue and eliminated ROS in tumor tissues. Besides, e-As4S4 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-As4S4 holds great potential for an alternative therapeutics in the treatment of breast cancer, due to its unique function of correcting the aggressive microenvironment.
Highlights
Metastasis is the leading cause of breast cancer mortality, which has been one major challenge in clinical treatment [1]
We have demonstrated that the bioavailability and the therapeutic effect of As4S4 were increased significantly on acute myeloid leukemia (AML) in vitro and in vivo when the crystal particles were reduced into nanoscale and encapsulated with hydrophilic polymers [11]
We showed that the oral administration of e-As4S4 led to arsenic accumulation in the tumor tissue, which reduced angiogenesis and inflammasome in the tumor microenvironment by downregulating the reactive oxygen species (ROS) level, while arsenic hardly accumulated in tumor tissue of raw As4S4 (r-As4S4) treated group
Summary
Metastasis is the leading cause of breast cancer mortality, which has been one major challenge in clinical treatment [1]. The treatment of TNBC is local therapy with surgery and/or radiotherapy followed by standard anthracycline and/or taxane-based systemic adjuvant treatment [3, 4]. Despite an initial response to systemic chemotherapy, patients with TNBC often follow an aggressive course of progression and metastasis and develop multidrug resistance to conventional therapies [5]. Patients with TNBC are less sensitive to typical endocrine therapies due to lack of the receptors [6]. There is still an unmet need in the treatment of breast cancer, and the development of
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