Arsenic Sulfide Nanoformulation Induces Megakaryocytic Differentiation through Histone Deacetylase Inhibition

Abstract

Arsenic sulfide (As 4 S 4 ) is a mineral drug that can be administrated orally and has been applied in several Chinese medicine formulations for the treatment on some kinds of myeloid leukemia. However, mechanisms of As 4 S 4 are not demonstrated adequately due to the poor water solubility of As 4 S 4 in its original crystal form. The authors previously fabricated water dissolvable arsenic sulfide nanoformulation (ee-As 4 S 4 ), which downregulated intracellular reactive oxygen species (ROS). As ROS is closely associated with the histone deacetylase (HDAC), in this study the effect of ee-As 4 S 4 on the HDAC activity in chronic myeloid leukemia (CML) cells and whether the effect can induce subsequent megakaryocytic differentiation and underlying mechanisms are investigated. Results show that ee-As 4 S 4 inhibits HDAC activity in CML cells, resulting in the suppression of cellular respiration. The inhibition of HDAC activity also leads to the transcriptional activation of RUNX1, which induces megakaryocytic differentiation in CML cell lines, evidenced by the significantly multiple nuclei and giant nuclear structure, upregulation of CD41a and the increased phosphorylation of ERK1/2. In conclusion, ee-As 4 S 4 is able to inhibit HDAC activity, and therefore induce significant megakaryocytic differentiation in CML cells through RUNX1-dependent pathways, which suggests its clinical potential as a complementary drug option for CML patients.

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].…”

Functional Nanorealgar Quantum Dots with Aggregation-Induced Emission Enhancement for Tumor Neovascular-Targeted Theranostics

“…Its therapeutic effects are mainly due to the active ingrdients in the mineral substances. Realgar has remarkable therapeutic effects on various malignancies, including hematopoietic tumors (e.g., acute promyelocytic leukemia, APL) and solid malignancies (e.g., glioma and breast carcinoma) [2][3][4][5]. Basic and clinical research have indicated that realgar is safe and effective for remission induction and maintenance therapy in patients with APL, which are significant for improving hematopoietic functions in patients [2,3].…”

“…Realgar has remarkable therapeutic effects on various malignancies, including hematopoietic tumors (e.g., acute promyelocytic leukemia, APL) and solid malignancies (e.g., glioma and breast carcinoma) [2][3][4][5]. Basic and clinical research have indicated that realgar is safe and effective for remission induction and maintenance therapy in patients with APL, which are significant for improving hematopoietic functions in patients [2,3]. Nevertheless, the poor water dispersibility, low organism-absorbing ability, and high liver/ kidney acute toxicity of bulk realgar may lead to low bioavailability and medication safety, limiting its use in practical biomedicine.…”

Fluorescent Realgar Nanoclusters for Nuclear Targeting-Triggered Tumor Theranostics

“…Besides common NMs, newfound nanoarsenicals have been known as excellent therapeutic agents for the treatment of cancer. − Classical arsenicals, including arsenic trioxide (As 2 O 3 , ATO) and arsenic sulfide (As 4 S 4 , realgar), have been used as oriental medicines by ancient Greeks and China dating back more than 2000 years. In the past decade, investigators have demonstrated that arsenicals as effective chemotherapeutic drugs could potentially be used in medical treatments of acute promyelocytic leukemia (APL), myeloma, glioma, and breast carcinoma. − In particular, the FDA-approved ATO was mainly used to treat APL in clinical application in 2000 . However, many unpredictable pharmacological and toxicological bases of arsenical agents were still limited, hindering their wide clinical applications .…”

“…In order to obtain enhanced therapeutic effects of the blood arsenic concentration in clinical practice, bulk-phase realgar materials can be administered by reduction to nanoscale or encapsulation with hydrophilic polymers in different ways (Table S1). Researches have shown that when the grain size of realgar is reduced to ultrasmall nanoscale (3–5 nm), its preternatural interface structure and optical properties are fundamentally changed. , The nano-realgar (NR) displays excellent fluorescence characteristics of similar QDs ranging from 287 to 450 nm emission, − as manifested by better biocompatibility and enhanced antitumor activity than crude realgar powder. − Few or no studies have evaluated the in vivo optical imaging of realgar QDs and their antiproliferative effect on solid tumors for present purposes. In our study, we have designed high-performance NR QDs with a wide fluorescence emission window in the 600–725 nm range, which can penetrate biological tissues with less interference from tissue or blood autofluorescence in vivo .…”