Abstract 1857: Hydrophilic As4S4 nanoparticles inhibit K562 cell activity through ROS modulation and autophagy induction

Abstract

Abstract Realgar is crystalized As4S4 that has been demonstrated to be effective in treating hematologic malignancies by oral administration [1]. Nevertheless, the low bioavailability due to its poor solubility in neutral or acidic aqueous solution not only leads to the over dose administration of arsenic in clinical practice but also hinders the study of pharmaceutical mechanism for realgar. We previously reported a solid dispersion of realgar (e-As4S4), in which the crystal realgar (r-As4S4) was fabricated into nanoparticles encapsulated by the hydrophilic polymer using the hot melting co-extrusion technique [2]. The e-As4S4 exhibited much higher bioavailability and improved treatment efficacy in the acute myeloid leukemia (AML) animal model compared with r-As4S4. This study investigated the effect of e-As4S4 has inhibitory on K562 cells and the underlying mechanisms. We showed that e-As4S4 down regulated the cellular ROS and HIF1-alpha in a concentration dependent manner. The low concentration of e-As4S4 induced both erythroid and megakaryocytic differentiation in the cells, evidenced by the up-regulation of CD235a and CD41 respectively, and the higher concentration induced cell cycle arrested in G2/M phase and apoptosis. Consistently, the proliferation rate and oxygen-consuming rate of the cells were reduced. Meanwhile the autophagy was detected when the cells were treated with e-As4S4, as well as the variation phosphorylation for p38 and Erk. These effects together induced the significant elimination of Bcr-Abl. In conclusion, e-As4S4 induced the bi-direction differentiation by modulating cellular ROS and inducing autophagy of the cells. These results therefore suggest that e-As4S4 represents a promising orally administrated drug for the treatment of CML. Reference 1. Zhu HH et al. Oral tetra-arsenic tetra-sulfide formula versus intravenous arsenic trioxide as first-line treatment of acute promyelocytic leukemia: a multicenter randomized controlled trial. J Clin Oncol. 2013; 31:4215-21. 2. Ma Q et al. Fabrication of water-soluble polymer-encapsulated As4S4 to increase oral bioavailability and chemotherapeutic efficacy in AML mice. Sci Rep. 2016; 6: 29348. Acknowledgement This work was supported by National Key R&D Program of China (2017YFA0205504) and CAMS Innovation Fund for Medical Sciences (CIFMS, 2016-I2M-3-004). Citation Format: Tao Wang, Tao Wen, Jie Meng, Jian Liu, Haiyan Xu. Hydrophilic As4S4 nanoparticles inhibit K562 cell activity through ROS modulation and autophagy induction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1857.