Darinaparsin is a novel organic arsenic compound with IC₅₀ values of 0.5–3.0µM against HL-60, Jurkat, HepG2, and A549 cells[1]. Darinaparsin is currently under preclinical and clinical investigation for relapsed/refractory lymphomas and solid tumors[2]. Darinaparsin accumulates in mitochondria, induces mitochondrial membrane depolarization, and triggers reactive oxygen species (ROS) bursts, thereby activating intrinsic apoptosis pathways[4]. Additionally, Darinaparsin downregulates pro-angiogenic factors such as VEGF and IL-8, inhibiting endothelial tube formation [4].
In vitro, treatment of human multiple myeloma cells (8226/S, KMS11) with 2µM Darinaparsin for 6–24 hours significantly upregulated BH3-only proteins like Noxa and Bim, activating the mitochondrial apoptosis pathway. In arsenic trioxide (ATO)-resistant cell lines (8226/S-ATOR05), Darinaparsin still induced apoptosis in a dose-dependent manner, with higher uptake efficiency than ATO in parental cells[5]. Pre-treatment of prostate (HI-LAPC-4), pancreatic (PANC-1), and other solid tumor cells with 3µmol/L Darinaparsin for 4 hours, followed by γ-irradiation under normoxia or hypoxia, significantly enhanced radiosensitivity and induced apoptosis in tumor cells, without sensitizing normal bone marrow and protecting intestinal crypt cells from radiation damage[6].
In vivo, Darinaparsin (100mg/kg) administered via intraperitoneal injection every other day for 10 days in nude mice bearing Du145 or PC3 xenografts significantly inhibited tumor growth without causing weight loss or other toxic effects[7]. Combined treatment with Darinaparsin (50mg/kg) and BMN673 (330mg/kg) via intraperitoneal injection every other day for 14 days in nude mice with DMS273 small-cell lung cancer xenografts also significantly inhibited tumor growth without causing weight loss or other toxic effects[8].
References:
[1] Mann KK, Wallner B, Lossos IS, et al. Darinaparsin: a novel organic arsenical with promising anticancer activity. Expert Opin Investig Drugs. 2009 Nov;18(11):1727-34.
[2] Frampton JE. Darinaparsin: First Approval. Drugs. 2022 Nov;82(16):1603-1609.
[3] Yuan B, Kikuchi H, Li J, et al. Cytotoxic Effects of Darinaparsin, a Novel Organic Arsenical, against Human Leukemia Cells. Int J Mol Sci. 2023 Jan 23;24(3):2282.
[4] Nielsen TH, Johnson N, Garnier N, et al. Monitoring Response and Resistance to the Novel Arsenical Darinaparsin in an AML Patient. Front Pharmacol. 2013 Feb 12;4:9.
[5] Matulis SM, Morales AA, Yehiayan L, et al. Darinaparsin induces a unique cellular response and is active in an arsenic trioxide-resistant myeloma cell line. Mol Cancer Ther. 2009 May;8(5):1197-206.
[6] Tian J, Zhao H, Nolley R, et al. Darinaparsin: solid tumor hypoxic cytotoxin and radiosensitizer. Clin Cancer Res. 2012 Jun 15;18(12):3366-76.
[7] Bansal N, Farley NJ, Wu L, et al. Darinaparsin inhibits prostate tumor-initiating cells and Du145 xenografts and is an inhibitor of hedgehog signaling. Mol Cancer Ther. 2015 Jan;14(1):23-30.
[8] Cao GZ, Ma LY, Zhang ZH, et al. Darinaparsin (ZIO-101) enhances the sensitivity of small-cell lung cancer to PARP inhibitors. Acta Pharmacol Sin. 2023 Apr;44(4):841-852.
Darinaparsin是一种新型有机砷化合物，对HL-60、Jurkat及HepG2、A549的IC₅₀为0.5–3.0µM[1]，目前用于复发/难治性淋巴瘤及实体瘤的临床前与临床研究[2]。研究发现，Darinaparsin过在线粒体内蓄积、诱导线粒体膜电位下降及活性氧（ROS）爆发，激活内源性凋亡通路[3]。此外，Darinaparsin还可下调NF-κB、IL-8等细胞因子，抑制炎症反应[4]。
在体外，Darinaparsin（2μM）处理人多发性骨髓瘤细胞（8226/S、KMS11）6–24h，可显著诱导Noxa、Bim等BH3-only蛋白上调并激活线粒体凋亡通路；在三氧化二砷（ATO）耐药株（8226/S-ATOR05）中，Darinaparsin仍能剂量依赖性诱导细胞凋亡，而对亲代株的摄取效率高于ATO[5]。Darinaparsin（3μmol/L）预处理前列腺（HI-LAPC-4）、胰腺（PANC-1）等多种实体瘤细胞4h，随后在常氧或缺氧条件下给予γ-射线照射，Darinaparsin显著增强肿瘤细胞放射敏感性并诱导凋亡，但对正常骨髓无放射增敏作用，且可保护肠道隐窝细胞免受辐射损伤[6]。
在体内，Darinaparsin（100mg/kg）隔日腹腔注射，用于处理携带Du145或PC3荷瘤的裸鼠，连续10天；结果显示，Darinaparsin显著抑制肿瘤生长，且未引起体重下降或其他毒性反应[7]。Darinaparsin（50mg/kg）联合BMN673（330mg/kg）隔日腹腔注射，用于处理携带DMS273小细胞肺癌异种移植瘤的裸鼠，持续14天；联合治疗显著抑制肿瘤生长，且未引起体重下降或其他毒性反应[8]。