Department of Microbiology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, 903-0215, Japan; Division of Health Sciences, Transdisciplinary Research Organization for Subtropics and Island Studies, University of the Ryukyus, Nishihara, Okinawa, 903-0213, Japan.
Department of Microbiology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, 903-0215, Japan.
Eur J Pharmacol. 2021 Oct 5;908:174373. doi: 10.1016/j.ejphar.2021.174373. Epub 2021 Jul 22.
Patients with adult T-cell leukemia (ATL), caused by the human T-cell leukemia virus type 1 (HTLV-1), exhibit poor prognosis owing to drug resistance. Pimozide is a dopamine D2 receptor antagonist and antipsychotic shown to exhibit anticancer activity. Herein, we investigated whether pimozide exerts anti-ATL effects and explored the mechanisms underlying these effects. Pimozide inhibited cell growth and survival in HTLV-1-infected T cells but not in the uninfected T cells. The dopamine D2 receptor subfamily mRNA expression levels in HTLV-1-infected T cells were high. Pimozide induced G1 cell cycle arrest concomitant with the upregulation of p21/p27/p53, and suppression of cyclin D2/E, cyclin-dependent kinase 2/4/6 and c-Myc expression, and pRb phosphorylation. Pimozide also induced apoptosis by activating caspases, upregulating pro-apoptotic proteins and downregulating anti-apoptotic proteins. Additionally, it promoted reactive oxygen species (ROS) generation and increased the expression of the endoplasmic reticulum stress marker activating transcription factor 4 and the DNA damage-inducible protein GADD45α and the phosphorylation of the DNA damage marker H2AX. Furthermore, pimozide-induced cytotoxicity was partially inhibited by a ROS scavenger, and pan-caspase and necroptosis inhibitors, indicating the involvement of caspase-dependent and -independent lethal pathways. The activities of the nuclear factor-κB, Akt, STAT3/5 and AP-1 signaling pathways were inhibited via the dephosphorylation of IκBα, IκB kinase α/β, Akt and STAT3/5, in addition to reduced JunB and JunD expression in HTLV-1-infected T cells. Pimozide also exhibited potent anti-ATL activity in the xenograft mouse model. These findings demonstrated the efficacy of pimozide as a potential therapeutic agent for ATL.
成人 T 细胞白血病（ATL）是由人类 T 细胞白血病病毒 1（HTLV-1）引起的，由于耐药性，患者预后不良。匹莫齐特是一种多巴胺 D2 受体拮抗剂和抗精神病药，具有抗癌活性。在此，我们研究了匹莫齐特是否对 ATL 具有抗作用，并探讨了这些作用的机制。匹莫齐特抑制 HTLV-1 感染的 T 细胞生长和存活，但不抑制未感染的 T 细胞。HTLV-1 感染的 T 细胞中多巴胺 D2 受体亚家族的 mRNA 表达水平较高。匹莫齐特诱导 G1 细胞周期停滞，同时上调 p21/p27/p53，下调 cyclin D2/E、细胞周期蛋白依赖性激酶 2/4/6 和 c-Myc 的表达，以及 pRb 磷酸化。匹莫齐特还通过激活半胱天冬酶、上调促凋亡蛋白和下调抗凋亡蛋白诱导细胞凋亡。此外，它还通过促进活性氧（ROS）的产生，增加内质网应激标记物激活转录因子 4、DNA 损伤诱导蛋白 GADD45α 的表达和 DNA 损伤标记物 H2AX 的磷酸化来促进细胞凋亡。此外，ROS 清除剂、泛半胱天冬酶和坏死性凋亡抑制剂部分抑制了匹莫齐特诱导的细胞毒性，表明细胞凋亡依赖和非依赖的致死途径的参与。NF-κB、Akt、STAT3/5 和 AP-1 信号通路的活性通过 HTLV-1 感染的 T 细胞中 IκBα、IκB 激酶α/β、Akt 和 STAT3/5 的去磷酸化以及 JunB 和 JunD 表达的减少而被抑制。匹莫齐特在异种移植小鼠模型中也表现出很强的抗 ATL 活性。这些发现表明匹莫齐特作为 ATL 的潜在治疗药物具有疗效。
