Abstract
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, a dopamine D2 receptor subfamily antagonist and antipsychotic drug, has been shown to exhibit anticancer activity. Herein, we investigated whether pimozide exerts anti-ATL effects and explored the mechanisms underlying these effects. While pimozide inhibited cell growth and survival in HTLV-1-infected T cells, it exerted limited effects on 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 the suppression of cyclin D2/E, CDK2/4/6 and c-Myc expression and pRb phosphorylation. Pimozide also induced apoptosis via the activation of caspases and upregulation of pro-apoptotic proteins and downregulation of anti-apoptotic proteins. Additionally, it promoted ROS generation and increased the expression of the ER stress marker ATF4 and the DNA damage-inducible protein GADD45a 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 NF-κB, Akt, STAT3/5 and AP-1 signaling pathways were inhibited via the dephosphorylation of IκBα, IKKα/β, Akt and STAT3/5, in addition to reduced JunB and JunD expression in HTLV-1-infected T cells in response to pimozide treatment. 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.
The Effect of Chronic Antipsychotic Drug on Hypothalamic Expression of Neural Nitric Oxide Synthase and Dopamine D2 Receptor in the Male Rat
