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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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive disease caused by infection with human T-cell leukemia virus type 1 (HTLV-1). Successful treatment is limited by resistance to chemotherapies. Therefore, there is an urgent need to develop novel effective strategies. Artesunate (ART), a widely used antimalarial compound, has been shown to exert cytotoxicity. Here, we aimed to assess the anti-ATLL activities of ART and to elucidate the possible molecular mechanisms involved in this effect. Compared with uninfected T cells, HTLV-1-infected T-cell lines were sensitive to ART-induced cytotoxicity. ART caused cell cycle arrest at G 1 and/or G 2 /M phases, which was associated with decreased expression of cyclin dependent kinase 1/2/4/6, cyclin B1/D2/E and c-Myc, and increased expression of p21. ART-induced apoptosis corresponded to activation of caspase-8/9/3; decreased expression of Bcl-xL, Bcl-2, myeloid cell leukemia-1, survivin, X-linked inhibitor of apoptosis protein and cellular inhibitor of apoptosis 1/2; and increased expression of Bak. ART increased intracellular reactive oxygen species and activation of the DNA damage marker γ-H2AX. Moreover, ART-induced cytotoxicity was partly reversed by treatment with a reactive oxygen species scavenger, iron chelator, and necroptosis or ferroptosis inhibitor, suggesting the involvement of caspase-dependent and -independent lethal pathways. These effects were correlated with inhibition of nuclear factor-κB and activator protein-1 signaling through dephosphorylation of IκBα, IκB kinase (IKK) α and IKKβ, and decreased expression of JunB and JunD. Importantly, intraperitoneal injection with ART lowered tumor burden in an ATLL murine model. These preclinical results provide a rationale for evaluating the efficacy of ART in patients with ATLL., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Modulation of monoaminergic systems has been the main stream of treatment for patients with mood disorders. However, recent evidence suggests that the glutamatergic system plays an important role in the pathophysiology of these disorders. This study pharmacologically characterized a structurally novel metabotropic glutamate 5 (mGlu5) receptor negative allosteric modulator, DSR-98776, and evaluated its effect on rodent models of depression and mania. First, DSR-98776 in vitro profile was assessed using intracellular calcium and radioligand binding assays. This compound showed dose-dependent inhibitory activity for mGlu5 receptors by binding to the same allosteric site as 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a known mGlu5 inhibitor. The in vivo therapeutic benefits of DSR-98776 were evaluated in common rodent models of depression and mania. In the rat forced swimming test, DSR-98776 (1-3mg/kg) significantly reduced rats immobility time after treatment for 7 consecutive days, while paroxetine (3 and 10mg/kg) required administration for 2 consecutive weeks to reduce rats immobility time. In the mouse forced swimming test, acute administration of DSR-98776 (10-30 mg/kg) significantly reduced immobility time. This effect was not influenced by 4-chloro-DL-phenylalanine methyl ester hydrochloride-induced 5-HT depletion. Finally, DSR-98776 (30 mg/kg) significantly decreased methamphetamine/chlordiazepoxide-induced hyperactivity in mice, which reflects this compound antimanic-like effect. These results indicate that DSR-98776 acts as an orally potent antidepressant and antimanic in rodent models and can be a promising therapeutic option for the treatment of a broad range of mood disorders with depressive and manic states., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Epoxyeicosatrienoic acids (EETs) are known to have beneficial pharmacological effects on various cardiovascular events. However, EETs are biologically metabolized by soluble epoxide hydrolase (sEH) to less active metabolites. In our search for potent sEH inhibitors, we optimized a series of cyclopropyl urea derivatives and identified compound 38 as a potent sEH inhibitor with minimal CYP inhibition and good oral absorption in rats. Administration of 38 to DOCA-salt rats suppressed urinary albumin and MCP-1 excretion without affecting systolic blood pressure., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

We studied the effects of AZD1152, an Aurora B kinase inhibitor, on Burkitt's lymphoma (BL) and Hodgkin's lymphoma (HL) in human tissues and cell cultures and in a murine xenograft model of lymphoma. Aurora kinase A and B levels were assessed by RT-PCR and immunohistochemistry. They were aberrantly expressed in BL and HL cell lines, and in lymph nodes from patients with BL and HL. Next, activation of the Aurora B promoter was detected by reporter gene assays. The promoter activity of Aurora B kinase was high in BL cell lines and the Aurora B promoter contained a positive regulatory region between -74 and -104 from the transcription initiation site. AZD1152-hQPA had antiproliferative effects in the BL and HL cell lines studied; inhibited the phosphorylation of histone H3 and retinoblastoma proteins, and resulted in cells with > 4N DNA content. AZD1152-hQPA induced caspase-dependent apoptosis of some cell lines, demonstrated by loss of mitochondrial membrane potential, activation of caspase-9, followed by activation of caspase-3. This effect was accompanied by the inhibition of survivin expression. In vivo efficacy was determined in NOD/SCID/γc(null) mice implanted with the Ramos human BL cell line. AZD1152 had anti-tumour effects in this murine xenograft model. There preclinical data suggest that the inhibition of Aurora B kinase is a potentially useful therapeutic strategy in BL and HL., (Copyright © 2011 Elsevier Inc. All rights reserved.)

We evaluated the anti-adult T-cell leukemia (ATL) effects of hippuristanol, an eukaryotic translation initiation inhibitor from the coral Isis hippuris. Hippuristanol inhibited proliferation of HTLV-1-infected T-cell lines and ATL cells, but not normal peripheral blood mononuclear cells. It induced cell cycle arrest during G₁ phase by reducing the expression of cyclin D1, cyclin D2, CDK4 and CDK6, and induced apoptosis by reducing the expression of Bcl-x(L), c-IAP2, XIAP and c-FLIP. The induced apoptosis was associated with activation of caspase-3, -8 and -9. Hippuristanol also suppressed IkappaBalpha phosphorylation and depleted IKKalpha, IKKgamma, JunB and JunD, resulting in inactivation of NF-kappaB and AP-1. It also suppressed carbonic anhydrase type II expression. In addition to its in vitro effects, hippuristanol suppressed tumor growth in mice with severe combined immunodeficiency harboring tumors induced by inoculation of HTLV-1-infected T cells. These preclinical data suggest that hippuristanol could be a potentially useful therapeutic agent for patients with ATL., (Copyright © 2011 Elsevier Inc. All rights reserved.)

To determine the effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) on phospholipase D (PLD) activity in osteoblast-like UMR-106 cells, we used cells prelabeled with [3H] myristic acid or [3H] arachidonic acid, which were preferentially incorporated to phosphatidylcholine. The treatment of [3H] myristate-labeled cells with TPA in the presence of 1% ethanol caused a dose-dependent formation of [3H] phosphatidylethanol (PEt), a product specific to PLD, suggesting an activation of this enzyme. Pretreatment of the cells with protein kinase C (PKC) inhibitors (GF109203X, staurosporine or H-7) abolished the TPA-dependent formation of PEt. The PEt formation in response to TPA treatment was not observed after the pretreatment of the cells with TPA to downregulate PKC. These results suggest the involvement of PKC in the TPA-induced activation of PLD. With [3H] arachidonate-labeled cells, TPA treatment in the absence of ethanol resulted in the liberation of [3H] arachidonic acid, which was gradually converted to prostaglandin E2 (PGE2), but the accumulations of [3H] phosphatidic acid (PA) and [3H] diacylglycerol (DAG) were very small and temporary. In contrast, PA was linearly accumulated following TPA treatment, when the cells were pretreated with an inhibitor of phosphatidate phosphohydrolase (PAP), propranolol, with no accumulation of either DAG or arachidonic acid. The TPA treatment of the cells pretreated with a DAG lipase inhibitor, RHC-80267, caused the generation of DAG after a lag period of approximately 5 min, with a very small and temporary accumulation of PA. The TPA treatment of cells pretreated with a cyclooxygenase (COX) inhibitor, indomethacin, blocked the PGE2 production. The TPA-induced PGE2 production was not affected by the pretreatment of cells with a phospholipase A2 inhibitor, p-bromophenacylbromide, or with a phospholipase C inhibitor, D-609. TPA also stimulated PGE2 production in osteoblastic cells that were enzymatically isolated from adult rat calvaria, and the experiments with lipid metabolizing enzyme inhibitors gave the same profile of inhibition of TPA-induced PGE2 production as was observed in UMR-106 cells. These results suggest that PA formed as a consequence of the activation of PLD by TPA is rapidly converted to arachidonic acid via a PAP/DAG lipase pathway, followed by a gradual conversion of arachidonic acid to PGE2 by COX in both UMR-106 cells and isolated adult osteoblastic cells, and that neither phospholipase A2 nor phospholipase C is involved in the TPA-induced PGE2 production. To the best of our knowledge, this is the first report that shows that the activation of PKC in osteoblastic cells leads to the production of PGE2 via a PLD/PAP/DAG lipase/COX pathway.