Biochemical and Biophysical Research Communications
Regular ArticleVesnarinone Inhibits Production of HIV-1 in Cultured Cells
Abstract
Vesnarinone, a synthetic oral cardiotonic agent that has been used for treatment of patients with congestive heart failure, was found to inhibit replication of HIV-1 in a peripheral blood lymphocytes model and in chronically infected macrophages at clinically achieved concentrations. Vesnarinone has no direct inhibitory activity against the reverse transcriptase of HIV-1, syncytium formation in short term assays, or retroviral protease. In addition, vesnarinone inhibits production of TNF-α and IL-6 by human peripheral blood mononucleated cells stimulated with LPS. These observations suggest that vesnarinone may be therapeutically useful in patients infected with HIV-1.
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Antitumor effect of a quinolinone derivative, vesnarinone, on mouse hepatoma
2000, Hepatology ResearchVesnarinone is a novel inotropic agent used in the treatment of heart failure. A number of recent studies have demonstrated that vesnarinone has a potential antitumor effect on several types of tumors. In the present study, we analyzed the in vitro and in vivo antitumor effects of vesnarinone on the MH134 mouse hepatoma cell line and tumor-bearing mice established by intraperitoneal implantation of MH134 cells. The antitumor effects were compared with those of CDDP, an anticancer drug in wide clinical use. In vitro study revealed that vesnarinone had an inhibitory effect on MH134 tumor cell growth, but this effect was lower than that of CDDP. Administration of vesnarinone directly into the peritoneal cavity of the tumor-bearing mice resulted in a significant increase in the survival time similar to that obtained by the administration of CDDP. No evident side effects were observed. These results suggest that vesnarinone may be therapeutically useful in clinical situations as a novel antitumor agent against hepatoma.
gp120- and TNF-α-induced modulation of human B cell function: Proliferation, cyclic AMP generation, Ig production, and B-cell receptor expression
2000, Journal of Allergy and Clinical ImmunologyBackground: It is well known that HIV-1 infection induces profound alterations in the immune system, including hyperactivation of B cells. TNF-α induces HIV-1 replication and immunodysregulation, including polyclonal B-cell activation. Objective: We sought to determine the effects of surface-binding HIV-1 envelope glycoprotein (gp120) and TNF-α on human B-cell function. Methods: HIV-1 seronegative peripheral blood human B cells were purified and activated by CD40 mAb and IL-4. In vitro studies of B-cell proliferation, cyclic AMP (cAMP) generation, receptor expression, and Ig production were performed. Results: gp120, an Ig superantigen, stimulated HIV-1 seronegative and HIV-1 seropositive human B-cell cAMP generation, proliferation, and Ig production. These gp120-induced B-cell responses were demonstrated to be specific as evidenced by the abrogation of the stimulatory response in the presence of anti-gp120 mAb, blocking of CD4 resulting in no change on gp120-induced B-cell responses, and the binding of gp120 in these B cells. TNF-α also stimulated cAMP generation, proliferation, and Ig production in B cells, and the binding of gp120 to these B cells stimulated by TNF-α further enhanced cell proliferation, cAMP generation, and Ig production. Antigenic expression of the B-cell receptor CD79b was down-regulated by gp120 but was not altered by the addition of TNF-α. Conclusion: gp120 modulation of TNF-α–induced B-cell receptor- and cAMP-mediated signal transduction events may be involved in the B-cell abnormalities observed in HIV-1 infection. (J Allergy Clin Immunol 2000;105:975-82.)
Ibudilast suppresses TNFα production by glial cells functioning mainly as type III phosphodiesterase inhibitor in the CNS
1999, Brain ResearchTumor necrosis factor α (TNFα) is considered to play a critical role in the development of various pathological processes in the central nervous system (CNS), such as neuronal degeneration, demyelination and HIV-related pathology. In order to search for the agents which suppress TNFα production in the CNS for future treatment of these pathological conditions, we examined the effects of ibudilast on TNFα production by murine microglia and astrocytes. Some actions of ibudilast are reportedly mediated by inhibition of type IV phosphodiesterase (PDE). Type IV PDE inhibitor has been shown to be the most effective for experimental autoimmune inflammatory demyelination. Therefore, we also determined the subtype of PDE inhibited by ibudilast. Ibudilast significantly and selectively suppressed TNFα production by microglia in a dose-dependent manner, without affecting their viability. The inhibition assay indicated that ibudilast is a rather selective inhibitor for type III PDE purified from brain, heart and kidney with moderate inhibitory activity against types I, II and IV PDEs from various tissues. Although it required 10 μM or higher concentrations to effectively suppress TNFα production in vitro, the combination of ibudilast with other subtypes of PDE inhibitors synergistically suppressed TNFα and nitric oxide production by microglia at 1 μM, a similar concentration that could be obtained in vivo at usual therapeutic dose. Thus, ibudilast, when used in a combination with other PDE inhibitors, will be useful for future strategies to treat intractable neurological diseases in which TNFα may play a causative role.
Effect of 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone (vesnarinone) on the growth of gastric cancer cell lines
1999, Cancer LettersVesnarinone (OPC-8212; 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone) is a synthetic oral cardiotonic agent that has been used for the treatment of patients with congestive heart failure. Six days of treatment with 30 μg/ml of vesnarinone induced 20–80% growth inhibitions in five out of six gastric carcinoma cell lines examined. Cell cycle analysis revealed that the vesnarinone-sensitive TMK-1 gastric cancer cell line exhibited a significant G0–G1 arrest without evidence of apoptotic cell death induction after 48 h of treatment. Interestingly, this phenomenon was preceded by a marked reduction in the expression of cyclin A, D1 and E as well as cyclin-dependent kinase 2 (CDK2). On the other hand, no significant change was observed in the expression of p21Waf1/Cip1, p27Kip1 nor various growth factors and their receptor genes. Overall these results indicate that vesnarinone inhibits the growth of gastric cancer cells by down-regulating G1 cyclins and CDK2 to induce G0–G1 arrest through a pathway different from that of cyclin inactivation by p21Waf1/Cip1 or p27Kip1.
The effect of vesnarinone on TNFα production in human peripheral blood mononuclear cells and microglia: A preclinical study for the treatment of multiple sclerosis
1999, Journal of NeuroimmunologyVesnarinone (OPC-8212) is a synthetic quinolinone derivative with inotropic and immunomodulatory effects. Vesnarinone has been shown to inhibit tumor necrosis factor-alpha (TNFα) produced by mitogen stimulated macrophages, and to inhibit phosphodiesterase (PDE) type III in cardiac muscle. TNFα and interferon-gamma (IFNγ) have been implicated in the pathogenesis of autoimmune diseases, and both cytokines are targets for therapeutic intervention. IFNγ can enhance autoimmune disease through direct effects, and indirectly by priming macrophages to produce TNFα. In this study, we demonstrate that while vesnarinone enhances basal TNFα levels, it inhibits TNFα production in peripheral blood mononuclear cells from multiple sclerosis (MS) patients and healthy donors stimulated with lipopolysaccharide (LPS) or primed with IFNγ and stimulated with suboptimal doses of LPS. In addition, vesnarinone inhibited TNFα production in primary adult human microglial cultures. However, in contrast to rolipram, another TNFα inhibiting agent, vesnarinone failed to inhibit TNFα production by myelin basic protein specific T-cell lines. As oral TNF inhibitors are currently being considered in the USA for clinical application in MS, the implications of our findings on the development of vesnarinone for treatment of MS are discussed.
Tumor necrosis factor a (TNFα) is considered to play a critical role in the development of various pathological processes in the central nervous system (CNS), such as neuronal degeneration, demyelination and gliosis. In order to search for agents which suppress TNFα production in the CNS for future treatment of these pathological conditions, the effects of a synthetic oral inotropic agent, vesnarinone, on murine microglia were examined. Vesnarinone significantly suppressed TNFα production by microglia in a dose-dependent manner, without affecting their viability, enzyme activity or expression of the major histocompatibility complex. Since the reported maximum serum concentration is high enough to suppress TNFα production in vitro (about 20 μM) after oral administration of the therapeutic dose of vesnarinone, this drug will be useful to treat intractable neurological diseases such as neurodegenerative disorders, multiple sclerosis or HIV-related neurological disorders.