We evaluated the effects of natural purine and pyrimidine nucleosides on protection from or reversal of 3'-azido-3'-deoxythymidine (AZT) cytotoxicity in human bone marrow progenitor cells by using clonogenic assays. The selectivity of the "protection" or "rescue" agents was examined in evaluating the antiretroviral activity of AZT in combination with these modulating agents and of AZT alone. Following exposure of human granulocyte-macrophage progenitor cells for 2 h to 5 ,uM AZT (70% inhibitory concentration), increasing concentrations of potential rescue agents were added. Cells were cultured, and colony formation was assessed after 14 days. At concentrations of up to 50 ,uM no natural 2'-deoxynucleosides, including thymidine, were able to reverse the toxic effects of AZT. Dose-dependent reversal was observed with uridine and cytidine, and essentially complete reversal was achieved with 50 ,uM uridine. In the protection studies, 100 ,uM thymidine almost completely antagonized the inhibition of granulocyte-macrophage colony formation produced by 1 ,zM AZT (50% inhibitory concentration), and 50 ,uM uridine effected 60% protection against a toxic concentration of AZT (5 ,uM) (70% inhibitory concentration). The antiretroviral activity of AZT in human peripheral blood mononuclear cells, assessed by reverse transcriptase assays, was substantially decreased in the presence of thymidine, whereas no impairment of suppression of viral replication was observed in the presence of uridine in combination with AZT at a molar ratio (uridine/AZT) as high as 10,000. This demonstration of the capacity of uridine to selectively rescue human bone marrow progenitor cells from the cytotoxicity of AZT suggests that use of uridine rescue regimen with AZT may have potential therapeutic benefit in the treatment of acquired immunodeficiency syndrome.3'-Azido-3'-deoxythymidine (AZT), a pyrimidine nucleoside synthesized two decades ago by Horwitz et al. (7), has recently been shown to transiently improve certain immunological functions in some patients with acquired immunodeficiency syndrome (AIDS) (3), resulting in a decrease in the incidence of opportunistic infections and prolonging survival. The antiretroviral effects of AZT are probably based upon its conversion through cellular kinases to AZT triphosphate, which binds to reverse transcriptase and thereby inhibits viral DNA synthesis by chain termination (4). Although AZT selectively inhibits the replication of human immunodeficiency virus type 1 (HIV) (10), its applications in preliminary clinical trials (11,15) were limited by expressions of bone marrow toxicity. Consistent with these expressions we recently reported (12) that continuous exposure to AZT for 14 days effected a dose-dependent inhibition of human granulocyte-macrophage CFU (CFU-GM) and erythroid burst-forming unit colonies, the 50% inhibitory concentrations being 0.9 ± 0.1 and 2.4 ± 0.4 ,uM for the respective colonies. Several pharmacologic approaches are potentially available to improve the chemotherapeutic selectivity...
Background/Aims: Ovarian cancer is often diagnosed at later stages with poor prognosis. Recent studies have associated the expression of deubiquitylase USP7 with the survival of ovarian cancers. Being a cysteine protease, USP7 could become a target for pharmacological intervention. Therefore, in this study, we assessed the influence of its inhibitor P5091 on ovarian cancer cells. Methods: Ovarian cancer cells were treated with P5091, and cell proliferation was measured with MTT assay; cell morphology was inspected under a phase-contrast microscope; cell cycle and cell death were examined by flow cytometry. To gain mechanistic insights into its effects, immunoblotting was performed to detect USP7, HDM2, p53, p21, apoptosis and autophagy related proteins. Results: P5091 effectively suppressed the growth of ovarian cancer cells, caused cell cycle blockage, and induced necrosis and apoptosis with more severe phenotypes observed in HeyA8 cells with wild-type p53 than in OVCAR-8 cells with mutant p53. P5091 also prompted autophagy, with more efficient p62 degradation in HeyA8. Conclusion: P5091 shows efficacy in suppressing ovarian cancers harbouring wild-type and mutant p53. Its effects seemed to be enhanced by wild-type p53. The potency of this USP7 inhibitor also correlated with autophagy to some extent. Therefore, the pharmacological targeting of USP7 may serve as a potential therapeutic strategy and warrants further investigation.
Three new sesquiterpenes (1-3), together with four known sesquiterpene lactones, were isolated from the flowers of Inula britannica var. chinensis. Structures were established on the basis of high-field 1D and 2D NMR methods supported by HRMS. All sesquiterpene lactones were tested for cytotoxicity as well as apoptotic ratio in human COLO 205, HT 29, HL-60, and AGS cancer cells. Compounds 3 and 4, two alpha-methylene gamma-lactone-bearing sesquiterpenes, were modestly active in these assays.
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