The potentiation of menadione on imatinib by downregulation of ABCB1 expression.

Imatinib was the first BCR-ABL inhibitor used in clinical practice to treat chronic myeloid leukaemia (CML) and significantly improve the life expectancy of CML patients in the chronic phase. However, a portion of CML patients are resistant to imatinib. This study aimed to determine whether menadione (Vitamin K3) can improve imatinib efficacy in CML and to thoroughly explore the combination regimen mechanism between imatinib and menadione. Menadione improved imatinib efficacy in K562 cells by downregulating ABCB1 expression and increased the intracellular concentration of imatinib, which confirmed that this combination regimen is more effective than imatinib monotherapy. The results demonstrate that menadione and imatinib combination therapy may be a promising approach to refractory CML.

Down-regulating NQO1 promotes cellular proliferation in K562 cells via elevating DNA synthesis.

BACKGROUND: NQO1 protein acts as a cellular protective system, on account of its role as a quinone reductase and redox regulator. Nonetheless, new NQO1 roles are emerging-including its regulation of the cellular proliferation of many tumor cells-and this enzyme has been found to relate to the incidence of various diseases, including chronic myeloid leukemia. However, the mechanisms through which NQO1 influences leukemia progression remain unclear. MARTIAL AND METHODS: The current study looks to name NQO1 as a novel molecular target that modulates DNA synthesis and chronic myeloid leukemia growth. RESULTS AND CONCLUSION: Our results indicate that the frequency of the T allele of NQO1 polymorphism in chronic myeloid leukemia patients is higher than that among healthy East Asian individuals (0.492 vs. 0.419) and much higher than the average level of the general population (0.492 vs. 0.289) (1000 Genomes). Functionally, NQO1 knockdown increases the protein expression of the TOP2A and MCM complex, and consequently promotes DNA synthesis and K562 cell growth. NQO1 knockdown also promotes tumorigenesis in a xenograft model. NQO1 overexpression, on the other hand, was found to have the opposite effects. SIGNIFICANCE: Our results show that NQO1 downregulation promotes K562 cellular proliferation via the elevation of DNA synthesis.

microRNA-605 rs2043556 polymorphisms affect clopidogrel therapy through modulation of CYP2B6 and P2RY12 in acute coronary syndrome patients.

Clopidogrel therapy reduces the occurrence of major vascular events in acute coronary syndrome (ACS) patients, but treatment efficacy is variable. The present study aims to determine the mechanisms that underlie associations between certain miRNA polymorphisms and clinical outcomes of clopidogrel therapy. Our study focused on 9 miRNA single nucleotide polymorphisms in addition to CYP2C19*2 and CYP2C19*3. We found that the miR-605 rs2043556 AG genotype significantly decreased the risk of acute myocardial infarction (odds ratio, OR = 0.13, 95%CI 0.02-0.96, P = .045) and that the rs2043556 GG genotype significantly decreased the risk of unstable angina (OR = 0.19, 95%CI 0.05-0.65, P = .008) in ACS patients receiving clopidogrel therapy for more than one year. Dual-luciferase analysis indicated that miR-605 significantly decreased the mRNA expression of CYP2B6 and P2RY12 (P < .01). In cells treated with miR-605-A, the protein and mRNA expression of CYP2B6 and P2RY12 were significantly lower than that of cells treated with miR-605-G (P < .05). The results demonstrate that miR-605 targets the mRNA of the CYP2B6 and P2RY12 genes, and that rs2043556 A/G polymorphisms in miR-605 modulate the mRNA and protein expression of CYP2B6 and P2RY12 differently, which may impact the effect of clopidogrel in ACS patients.

Effect of carboxylesterase 1 S75N on clopidogrel therapy among acute coronary syndrome patients.

Carboxylesterase 1 (CES1) hydrolyzes the prodrug clopidogrel to an inactive carboxylic acid metabolite. The effects of CES1 S75N (rs2307240,C>T) on clopidogrel response among 851 acute coronary syndrome patients who came from the north, central and south of China were studied. The occurrence ratios of each endpoint in the CC group were significantly higher than in the CT + TT group for cerebrovascular events (14% vs 4.8%, p < 0.001, OR = 0.31), acute myocardial infarction (15.1% vs 6.1%, p < 0.001, OR = 0.37) and unstable angina (62.8% vs 37.7%, p < 0.001, OR = 0.36). The results showed that there was a significant association between CES1 S75N (rs2307240) and the outcome of clopidogrel therapy. Moreover, the frequency of the T allele of rs2307240 in acute coronary syndrome patients (MAF = 0.22) was more than four times higher than that in the general public (MAF = 0.05).

Effects of four novel genetic polymorphisms on clopidogrel efficacy in Chinese acute coronary syndromes patients.

Dual antiplatelet therapy is the gold standard for the clinical treatment of coronary artery disease, especially for acute coronary syndromes patients. However, a substantial number of patients do not respond to clopidogrel despite a standardized dosage regimen, and this is directly associated with poor prognosis. Genetic polymorphisms may be one of the most important factors that contribute to this phenomenon. In this study, we aimed to detect new single nucleotide polymorphisms that can influence the efficacy of clopidogrel in 851 acute coronary syndromes (ACS) patients. Four outcomes (cerebrovascular event, Acute Myocardium Infarction, unstable angina and death) were used as endpoints among three cohorts (northern, central and southern China) of acute coronary syndromes patients. Three SNPs (rs2244923, rs2773341 and rs34428341) were significantly associated with at least one outcome in all subjects. One SNP rs16863352, may play a role in predicting unstable angina in acute coronary syndrome patients ≥75years of age.