RESUMEN
Fatty acid oxidation dependency of leukemia cells has been documented in recent studies. Pharmacologic inhibition of fatty acid oxidation, thereby, displays significant effects in suppressing leukemia. 2-Bromopalmitate, a palmitate analogue, was initially identified as an inhibitor of fatty acid oxidation, and recently recognized as an inhibitor of protein palmitoylation. However, the effects of 2-Bromopalmitate on leukemia and its cellular targets remain obscure. Herein, we discover in cultured cell lines, a transplantable mouse model, and primary blasts that 2-Bromopalmitate presents synergistic differentiation induction with all-trans retinoic acid in acute promyelocytic leukemia. Moreover, 2-Bromopalmitate overcomes all-trans retinoic acid resistance in all-trans retinoic acid-resistant cells and leukemic mice. Mechanistically, 2-Bromopalmitate covalently binds at cysteine 105 and cysteine 174 of retinoic acid receptor alpha (RARα) and stabilizes RARα protein in the presence of all-trans retinoic acid which is known to induce RARα degradation, leading to enhanced transcription of RARα-target genes. Mutation of both cysteines largely abrogates the synergistic effect of 2-Bromopalmitate on all-trans retinoic acid-induced differentiation, demonstrating that 2-Bromopalmitate promotes all-trans retinoic acid-induced differentiation through binding RARα. All-trans retinoic acid-based regimens including arsenic trioxide or chemotherapy, as preferred therapy for acute promyelocytic leukemia, induce adverse events and irreversible resistance. We expect that combining all-trans retinoic acid with 2-Bromopalmitate would be a promising therapeutic strategy for acute promyelocytic leukemia, especially for overcoming all-trans retinoic acid resistance of relapsed acute promyelocytic leukemia patients.
Asunto(s)
Sistemas de Liberación de Medicamentos , Resistencia a Antineoplásicos/efectos de los fármacos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Proteínas de Neoplasias/agonistas , Palmitatos/farmacología , Receptor alfa de Ácido Retinoico/agonistas , Tretinoina/farmacología , Humanos , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patología , Proteínas de Neoplasias/metabolismo , Receptor alfa de Ácido Retinoico/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: We aimed to compare the effectiveness of liraglutide vs. pioglitazone on hepatic fat content and serum fetuin A levels in patients with type 2 diabetes mellitus and non-alcoholic fatty liver disease. METHODS: This was a single-center, open-label, prospective, and randomized trial using a parallel design and lasting 24 weeks. Sixty patients with type 2 diabetes mellitus and non-alcoholic fatty liver disease were randomly assigned to the liraglutide and pioglitazone groups on a 1:1 basis using a computer-generated sequence. Fetuin-A levels were determined using enzyme-linked immunosorbent assay. Hepatic fat content was measured using proton 1H-MRS on a 1.5T whole-body MRI scanner. All analyses were performed with SPSS version 13.0. RESULTS: In the liraglutide group, fetuin-A levels decreased after 24 weeks (666.1±109.4 vs. 443.7±90.5µg/mL, P<0.05). In the pioglitazone group, fetuin-A levels also decreased after 24 weeks (659.3±111.8 vs. 538.1± 101.0µg/mL, P<0.05) but not to the level of the liraglutide group. The liraglutide treatment resulted in a decrease in 1H-MRS (24.1±3.0 vs. 20.1±3.8, P<0.05). After 24 weeks, ΔFetuin-A was positively correlated with Δweight (r=0.756, P=0.035), ΔBMI (r=0.653, P=0.006), Δwaist circumference (r=0.767, P=0.010), and Δ1H-MRS (r=0.732, P=0.004) in the liraglutide group. CONCLUSIONS: Liraglutide treatment resulted in a decrease in hepatic fat content and fetuin-A compared with pioglitazone treatment in patients with T2DM and NAFLD. Fetuin-A is positively correlated with weight and hepatic fat content. The reduction in the hepatic fat content may be attributed to weight loss rather than reduction of glucose.