Inhibition of monocarboxyate transporter 1 by AZD3965 as a novel therapeutic approach for diffuse large B-cell lymphoma and Burkitt lymphoma.
Inhibition of monocarboxyate transporter 1 by AZD3965 as a novel therapeutic approach for diffuse large B-cell lymphoma and Burkitt lymphoma.
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AZD3965 抑制单羧酸转运蛋白 1 作为弥漫性大 B 细胞淋巴瘤和伯基特淋巴瘤的新型治疗方法。
DOI：
10.3324/haematol.2016.163030
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发表时间：
2017-07
期刊：
影响因子：
10.1
通讯作者：
Wedge SR
中科院分区：
文献类型：
--
作者：
Noble RA;Bell N;Blair H;Sikka A;Thomas H;Phillips N;Nakjang S;Miwa S;Crossland R;Rand V;Televantou D;Long A;Keun HC;Bacon CM;Bomken S;Critchlow SE;Wedge SR
单羧酸转运蛋白1的抑制已被提出作为一种治疗方法，以扰乱缺乏单羧酸转运蛋白4的肿瘤细胞中的乳酸穿梭。我们研究了单羧酸转运蛋白1抑制剂AZD 3965，目前在I期临床研究中，作为一种潜在的治疗弥漫性大B细胞淋巴瘤和伯基特淋巴瘤。虽然在120例弥漫性大B细胞淋巴瘤和10例伯基特淋巴瘤患者的肿瘤中发现了广泛的单羧酸转运蛋白1蛋白，但在73%的弥漫性大B细胞淋巴瘤样品中检测不到单羧酸转运蛋白4蛋白表达，并且在每个伯基特淋巴瘤样品中检测不到或可忽略不计。AZD 3965处理导致一组单羧酸转运蛋白4蛋白表达较低的淋巴瘤细胞系中细胞内乳酸盐快速蓄积，并有效抑制其增殖。AZD 3965在淋巴瘤细胞中诱导的代谢变化与糖酵解的反馈抑制一致。在体内也观察到了显著的细胞抑制反应：每日口服AZD 3965治疗24天，可抑制99%的CA 46伯基特淋巴瘤生长。在体外连续7周将CA 46细胞暴露于AZD 3965导致对氧化磷酸化的更大依赖性。AZD 3965与线粒体复合物I（氧化磷酸化的核心）抑制剂联合使用，在体外诱导了显著的淋巴瘤细胞死亡，并在体内降低了CA 46疾病负担。这些数据支持AZD 3965在肿瘤单羧酸转运蛋白4低表达的伯基特淋巴瘤和弥漫性大B细胞淋巴瘤患者中的临床检查，并强调了联合策略最佳靶向肿瘤代谢表型的潜力。
Inhibition of monocarboxylate transporter 1 has been proposed as a therapeutic approach to perturb lactate shuttling in tumor cells that lack monocarboxylate transporter 4. We examined the monocarboxylate transporter 1 inhibitor AZD3965, currently in phase I clinical studies, as a potential therapy for diffuse large B-cell lymphoma and Burkitt lymphoma. Whilst extensive monocarboxylate transporter 1 protein was found in 120 diffuse large B-cell lymphoma and 10 Burkitt lymphoma patients’ tumors, monocarboxylate transporter 4 protein expression was undetectable in 73% of the diffuse large B-cell lymphoma samples and undetectable or negligible in each Burkitt lymphoma sample. AZD3965 treatment led to a rapid accumulation of intracellular lactate in a panel of lymphoma cell lines with low monocarboxylate transporter 4 protein expression and potently inhibited their proliferation. Metabolic changes induced by AZD3965 in lymphoma cells were consistent with a feedback inhibition of glycolysis. A profound cytostatic response was also observed in vivo: daily oral AZD3965 treatment for 24 days inhibited CA46 Burkitt lymphoma growth by 99%. Continuous exposure of CA46 cells to AZD3965 for 7 weeks in vitro resulted in a greater dependency upon oxidative phosphorylation. Combining AZD3965 with an inhibitor of mitochondrial complex I (central to oxidative phosphorylation) induced significant lymphoma cell death in vitro and reduced CA46 disease burden in vivo. These data support clinical examination of AZD3965 in Burkitt lymphoma and diffuse large B-cell lymphoma patients with low tumor monocarboxylate transporter 4 expression and highlight the potential of combination strategies to optimally target the metabolic phenotype of tumors.