Pre-clinical pharmacology of AZD3965, a selective inhibitor of MCT1: DLBCL, NHL and Burkitt's lymphoma anti-tumor activity.
Pre-clinical pharmacology of AZD3965, a selective inhibitor of MCT1: DLBCL, NHL and Burkitt's lymphoma anti-tumor activity.
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DOI：
10.18632/oncotarget.18215
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发表时间：
2017-09-19
期刊：
影响因子：
--
通讯作者：
Critchlow SE
中科院分区：
文献类型：
--
作者：
Curtis NJ;Mooney L;Hopcroft L;Michopoulos F;Whalley N;Zhong H;Murray C;Logie A;Revill M;Byth KF;Benjamin AD;Firth MA;Green S;Smith PD;Critchlow SE
肿瘤通常表现为糖酵解表型，通过糖酵解和伴随的乳酸合成而增加流量。为了维持糖酵解通量和防止细胞内酸化，肿瘤通过乳酸转运体(MCT1-4)排出乳酸。乳酸转运的抑制剂有可能抑制糖酵解和肿瘤生长。我们开发了一种MCT1的小分子抑制剂(AZD3965)，并在一组细胞系上评估了它的活性。我们探索了它作为单一疗法以及与阿霉素或利妥昔单抗联合治疗的抗肿瘤活性。AZD3965是一种有效的MCT1抑制剂，对MCT2有抑制作用，但比MCT3和MCT4有选择性。在体外，AZD3965抑制了一系列细胞系的生长，尤其是血液学细胞。AZD3965抑制MCT1可抑制乳酸外流，导致糖酵解中间产物积聚。在体内，AZD3965在Raji Burkitt淋巴瘤模型中导致乳酸积聚，并显著抑制肿瘤生长。此外，AZD3965可以与多柔比星或利妥昔单抗联合使用，后者是DLBCL和Burkitt淋巴瘤R-CHOP治疗标准的组成部分。AZD3965对乳酸转运的抑制作用与GLS1体外抑制作用相结合，与单独用药相比，对细胞生长抑制和细胞死亡的抑制作用增强。将AZD3965与新型和标准护理抑制剂相结合的能力为血液病癌症提供了新的组合机会。
Tumors frequently display a glycolytic phenotype with increased flux through glycolysis and concomitant synthesis of lactate. To maintain glycolytic flux and prevent intracellular acidification, tumors efflux lactate via lactate transporters (MCT1-4). Inhibitors of lactate transport have the potential to inhibit glycolysis and tumor growth. We developed a small molecule inhibitor of MCT1 (AZD3965) and assessed its activity across a panel of cell lines. We explored its antitumor activity as monotherapy and in combination with doxorubicin or rituximab. AZD3965 is a potent inhibitor of MCT1 with activity against MCT2 but selectivity over MCT3 and MCT4. In vitro, AZD3965 inhibited the growth of a range of cell lines especially haematological cells. Inhibition of MCT1 by AZD3965 inhibited lactate efflux and resulted in accumulation of glycolytic intermediates. In vivo, AZD3965 caused lactate accumulation in the Raji Burkitt’s lymphoma model and significant tumor growth inhibition. Moreover, AZD3965 can be combined with doxorubicin or rituximab, components of the R-CHOP standard-of-care in DLBCL and Burkitt’s lymphoma. Finally, combining lactate transport inhibition by AZD3965 with GLS1 inhibition in vitro, enhanced cell growth inhibition and cell death compared to monotherapy treatment. The ability to combine AZD3965 with novel, and standard-of-care inhibitors offers novel combination opportunities in haematological cancers.
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