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首页> 外文期刊>Oncology reports >Benzimidazole derivative, BMT-1, induces apoptosis in multiple myeloma cells via a mitochondrial-mediated pathway involving H+/K+-ATPase inhibition
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Benzimidazole derivative, BMT-1, induces apoptosis in multiple myeloma cells via a mitochondrial-mediated pathway involving H+/K+-ATPase inhibition

机译：苯并咪唑衍生物BMT-1通过线粒体介导的H + / K + -ATPase抑制途径诱导多发性骨髓瘤细胞凋亡

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摘要

2-(1H-benzimidazol-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol (BMT-1), a bicyclic compound, belongs to the benzimidazole group and consists of the fusion of benzene and imidazole. The objective of the present study was to assess the effect of BMT-1 on the proliferation of multiple myeloma (MM) cells and identify whether BMT-1 induces apoptosis in MM cells. Our results showed a dose- and time-dependent decrease in the proliferation of MM cells treated with BMT-1. Further studies revealed that the antiproliferative effects of BMT-1 were caused by induction of apoptosis with activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase in MM cells. In addition, BMT-1 induced the loss of mitochondrial membrane potential resulting in the activation of caspase-8 and -9. Furthermore, the MM cells treated with BMT-1 showed a more acidic intracellular pH (pHi) as indicated by a lower FL1/FL2 ratio caused by inhibition of H+/K+-ATPase. Collectively, these findings demonstrated that a decrease in pHi, caused by H+/K+-ATPase inhibition induced by BMT-1, triggered the dysfunction of the mitochondria resulting in the apoptosis of MM cells. Therefore, BMT-1 may be used as a lead compound for the design and development of new agents with which to treat MM and other forms of cancer.
机译：双环化合物2-（1H-苯并咪唑-2-基）-4,5,6,7-四氢-2H-吲唑-3-醇（BMT-1）属于苯并咪唑基团，由苯和咪唑。本研究的目的是评估BMT-1对多发性骨髓瘤（MM）细胞增殖的影响，并确定BMT-1是否诱导MM细胞凋亡。我们的结果表明，用BMT-1处理的MM细胞的增殖呈剂量和时间依赖性降低。进一步的研究表明，BMT-1的抗增殖作用是通过激活caspase-3诱导凋亡和MM细胞中的聚ADP-核糖聚合酶裂解而引起的。另外，BMT-1引起线粒体膜电位的丧失，导致caspase-8和-9的激活。此外，BMT-1处理的MM细胞显示出更酸性的细胞内pH（pHi），这是由抑制H + / K + -ATPase引起的较低的FL1 / FL2比所表明的。总的来说，这些发现表明，由BMT-1诱导的H + / K + -ATPase抑制引起的pHi降低引发线粒体功能障碍，导致MM细胞凋亡。因此，BMT-1可用作设计和开发用于治疗MM和其他形式癌症的新药物的先导化合物。

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