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首页> 外文期刊>Expert opinion on therapeutic targets >Targeting the liver kinase B1/AMP-activated protein kinase pathway as a therapeutic strategy for hematological malignancies
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Targeting the liver kinase B1/AMP-activated protein kinase pathway as a therapeutic strategy for hematological malignancies

机译：靶向肝激酶B1 / AMP激活的蛋白激酶途径作为血液系统恶性肿瘤的治疗策略

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Introduction: Despite considerable advances, several hematological malignancies remain incurable with standard treatments. Therefore, there is a need for novel targeted and less toxic therapies, particularly for patients who develop resistance to traditional chemotherapeutic drugs. The liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signaling pathway has recently emerged as a tumor suppressor axis. A critical point is that the LKB1/AMPK network remains functional in a wide range of cancers and could be stimulated by drugs, such as N,N-dimethylimidodicarbonimidic diamide (metformin) or 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR). Areas covered: The literature data show that drugs activating LKB1/AMPK signaling induced cell cycle arrest, caspase-dependent apoptosis or autophagy in hematopoietic tumors. Moreover, metformin effectively inhibited mammalian target of rapamycin complex 1 (mTORC1)-controlled oncogenetic protein translation, which does not occur with allosteric mTORC1 inhibitors, such as rapamycin and its derivatives. Metformin was also capable of targeting leukemic stem cells, the most relevant target for leukemia eradication. Expert opinion: Data emerging from preclinical settings suggest that the LKB1/AMPK pathway is critically involved in regulating proliferation and survival of malignant hematopoietic cells. Thus, it is proposed that drugs activating the LKB1/AMPK axis may offer a novel and less toxic treatment option for some types of hematological malignancies.
机译：简介：尽管取得了长足的进步，但使用标准疗法仍无法治愈一些血液系统恶性肿瘤。因此，需要新颖的靶向且毒性较小的疗法，尤其是对于对传统化学疗法药物产生抗性的患者。肝激酶B1（LKB1）/ AMP激活的蛋白激酶（AMPK）信号通路最近已成为肿瘤抑制轴。关键点在于，LKB1 / AMPK网络在多种癌症中仍可正常运行，并可能被N，N-二甲基亚氨基二碳二亚氨基二甲酰胺（metformin）或5-氨基咪唑-4-羧酰胺1-β-D-核呋喃糖苷（AICAR）。涵盖领域：文献数据表明，激活LKB1 / AMPK信号的药物可诱导造血肿瘤细胞周期阻滞，胱天蛋白酶依赖性凋亡或自噬。此外，二甲双胍可有效抑制雷帕霉素复合物1（mTORC1）控制的致癌基因蛋白质翻译的哺乳动物靶标，而变构mTORC1抑制剂（例如雷帕霉素及其衍生物）则不会发生这种情况。二甲双胍还能够靶向白血病干细胞，这是消除白血病最相关的靶标。专家意见：来自临床前环境的数据表明，LKB1 / AMPK通路关键参与调节恶性造血细胞的增殖和存活。因此，提出了激活LKB1 / AMPK轴的药物可以为某些类型的血液系统恶性肿瘤提供新颖且毒性较小的治疗选择。

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