Inhibition of nucleo-cytoplasmic shuttling through XPO1/CRM1: a unique therapeutic approach for treatment of haematological and solid malignancies

S. Sneha, P. NagareR., Bindhya Sadhanandhan, Ram Shankar, S. Suresh, T. Ganesan, M. Garg
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Abstract

Cancer is one of the leading cause of morbidity and mortality worldwide. Regulated nucleo-cytoplasmic shuttling is very crucial for maintaining cellular homeostasis. Emerging evidence suggests that deregulation of the nucleo-cytoplasmic transport results in abnormal cell growth, cell cycle, apoptosis, tumor progression and drug resistance. Exportin-1 (also called as chromosome region maintenance 1) belongs to karyopherin-β superfamily and is the main mediator of nuclear export in several cell types. The XPO1 / CRM1 protein is overexpressed in liposarcoma, Ewing sarcoma, ovarian carcinoma, pancreatic cancer, hepatocellular carcinoma, lung carcinoma, osteosarcoma, gastric carcinoma, melanoma, glioma, acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid/lymphoid leukemia as well as multiple myeloma. Hot spot mutations were observed in many cancers. Higher levels of XPO1 / CRM1 are associated with poor prognosis, resistance to chemotherapy and recurrence in a large number of human malignancies. There are growing evidence that provided the foundation that inhibition of nuclear export by inhibiting nuclear export receptor ( XPO1 ) might be a potential targeted therapeutic approach for the treatment of human cancers in the clinic. In the present review, we will discuss the role of XPO1 in cancers and potential of selective inhibitors of nuclear export ( XPO1 inhibitors) to restore the normal function of tumor suppressor and growth regulatory proteins by blocking their export. Selinexor (KPT-330) is an orally available, highly potent and is being tested in human phase-I/II clinical trials in both haematological and solid malignancies.
通过XPO1/CRM1抑制核细胞质穿梭:治疗血液病和实体恶性肿瘤的独特治疗方法
癌症是全世界发病率和死亡率的主要原因之一。核细胞质穿梭调节对维持细胞内稳态至关重要。越来越多的证据表明,核质转运的失调导致细胞生长异常、细胞周期、细胞凋亡、肿瘤进展和耐药。输出蛋白-1(也称为染色体区域维持1)属于核丝蛋白-β超家族,是几种细胞类型的核输出的主要介质。XPO1 / CRM1蛋白在脂肪肉瘤、尤因肉瘤、卵巢癌、胰腺癌、肝细胞癌、肺癌、骨肉瘤、胃癌、黑色素瘤、胶质瘤、急性髓性白血病、急性淋巴细胞白血病、慢性髓性/淋巴性白血病以及多发性骨髓瘤中过表达。在许多癌症中都观察到热点突变。在大量人类恶性肿瘤中,较高水平的XPO1 / CRM1与预后不良、化疗耐药和复发有关。越来越多的证据表明,通过抑制核输出受体(XPO1)抑制核输出可能成为临床治疗人类癌症的潜在靶向治疗方法。在这篇综述中,我们将讨论XPO1在癌症中的作用,以及选择性核输出抑制剂(XPO1抑制剂)通过阻断肿瘤抑制蛋白和生长调节蛋白的输出来恢复其正常功能的潜力。Selinexor (KPT-330)是一种口服有效的高效药物,目前正在血液和实体恶性肿瘤的人体i /II期临床试验中进行测试。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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