Role of NF-E2 related factor 2 (Nrf2) on chemotherapy resistance in acute myeloid leukemia (AML) and the effect of pharmacological inhibition of Nrf2.
Role of NF-E2 related factor 2 (Nrf2) on chemotherapy resistance in acute myeloid leukemia (AML) and the effect of pharmacological inhibition of Nrf2.
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DOI：
10.1371/journal.pone.0177227
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Balasubramanian P
中科院分区：
文献类型：
--
作者：
Karathedath S;Rajamani BM;Musheer Aalam SM;Abraham A;Varatharajan S;Krishnamurthy P;Mathews V;Velayudhan SR;Balasubramanian P
阿糖胞苷(Ara-C)和柔红霉素(DNR)是急性髓系白血病(AML)治疗的主要药物。耐药性和毒副作用是治疗成功的主要威胁，因此有必要选择毒性较低的替代疗法。核因子-E2相关因子-2(Nrf2)是抗氧化剂反应的主要调节因子，与实体瘤的化疗耐药有关。然而，关于Nrf2在AML化疗耐药中的作用以及药物抑制剂Brusatol在调节这种耐药中的作用，人们知之甚少。对Ara-C、ATO、DNR体外IC50较高的AML原代标本NRF2RNA表达显著升高。在耐药的AML细胞系中，NRF2的基因特异性敲除通过降低细胞清除ROS的能力来减少Nrf2下游抗氧化靶标的表达，从而提高了对这些药物的敏感性。用Nrf2的药理抑制剂Brusatol治疗可提高对Ara-C、ATO和DNR的敏感性，并降低克隆形成能力。稳定高表达NRF2的AML细胞株对ATO、DNR和Ara-C的耐药性增加，下游靶点表达增加。这项研究表明，Nrf2可能是AML理想的药物靶点，尤其是通过ROS发挥作用的药物，提示Nrf2抑制剂与化疗药物联合使用来调节AML的耐药性是可能的。
Cytarabine (Ara-C) and Daunorubicin (Dnr) forms the backbone of acute myeloid leukemia (AML) therapy. Drug resistance and toxic side effects pose a major threat to treatment success and hence alternate less toxic therapies are warranted. NF-E2 related factor-2 (Nrf2), a master regulator of antioxidant response is implicated in chemoresistance in solid tumors. However, little is known about the role of Nrf2 in AML chemoresistance and the effect of pharmacological inhibitor brusatol in modulating this resistance. Primary AML samples with high ex-vivo IC50 to Ara-C, ATO, Dnr had significantly high NRF2 RNA expression. Gene-specific knockdown of NRF2 improved sensitivity to these drugs in resistant AML cell lines by decreasing the expression of downstream antioxidant targets of Nrf2 by compromising the cell’s ability to scavenge the ROS. Treatment with brusatol, a pharmacological inhibitor of Nrf2, improved sensitivity to Ara-C, ATO, and Dnr and reduced colony formation capacity. AML cell lines stably overexpressing NRF2 showed increased resistance to ATO, Dnr and Ara-C and increased expression of downstream targets. This study demonstrates that Nrf2 could be an ideal druggable target in AML, more so to the drugs that function through ROS, suggesting the possibility of using Nrf2 inhibitors in combination with chemotherapeutic agents to modulate drug resistance in AML.