Enhanced Degradation of Dihydrofolate Reductase through Inhibition of NAD Kinase by Nicotinamide Analogs
Enhanced Degradation of Dihydrofolate Reductase through Inhibition of NAD Kinase by Nicotinamide Analogs
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DOI：
10.1124/mol.112.080218
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发表时间：
2013-02-01
影响因子：
3.6
通讯作者：
Abali, Emine Ercikan
中科院分区：
文献类型：
--
作者：
Hsieh, Yi-Ching;Tedeschi, Philip;Abali, Emine Ercikan
二氢叶酸还原酶 (DHFR) 由于其在 DNA 合成中的重要作用，已被用于治疗多种人类疾病，包括癌症、自身免疫性疾病和传染病。甲氨蝶呤（MTX）是一种DHFR紧密结合抑制剂，是癌症治疗中应用最广泛的药物之一，对治疗急性淋巴细胞白血病、非霍奇金淋巴瘤和骨肉瘤特别有效。其在癌症中使用的限制包括自然耐药性和获得性耐药性，这是由于细胞摄取减少以及由于聚谷氨酰化物形成受损和较高剂量时的毒性而导致的保留减少而导致的获得性耐药性。在这里，我们描述了一种新机制，通过抑制 NAD 激酶（负责生成 NADP 的唯一酶，NADP 通过脱氢酶/还原酶快速转化为 NADPH），通过消耗肿瘤细胞中的辅因子来诱导 DHFR 降解。我们发现了一种 NAD 激酶抑制剂，即硫代烟酰胺腺嘌呤二核苷酸磷酸 (NADPS)，它会加速 DHFR 的降解并抑制癌细胞的生长。重要的是，NADPS 与 MTX 的联合治疗在转移性结肠癌细胞系中显示出显着的协同作用，并且在 MTX 转运抵抗性白血病细胞系中有效。我们认为 NAD 激酶是进一步开发癌症治疗抑制剂的有效靶点。
Dihydrofolate reductase (DHFR), because of its essential role in DNA synthesis, has been targeted for the treatment of a wide variety of human diseases, including cancer, autoimmune diseases, and infectious diseases. Methotrexate (MTX), a tight binding inhibitor of DHFR, is one of the most widely used drugs in cancer treatment and is especially effective in the treatment of acute lymphocytic leukemia, non-Hodgkin's lymphoma, and osteosarcoma. Limitations to its use in cancer include natural resistance and acquired resistance due to decreased cellular uptake and decreased retention due to impaired polyglutamylate formation and toxicity at higher doses. Here, we describe a novel mechanism to induce DHFR degradation through cofactor depletion in neoplastic cells by inhibition of NAD kinase, the only enzyme responsible for generating NADP, which is rapidly converted to NADPH by dehydrogenases/reductases. We identified an inhibitor of NAD kinase, thionicotinamide adenine dinucleotide phosphate (NADPS), which led to accelerated degradation of DHFR and to inhibition of cancer cell growth. Of importance, combination treatment of NADPS with MTX displayed significant synergy in a metastatic colon cancer cell line and was effective in a MTX-transport resistant leukemic cell line. We suggest that NAD kinase is a valid target for further inhibitor development for cancer treatment.