Docosahexaenoic acid and disulfiram act in concert to kill cancer cells: a mutual enhancement of their anticancer actions.
Docosahexaenoic acid and disulfiram act in concert to kill cancer cells: a mutual enhancement of their anticancer actions.
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DOI：
10.18632/oncotarget.14702
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发表时间：
2017-03-14
期刊：
影响因子：
--
通讯作者：
Ding WQ
中科院分区：
文献类型：
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作者：
Jiao Y;Hannafon BN;Zhang RR;Fung KM;Ding WQ
我们之前报道了氯碘羟喹和二十二碳六烯酸（DHA）在人类癌细胞中的协同抗癌作用。然而，氯碘羟喹因其神经毒性而被禁止进入临床。这项研究确定双硫仑 (DSF) 作为氯碘羟喹的替代化合物，与 DHA 协同作用，更有效地杀死癌细胞并抑制肿瘤生长。与单独使用 DSF 和 DHA 相比，DSF 和 DHA 治疗在体外和体内诱导更大的凋亡细胞死亡并抑制肿瘤生长。机制研究表明，DSF 增强 DHA 诱导的细胞氧化应激，上调 Nrf2 介导的血红素加氧酶 1 (HO-1) 基因转录即可证明这一点。另一方面，在选定的癌症模型系统中，发现 DHA 可以增强 DSF 诱导的乳腺球形成和干细胞频率的抑制，表明癌细胞干性的改变参与了 DSF 和 DHA 的联合抗癌作用。因此，DHA 和 DSF 这两种临床批准的药物协同作用，可以更有效地杀死癌细胞。这种组合作用涉及增强细胞氧化应激和抑制癌细胞干性。
We previously reported a synergistic anticancer action of clioquinol and docosahexaenoic acid (DHA) in human cancer cells. However, clioquinol has been banned from the clinic due to its neurotoxicity. This study identified disulfiram (DSF) as a substitute compound to clioquinol, acting in concert with DHA to more effectively kill cancer cells and suppress tumor growth. Treatment with DSF and DHA induced greater apoptotic cell death and suppression of tumor growth in vitro and in vivo, as compared to DSF and DHA used alone. Mechanistic studies demonstrated that DSF enhances DHA-induced cellular oxidative stress as evidenced by up-regulation of Nrf2-mediated heme oxygenase 1 (HO-1) gene transcription. On the other hand, DHA was found to enhance DSF-induced suppression of mammosphere formation and stem cell frequency in a selected cancer model system, indicating that alterations to cancer cell stemness are involved in the combinatory anticancer action of DSF and DHA. Thus, DHA and DSF, both clinically approved drugs, act in concert to more effectively kill cancer cells. This combinatory action involves an enhancement of cellular oxidative stress and suppression of cancer cell stemness.