Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Division of Hematology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
Biomed Pharmacother. 2018 Nov;107:1010-1019. doi: 10.1016/j.biopha.2018.08.065. Epub 2018 Aug 24.
The treatment for leukemic malignancies remains a challenge despite the wide use of conventional chemotherapies. Therefore, new therapeutic approaches are highly demanded. TNF-related apoptosis-inducing ligand (TRAIL) represents a targeted therapy against cancer because it induces apoptosis only in tumor cells. TRAIL is currently under investigation for the treatment of leukemia. Preclinical studies evaluated the potential therapeutic efficacy of TRAIL on cell lines and clinical samples and showed promising results. However, like most anti-cancer drugs, resistance to TRAIL-induced apoptosis may limit its clinical efficacy. It is critical to understand the molecular mechanisms of TRAIL. Therefore, rational therapeutic drug combinations for clinical trials of TRAIL-based therapies might be achieved. In a variety of leukemic cells, overexpression of X-linked inhibitor of apoptosis protein (XIAP), a negative regulator of apoptosis pathway, has been discovered. Implication of XIAP in the ineffective induction of cell death by TRAIL in leukemia has been explored in several resistant cell lines. XIAP inhibitors restored TRAIL sensitivity in resistant cells and primary leukemic blasts. Moreover, TRAIL resistance in leukemic cells could be overcome by the effects of several anti-leukemic agents via the mechanisms of XIAP downregulation. Here, we discuss targeting XIAP, a strategy to restore TRAIL sensitivity in leukemia to acquire more insights into the mechanisms of TRAIL resistance. The concluding remarks may lead to identify putative ways to resensitize tumors.
尽管常规化疗得到广泛应用，但白血病恶性肿瘤的治疗仍然是一个挑战。因此，非常需要新的治疗方法。TNF 相关凋亡诱导配体（TRAIL）是一种针对癌症的靶向治疗方法，因为它仅在肿瘤细胞中诱导凋亡。TRAIL 目前正在被研究用于治疗白血病。临床前研究评估了 TRAIL 在细胞系和临床样本中的潜在治疗效果，并显示出有希望的结果。然而，与大多数抗癌药物一样，对 TRAIL 诱导的细胞凋亡的抵抗可能会限制其临床疗效。了解 TRAIL 的分子机制至关重要。因此，合理的 TRAIL 联合治疗药物组合可能会在临床试验中实现。在多种白血病细胞中，已经发现凋亡蛋白抑制因子 X 连锁（XIAP）的过表达，这是凋亡途径的负调节剂。在几种耐药细胞系中已经探讨了 XIAP 在 TRAIL 诱导白血病细胞死亡无效中的作用。XIAP 抑制剂在耐药细胞和原发性白血病母细胞中恢复了 TRAIL 的敏感性。此外，几种抗白血病药物通过 XIAP 下调机制可以克服白血病细胞对 TRAIL 的耐药性。在这里，我们讨论了靶向 XIAP 的策略，以恢复白血病中 TRAIL 的敏感性，从而更深入地了解 TRAIL 耐药性的机制。结语可能会确定重新敏感肿瘤的潜在方法。
