The role of XIAP in resistance to TNF-related apoptosis-inducing ligand (TRAIL) in Leukemia - 20/09/18
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Highlights |
• | XIAP protein is overexpressed in leukemic cells. |
• | High XIAP levels in linked with poor prognosis in leukemia. |
• | XIAP plays an important role in resistance to TRAIL-induced apoptosis in leukemia. |
Abstract |
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.
Le texte complet de cet article est disponible en PDF.Abbreviations : TRAIL, XIAP, cFLIP, bcl-2, IAP, Mcl-1, Apo-2L, DR, DcR, DISC, FADD, Bid, BAX, NK cell, NFκB, IκBα
Keywords : TRAIL, XIAP, Apoptosis, Leukemia, Drug resistance
Plan
Vol 107
P. 1010-1019 - novembre 2018 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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