Exploiting inhibitor of apoptosis proteins as therapeutic targets in hematological malignancies

Abstract

Resistance to apoptosis is one of the hallmarks of human cancers and contributes to the insensitivity of many cancers to commonly used treatment approaches. Inhibitor of apoptosis (IAP) proteins, a family of anti-apoptotic proteins, have an important role in evasion of apoptosis, as they can both block apoptosis-signaling pathways and promote survival. High expression of IAP proteins is observed in multiple cancers, including hematological malignancies, and has been associated with unfavorable prognosis and poor patients' outcome. Therefore, IAP proteins are currently considered as promising molecular targets for therapy. Indeed, drug-discovery approaches over the last decade aiming at neutralizing IAP proteins have resulted in the generation of small-molecule inhibitors or antisense oligonucleotides that demonstrated in vitro and in vivo antitumor activities in preclinical studies. As some of these strategies have already entered the stage of clinical evaluation, for example, in leukemia, an update on this promising molecular-targeted strategy to interfere with apoptotic pathways is of broad interest.

Identification of a novel synergistic induction of cell death by Smac mimetic and HDAC inhibitors in acute myeloid leukemia cells

“…High expression levels of IAP proteins including XIAP and cIAP2 have been linked to poor prognosis in AML in several independent studies [8][9][10]12,27]. Furthermore, we demonstrated that Smac mimetic sensitizes AML cell lines and primary AML samples for cytarabineinduced cell death [16].…”

“…Consistently, treatment with BV6/HDACI/zVAD.fmk Second, Smac mimetic in combination with HDACIs may pave the avenue to more effective treatment options to overcome evasion of apoptosis in AML by triggering necroptosis as an alternative cell death program. Treatment resistance of AML is often caused by the inability of cells to undergo apoptosis [27], thus underlining the significance of necroptosis induction by Smac mimetic/HDACIs combination therapy in order to bypass evasion of apoptosis.…”

“…Defects in cell death programs including overexpression of IAP proteins contribute to treatment resistance and poor outcome in AML [27]. Therefore, novel approaches are necessary to reactivate cell death programs in AML.…”

The SMAC mimetic BV6 induces cell death and sensitizes different cell lines to TNF-α and TRAIL-induced apoptosis

“…6,15 In the last decade, several research efforts were exerted to develop new small molecules mimicking SMAC activity for the use in cancer therapy. [16][17][18][19][20] Interestingly, recent studies have shown the ability of SMAC mimetics to induce degradation of cIAPs, leading to activation of the noncanonical NF-kB pathway and TNF-dependant apoptosis. 21,22 Moreover, there are several ongoing clinical studies to prove the antitumor efficacy of SMAC mimetics either alone or in combination with chemotherapy in different tumor types.…”

Redox-active and Redox-silent Compounds: Synergistic Therapeutics in Cancer

“…The ability of cancer cells to evade apoptosis can be induced by a range of different alterations including physiological changes such as activation/upregulation of mitogenic signalling pathways (i.e. MAPK, Akt) or inactivation/downregulation of certain apoptotic molecules [66]. The anti-apoptotic IAPs have an important role in helping cancer cells evade apoptosis, as they can both block apoptosis signalling pathways and promote survival [66,67].…”