Promises and Challenges of Smac Mimetics as Cancer Therapeutics

Abstract

Inhibitor of Apoptosis (IAP) proteins block programmed cell death and are expressed at high levels in various human cancers, thus making them attractive targets for cancer drug development.

MAP30 promotes apoptosis of U251 and U87 cells by suppressing the LGR5 and Wnt/β-catenin signaling pathway, and enhancing Smac expression

“…Evasion of programmed cell death is a hallmark of human cancer (39). Smac is considered to be an important anticancer factor in the mitochondrial apoptosis pathway, which binds directly to and neutralizes inhibitor of apoptosis (IAP) proteins, thus leading to activation of the intrinsic pathway of apoptosis (39)(40)(41)(42).…”

“…Evasion of programmed cell death is a hallmark of human cancer (39). Smac is considered to be an important anticancer factor in the mitochondrial apoptosis pathway, which binds directly to and neutralizes inhibitor of apoptosis (IAP) proteins, thus leading to activation of the intrinsic pathway of apoptosis (39)(40)(41)(42). In addition, Smac mimetic-mediated depletion of IAP proteins may lead to ubiquitination, proteasomal degradation of substrates and activation of nuclear factor κB (NF-κB), a transcription factor with important functions in cell death and survival signaling, and all the functions of Smac promote apoptosis (39,41,43).…”

Prostat Kanseri Tedavisinin Geleceği Apoptotik İndükleyicilerde mi?

“…Aynı şekilde HGS1029 (Human Genome Science), solid organ tümörlerinde pan-IAP inhibitörü olarak çalışılan bir moleküldür. Solid tümörlerde yapılan faz 1 çalışmasında, HGS1029 inhibitörünün tek başına uygulanması iyi tolere edilmiş ve cIAP-1 miktarı periferal mononükleer hücrelerde önemli ölçüde düştüğü kaydedilmiştir (28). Tedavi için hedef alınan diğer bir IAP ajanı survivindir.…”

Apoptosis-sensitizing activity of birinapant in head and neck squamous cell carcinoma cell lines

“…The extrinsic pathway is activated from the direct cellular environment by extracellular ligands that bind tumor necrosis factor receptor-superfamily (TNFR) members, including Fas or TNFR1. The intrinsic pathway of apoptosis is induced in response to nuclear stress, resulting in the release of second mitochondria-derived activator of caspase (SMAC)/direct IAP-binding protein with low PI, among other factors from the mitochondria, and the formation of the 'apoptosome' (6). Caspase cascades are activated via the intrinsic and extrinsic pathways and result in apoptosis.…”

“…Potent antagonists of IAPs, including SMAC, eliminate their inhibitory effect by directly binding these proteins (8,9). 'SMAC mimetics', synthetic SMAC analogs, including birinapant, which degrades cIAP1/2 and inhibits XIAP, result in caspase activation by interacting with IAPs and blocking their signaling pathways (6). Overexpressed in solid tumors of the head and neck, IAPs serve an important function as predictors of the cisplatin response and patient prognosis (10,11).…”