The non‐peptidomimetic IAP antagonist ASTX660 sensitizes colorectal cancer cells for extrinsic apoptosis

Autor: Martin Ehrenschwender, Gertrud Knoll
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Programmed cell death
Indoles
Cell Survival
Peptidomimetic
Morpholines
Cell
TNF
610 Medizin
Down-Regulation
TRAIL
Inhibitor of apoptosis
Piperazines
General Biochemistry
Genetics and Molecular Biology
Inhibitor of Apoptosis Proteins
TNF-Related Apoptosis-Inducing Ligand
03 medical and health sciences
0302 clinical medicine
Cell Line
Tumor
Humans
Medicine
Pyrroles
lcsh:QH301-705.5
Research Articles
Cell Proliferation
ASTX660
ddc:610
business.industry
apoptosis
Cancer
Drug Synergism
Dipeptides
HCT116 Cells
medicine.disease
XIAP
Gene Expression Regulation
Neoplastic
030104 developmental biology
medicine.anatomical_structure
SMAC mimetic
lcsh:Biology (General)
Apoptosis
030220 oncology & carcinogenesis
Cancer research
Tumor necrosis factor alpha
Colorectal Neoplasms
business
HT29 Cells
Signal Transduction
Research Article
Zdroj: FEBS Open Bio, Vol 11, Iss 3, Pp 714-723 (2021)
FEBS Open Bio
Popis: Apoptosis resistance worsens treatment response in cancer and is associated with poor prognosis. Inhibition of anti‐apoptotic proteins can restore cell death and improve treatment efficacy. cIAP1, cIAP2, and XIAP belong to the inhibitor of apoptosis protein (IAP) family and block apoptosis. Targeting IAPs with peptides or peptidomimetics mimicking the IAP‐antagonizing activity of the cell's endogenous IAP antagonist SMAC (SMAC mimetics) showed promising results and fueled development of novel compounds. ASTX660 belongs to the recently introduced class of non‐peptidomimetic IAP antagonists and successfully completed phase I clinical trials. However, ASTX660 has thus far only been evaluated in few cancer entities. Here, we demonstrate that ASTX660 has cell death‐promoting activity in colorectal cancer and provide a head‐to‐head comparison with birinapant, the clinically most advanced peptidomimetic IAP antagonist. ASTX660 facilitates activation of the extrinsic apoptosis pathway upon stimulation with the death ligands TNF and TRAIL and boosts effector caspase activation and subsequent apoptosis. Mechanistically, ASTX660 enhances amplification of death receptor‐generated apoptotic signals in a mitochondria‐dependent manner. Failure to activate the mitochondria‐associated (intrinsic) apoptosis pathway attenuated the apoptosis‐promoting effect of ASTX660. Further clinical studies are warranted to highlight the therapeutic potential of ASTX660 in colorectal cancer.
Inhibitor of apoptosis proteins (IAPs) contribute to apoptosis resistance in cancer, a main cause of treatment failure. We demonstrate that the novel non‐peptidomimetic IAP antagonist ASTX660 promotes cell death in colorectal cancer. ASTX660 facilitates activation of the extrinsic apoptosis pathway upon stimulation with the death ligands TNF and TRAIL, boosts effector caspase activation, and enhances subsequent apoptosis.
Databáze: OpenAIRE
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