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Open AccessArticle

XIAP as a Target of New Small Organic Natural Molecules Inducing Human Cancer Cell Death

1
Departamento de Química, Facultad de Ciencias, Universidad Nacional de Colombia, Bogotá 111321, Colombia
2
Facultad de Ciencias, Universidad de Ciencias Aplicadas y Ambientales, Bogotá 111166, Colombia
3
Tumour Cell Death Laboratory, Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK
4
Department of Biomedical and Clinical Sciences “Luigi Sacco” (DIBIC), Università degli Studi di Milano, 20157 Milano, Italy
5
Grupo de Muerte Celular, Instituto de Genética, Universidad Nacional de Colombia, Bogotá 111321, Colombia
6
Department for Innovation in Biological, Agro-food and Forest systems (DIBAF), Università degli Studi della Tuscia, 01100 Viterbo, Italy
7
Unit of Clinical Pharmacology, University Hospital “Luigi Sacco”-ASST Fatebenefratelli Sacco, 20157 Milano, Italy
8
Scientific Institute IRCCS “Eugenio Medea”, 23842 Bosisio Parini, Italy
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(9), 1336; https://doi.org/10.3390/cancers11091336
Received: 27 August 2019 / Accepted: 4 September 2019 / Published: 9 September 2019
(This article belongs to the Special Issue Role of Natural Bioactive Compounds in the Rise and Fall of Cancers)
X-linked inhibitor of apoptosis protein (XIAP) is an emerging crucial therapeutic target in cancer. We report on the discovery and characterisation of small organic molecules from Piper genus plants exhibiting XIAP antagonism, namely erioquinol, a quinol substituted in the 4-position with an alkenyl group and the alkenylphenols eriopodols A–C. Another isolated compound was originally identified as gibbilimbol B. Erioquinol was the most potent inhibitor of human cancer cell viability when compared with gibbilimbol B and eriopodol A was listed as intermediate. Gibbilimbol B and eriopodol A induced apoptosis through mitochondrial permeabilisation and caspase activation while erioquinol acted on cell fate via caspase-independent/non-apoptotic mechanisms, likely involving mitochondrial dysfunctions and aberrant generation of reactive oxygen species. In silico modelling and molecular approaches suggested that all molecules inhibit XIAP by binding to XIAP-baculoviral IAP repeat domain. This demonstrates a novel aspect of XIAP as a key determinant of tumour control, at the molecular crossroad of caspase-dependent/independent cell death pathway and indicates molecular aspects to develop tumour-effective XIAP antagonists. View Full-Text
Keywords: phytochemicals; small organic agents; Piper eriopodon, alkenylphenols; human cancer cells; cell death; apoptosis; caspase-independent cell death; XIAP antagonists; XIAP-BIR3 domain phytochemicals; small organic agents; Piper eriopodon, alkenylphenols; human cancer cells; cell death; apoptosis; caspase-independent cell death; XIAP antagonists; XIAP-BIR3 domain
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Muñoz, D.; Brucoli, M.; Zecchini, S.; Sandoval-Hernandez, A.; Arboleda, G.; Lopez-Vallejo, F.; Delgado, W.; Giovarelli, M.; Coazzoli, M.; Catalani, E.; Palma, C.D.; Perrotta, C.; Cuca, L.; Clementi, E.; Cervia, D. XIAP as a Target of New Small Organic Natural Molecules Inducing Human Cancer Cell Death. Cancers 2019, 11, 1336.

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