XIAP as a target of new small organic natural molecules inducing human cancer cell death

Muñoz, D. et al. (2019) XIAP as a target of new small organic natural molecules inducing human cancer cell death. Cancers, 11, 1336. (doi: 10.3390/cancers11091336)

Abstract

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.

• Item Type: Articles
• Additional Information: Funding: The research has been supported by grants from the Italian Ministry of Education, University and Research: “PRIN2015” to E.Clem./D.C. and “Departments of Excellence-2018” Program (Dipartimenti di Eccellenza) to DIBAF (University of Tuscia, Viterbo, Italy) (Project “Landscape 4.0 - food, wellbeing and environment”). Authors also acknowledge the financial support provided by the Universidad Nacional de Colombia (Bogotá) and the Administrative Department of Science, Technology and Innovation from Colombia “COLCIENCIAS” (Grant No. 528-2011) to D.M.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Brucoli, Martina
• Authors: Muñoz, D., Brucoli, M., Zecchini, S., Sandoval-Hernandez, A., Arboleda, G., Lopez-Vallejo, F., Delgado, W., Giovarelli, M., Coazzoli, M., Catalani, E., De Palma, C., Perrotta, C., Cuca, L., Clementi, E., and Cervia, D.
• College/School: College of Medical Veterinary and Life Sciences
• Journal Name: Cancers
• Publisher: MDPI
• ISSN: 2072-6694
• ISSN (Online): 2072-6694
• Published Online: 09 September 2019
• Copyright Holders: Copyright © 2019 by the authors.
• First Published: First published in Cancers 11:1336
• Publisher Policy: Reproduced under a Creative Commons license