Please use this identifier to cite or link to this item:
https://hdl.handle.net/10316/107532
Title: | Discovery of a small-molecule protein kinase Cδ-selective activator with promising application in colon cancer therapy | Authors: | Bessa, Cláudia Soares, Joana Raimundo, Liliana Loureiro, Joana B. Gomes, Célia Reis, Flávio Soares, Miguel L. Santos, Daniel Dureja, Chetna Chaudhuri, Saumya R. Lopez-Haber, Cynthia Kazanietz, Marcelo G. Gonçalves, Jorge Simões, Maria F. Rijo, Patrícia Saraiva, Lucília |
Issue Date: | 18-Jan-2018 | Publisher: | Springer Nature | Project: | FEDER funds POCI/01/0145/FEDER/007728, FCOMP-01-0124-FEDER-028417 and POCI-01-0145-FEDER-007440, through Programa Operacional Factores de Competitividade—COMPETE) and National Funds (FCT/MEC, Fundação para a Ciência e Tecnologia and Ministério da Educação e Ciência) under the Partnership Agreement PT2020 UID/MULTI/ 04378/2013, UID/NEU/04539/2013, UID/DTP/04567/2016, and the project (3599-PPCDT) PTDC/DTP-FTO/1981/2014—POCI-01-0145-FEDER-016581, as well as Centro 2020 Regional Operational Programmes (CENTRO-01-0145- FEDER-000012: HealthyAging2020). FCT fellowships: SFRH/BD/87109/2012 (C. Bessa), SFRH/BD/117949/2016 (L. Raimundo), and SFRH/BD/128673/2017 (J. B. Loureiro). | Serial title, monograph or event: | Cell Death and Disease | Volume: | 9 | Issue: | 2 | Abstract: | Protein kinase C (PKC) isozymes play major roles in human diseases, including cancer. Yet, the poor understanding of isozymes-specific functions and the limited availability of selective pharmacological modulators of PKC isozymes have limited the clinical translation of PKC-targeting agents. Here, we report the first small-molecule PKCδ-selective activator, the 7α-acetoxy-6β-benzoyloxy-12-O-benzoylroyleanone (Roy-Bz), which binds to the PKCδ-C1-domain. Roy-Bz potently inhibited the proliferation of colon cancer cells by inducing a PKCδ-dependent mitochondrial apoptotic pathway involving caspase-3 activation. In HCT116 colon cancer cells, Roy-Bz specifically triggered the translocation of PKCδ but not other phorbol ester responsive PKCs. Roy-Bz caused a marked inhibition in migration of HCT116 cells in a PKCδ-dependent manner. Additionally, the impairment of colonosphere growth and formation, associated with depletion of stemness markers, indicate that Roy-Bz also targets drug-resistant cancer stem cells, preventing tumor dissemination and recurrence. Notably, in xenograft mouse models, Roy-Bz showed a PKCδ-dependent antitumor effect, through anti-proliferative, pro-apoptotic, and anti-angiogenic activities. Besides, Roy-Bz was non-genotoxic, and in vivo it had no apparent toxic side effects. Collectively, our findings reveal a novel promising anticancer drug candidate. Most importantly, Roy-Bz opens the way to a new era on PKC biology and pharmacology, contributing to the potential redefinition of the structural requirements of isozyme-selective agents, and to the re-establishment of PKC isozymes as feasible therapeutic targets in human diseases. | URI: | https://hdl.handle.net/10316/107532 | ISSN: | 2041-4889 | DOI: | 10.1038/s41419-017-0154-9 | Rights: | openAccess |
Appears in Collections: | FMUC Medicina - Artigos em Revistas Internacionais I&D IBILI - Artigos em Revistas Internacionais |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
Discovery-of-a-smallmolecule-protein-kinase-Cselective-activator-with-promising-application-in-colon-cancer-therapy-articleCell-Death-and-Disease.pdf | 8.76 MB | Adobe PDF | View/Open |
SCOPUSTM
Citations
23
checked on Apr 22, 2024
WEB OF SCIENCETM
Citations
22
checked on Apr 2, 2024
Page view(s)
52
checked on Apr 23, 2024
Download(s)
7
checked on Apr 23, 2024
Google ScholarTM
Check
Altmetric
Altmetric
This item is licensed under a Creative Commons License