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: | POCI/01/0145/FEDER/007728 FCOMP-01-0124-FEDER-028417 POCI-01-0145-FEDER-007440 UID/MULTI/04378/2013 UID/DTP/04567/2016 ENTRO-01-0145- FEDER-000012 SFRH/BD/87109/2012 SFRH/BD/117949/2016 info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID/NEU/04539/2013/PT |
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 May 27, 2024
WEB OF SCIENCETM
Citations
22
checked on Jun 2, 2024
Page view(s)
99
checked on Oct 16, 2024
Download(s)
18
checked on Oct 16, 2024
Google ScholarTM
Check
Altmetric
Altmetric
This item is licensed under a Creative Commons License