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 
PT2020UID/NEU/04539/2013 
ENTRO-01-0145- FEDER-000012 
SFRH/BD/87109/2012 
SFRH/BD/117949/2016 
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

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