Please use this identifier to cite or link to this item: https://hdl.handle.net/10216/126482
Author(s): Bessa C
Soares J
Raimundo L
Loureiro J
Gomes C
Reis F
Soares ML
Santos D
Dureja C
Chaudhuri S
Lopez-Haber C
Kazanietz M
Gonçalves J
Simões M
Rijo P
Saraiva L
Title: Discovery of a small-molecule protein kinase Cd-selective activator with promising application in colon cancer therapy
Publisher: Nature
Issue Date: 2018
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 PKCd-selective activator, the 7a-acetoxy-6ß-benzoyloxy-12-O-benzoylroyleanone (Roy-Bz), which binds to the PKCd-C1-domain. Roy-Bz potently inhibited the proliferation of colon cancer cells by inducing a PKCd-dependent mitochondrial apoptotic pathway involving caspase-3 activation. In HCT116 colon cancer cells, Roy-Bz specifically triggered the translocation of PKCd but not other phorbol ester responsive PKCs. Roy-Bz caused a marked inhibition in migration of HCT116 cells in a PKCd-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 PKCd-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/10216/126482
Source: Cell Death and Disease, vol.9(2):23
Related Information: info:eu-repo/grantAgreement/FCT/5876/147358/PT
info:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBD%2F87109%2F2012/PT
Document Type: Artigo em Revista Científica Internacional
Rights: openAccess
License: http://creativecommons.org/licenses/by/4.0/
Appears in Collections:I3S - Artigo em Revista Científica Internacional

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