Discovery of a small-molecule protein kinase C delta-selective activator with promising application in colon cancer therapy

• Type: Article in International Scientific Journal
• Date: 2018

Authors

Bessa, C (Author) Other; Soares, J (Author) Other; Raimundo, L (Author) Other; Loureiro, JB (Author) Other; Gomes, C (Author) Other; Reis, F (Author) Other; Soares, ML (Author) FMUP; Santos, D (Author) Other; Dureja, C (Author) Other; Chaudhuri, SR (Author) Other; Lopez Haber, C (Author) Other; Kazanietz, MG (Author) Other; Goncalves, J (Author) Other; Simoes, MF (Author) Other; Rijo, P (Author) Other; Lucilia Saraiva (Author) FFUP

Journal

Title: Cell Death & Disease

Vol. 9

ISSN: 2041-4889

Indexing

ISI Web of Knowledge - 15 Citations

Scopus - 15 Citations

Other information

Authenticus ID: P-00N-GF9

DOI: 10.1038/s41419-017-0154-9

Abstract (EN): 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 PKC delta-selective activator, the 7 alpha-acetoxy-6 beta-benzoyloxy-12-O-benzoylroyleanone (Roy-Bz), which binds to the PKC delta-C1-domain. Roy-Bz potently inhibited the proliferation of colon cancer cells by inducing a PKC delta-dependent mitochondrial apoptotic pathway involving caspase-3 activation. In HCT116 colon cancer cells, Roy-Bz specifically triggered the translocation of PKC delta but not other phorbol ester responsive PKCs. Roy-Bz caused a marked inhibition in migration of HCT116 cells in a PKC delta-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 PKC delta-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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 16