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

Bessa, Cláudia and Soares, Joana and Raimundo, Liliana and Loureiro, Joana B and Gomes, Célia and Reis, Flávio and Soares, Miguel L and Santos, Daniel and Dureja, Chetna and Chaudhuri, Saumya R and Lopez-Haber, Cynthia and Kazanietz, Marcelo G and Gonçalves, Jorge and Simões, Maria F and Rijo, Patrícia and Saraiva, Lucília (2018) Discovery of a small-molecule protein kinase Cδ-selective activator with promising application in colon cancer therapy. Cell death & disease, 9 (2). p. 23. ISSN 2041-4889

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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.

Item Type: Article
Additional Information: Open Access
Subjects: Q Science > QR Microbiology
Depositing User: Dr. K.P.S.Sengar
Date Deposited: 19 Sep 2018 08:02
Last Modified: 19 Sep 2018 08:02

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