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

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

SUBMITTER: Bessa C

PROVIDER: S-EPMC5833815 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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

Bessa Cláudia C Soares Joana J Raimundo Liliana L Loureiro Joana B JB Gomes Célia C Reis Flávio F Soares Miguel L ML Santos Daniel D Dureja Chetna C Chaudhuri Saumya R SR Lopez-Haber Cynthia C Kazanietz Marcelo G MG Gonçalves Jorge J Simões Maria F MF Rijo Patrícia P Saraiva Lucília L

Cell death & disease 20180118 2

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 ...[more]

PMID: 29348560

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Dataset Information

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

Publications

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

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