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

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.

Cláudia Bessa 1, Joana Soares 1, Liliana Raimundo 1, Joana B. Loureiro 1, Célia Gomes 2, Flávio Reis 2, Miguel L. Soares 3, Daniel Santos 4, Chetna Dureja 5, Saumya R. Chaudhuri 5, Cynthia Lopez-Haber 6, Marcelo G. Kazanietz 6, Jorge Gonçalves 7, Maria F. Simões 8,9, Patrícia Rijo 8,9 and Lucília Saraiva 1

1 UCIBIO/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.

2 Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, & CNC.IBILI Research Consortium, University of Coimbra, Coimbra, Portugal.

3 Laboratório de Apoio à Investigação em Medicina Molecular, Departamento de Biomedicina, Faculdade de Medicina da Universidade do Porto, Porto, Portugal.

4 REQUIMTE, Faculdade de Ciências da Universidade do Porto, Porto, Portugal.

5 CSIR-Institute of Microbial Technology, Sector 39A, Chandigarh, India.

6 Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.

7 Laboratório de Farmacologia, Departamento de Ciências do Medicamento, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.

8 CBIOS-Centro de Investigação em Biociências e Tecnologias da Saúde, Universidade Lusófona, Lisboa, Portugal.

9 iMed.ULisboa, Instituto de Investigação do Medicamento, Faculdade de Farmácia da Universidade de Lisboa, Lisboa, Portugal.

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