2. Academic Validation
  3. Antitumoral activity of a CDK12 inhibitor in colorectal cancer through a liposomal formulation

Antitumoral activity of a CDK12 inhibitor in colorectal cancer through a liposomal formulation

  • Biomed Pharmacother. 2024 Sep:178:117165. doi: 10.1016/j.biopha.2024.117165.
Cristina Díaz-Tejeiro 1,  María Arenas-Moreira 2,  Adrián Sanvicente 3,  Lucía Paniagua-Herranz 4,  Pilar Clemente-Casares 5,  Ivan Bravo 2,  Carlos Alonso-Moreno 2,  Cristina Nieto-Jiménez 6,  Alberto Ocaña 7
Affiliations

Affiliations

  • 1 Experimental Therapeutics in Cancer Unit, Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC), Madrid, Spain; Facultad de Medicina, Universidad Complutense de Madrid, Madrid 28040, Spain.
  • 2 Universidad de Castilla-La Mancha, Unidad nanoDrug, Facultad de Farmacia-Centro de Innovación en Química Avanzada (ORFEO-CINQA), Albacete 02008, Spain.
  • 3 Experimental Therapeutics in Cancer Unit, Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC), Madrid, Spain; Facultad de Ciencias Químicas, Universidad Complutense de Madrid, Madrid 28040, Spain.
  • 4 Experimental Therapeutics in Cancer Unit, Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
  • 5 Laboratorio de Virología Molecular, Centro Regional de Investigaciones Biomédicas, Facultad de Farmacia de Albacete, Universidad de Castilla-La Mancha, Albacete 02008, Spain; Grupo de Medicina Molecular, Laboratorio de Virología Molecular, Instituto de Biomedicina (IB)), Facultad de Farmacia de Albacete, Universidad de Castilla-La Mancha, Albacete 02008, Spain.
  • 6 Experimental Therapeutics in Cancer Unit, Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC), Madrid, Spain. Electronic address: cnietoj@salud.madrid.org.
  • 7 Experimental Therapeutics in Cancer Unit, Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC), Madrid, Spain; Medical Oncology Department, Hospital Clínico Universitario San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), and CIBERONC, Madrid, Spain; START Madrid-Fundación Jiménez Díaz (FJD) Early Phase Program, Fundación Jiménez Díaz Hospital, Madrid, Spain. Electronic address: Alberto.ocana@salud.madrid.org.
PMID: 39059354 DOI: 10.1016/j.biopha.2024.117165
Abstract

Colorectal Cancer (CRC) is the third most common Cancer worldwide. Recent experiments suggest that CDK12 can be a good therapeutic target in CRC, and therefore, novel inhibitors targeting this protein are currently in preclinical development. Lipid-based formulations of chemical entities have demonstrated the ability to enhance activity while improving the safety profile. In the present work, we explore the antitumor activity of a new CDK12 Inhibitor (CDK12-IN-E9, CDK12i) and its lipid-based formulation (LP-CDK12i) in CRC models, to increase efficacy. SW620, SW480 and HCT116 CRC cell lines were used to evaluate the inhibitor and the liposomal formulation using MTT proliferation assay, 3D invasion cultures, flow cytometry, Western blotting and immunofluorescence experiments. Free-cholesterol liposomal formulations of CDK12i (LP-CDK12i) were obtained by solvent injection method and fully characterized by size, shape, polydispersity, encapsulation efficiency, and release profile and stability assessments. LP-CDK12i induced a higher antiproliferative effect compared with CDK12i as a free agent. The IC50 value was lower across all cell lines tested, leading to a reduction in cell proliferation and the formation of 3D structures. Evaluation of Apoptosis revealed an increase in cell death, while biochemical studies demonstrated modifications of Apoptosis and DNA damage components. In conclusion, we confirm the role of targeting CDK12 for the treatment of CRC and describe, for the first time, a liposomal formulation of a CDK12i with higher antiproliferative activity compared with the free compound.

Keywords

CDK12; Colorectal Cancer cancer; Cyclin-dependant kinases; lipid-based nanoparticles.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-117203A
    99.97%, CDK12 Inhibitor
    CDK