Combined inhibition of class 1-PI3K-alpha and delta isoforms causes senolysis by inducing p21

Humans Cellular Senescence / drug effects Cyclin-Dependent Kinase Inhibitor p21 / metabolism HCT116 Cells Proteasome Endopeptidase Complex / metabolism Apoptosis / drug effects Phosphoinositide-3 Kinase Inhibitors / pharmacology MCF-7 Cells Proteolysis / drug effects A549 Cells Wortmannin / pharmacology Senotherapeutics / pharmacology Class I Phosphatidylinositol 3-Kinases / metabolism DNA Damage / drug effects Pyrimidines Quinazolines

Journal

Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092

Informations de publication

Date de publication:
29 May 2024
Historique:
received: 27 09 2023
accepted: 16 05 2024
revised: 13 05 2024
medline: 30 5 2024
pubmed: 30 5 2024
entrez: 29 5 2024
Statut: epublish

Résumé

The targeted elimination of radio- or chemotherapy-induced senescent cells by so-called senolytic substances represents a promising approach to reduce tumor relapse as well as therapeutic side effects such as fibrosis. We screened an in-house library of 178 substances derived from marine sponges, endophytic fungi, and higher plants, and determined their senolytic activities towards DNA damage-induced senescent HCT116 colon carcinoma cells. The Pan-PI3K-inhibitor wortmannin and its clinical derivative, PX-866, were identified to act as senolytics. PX-866 potently induced apoptotic cell death in senescent HCT116, MCF-7 mammary carcinoma, and A549 lung carcinoma cells, independently of whether senescence was induced by ionizing radiation or by chemotherapeutics, but not in proliferating cells. Other Pan-PI3K inhibitors, such as the FDA-approved drug BAY80-6946 (Copanlisib, Aliqopa®), also efficiently and specifically eliminated senescent cells. Interestingly, only the simultaneous inhibition of both PI3K class I alpha (with BYL-719 (Alpelisib, Piqray®)) and delta (with CAL-101 (Idelalisib, Zydelig®)) isoforms was sufficient to induce senolysis, whereas single application of these inhibitors had no effect. On the molecular level, inhibition of PI3Ks resulted in an increased proteasomal degradation of the CDK inhibitor p21

Identifiants

DOI: 10.1038/s41419-024-06755-x PMID: 38811535
pubmed: 38811535
doi: 10.1038/s41419-024-06755-x
pii: 10.1038/s41419-024-06755-x
doi:

Substances chimiques

Cyclin-Dependent Kinase Inhibitor p21 0
Proteasome Endopeptidase Complex EC 3.4.25.1
Phosphoinositide-3 Kinase Inhibitors 0
CDKN1A protein, human 0
Wortmannin XVA4O219QW
Senotherapeutics 0
Class I Phosphatidylinositol 3-Kinases EC 2.7.1.137
copanlisib WI6V529FZ9
Pyrimidines 0
Quinazolines 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

373

Subventions

Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : SO 881/5-1

Informations de copyright

© 2024. The Author(s).

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Auteurs

Judith Neuwahl (J)

Laboratory of Molecular Radiooncology, Clinic and Policlinic for Radiation Therapy and Radiooncology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.

Chantal A Neumann (CA)

Laboratory of Molecular Radiooncology, Clinic and Policlinic for Radiation Therapy and Radiooncology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.

Annika C Fitz (AC)

Laboratory of Molecular Radiooncology, Clinic and Policlinic for Radiation Therapy and Radiooncology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.

Anica D Biermann (AD)

Laboratory of Molecular Radiooncology, Clinic and Policlinic for Radiation Therapy and Radiooncology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
Experimental Nephrology, Clinic for Nephrology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.

Maja Magel (M)

Laboratory of Molecular Radiooncology, Clinic and Policlinic for Radiation Therapy and Radiooncology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital of RWTH, Aachen, Germany.

Annabelle Friedrich (A)

Institute of Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.

Lorenz Sellin (L)

Experimental Nephrology, Clinic for Nephrology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.

Björn Stork (B)

Institute of Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
ORCID: 0000-0002-4167-7806

Roland P Piekorz (RP)

Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.

Peter Proksch (P)

Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.

Wilfried Budach (W)

Laboratory of Molecular Radiooncology, Clinic and Policlinic for Radiation Therapy and Radiooncology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.

Reiner U Jänicke (RU)

Laboratory of Molecular Radiooncology, Clinic and Policlinic for Radiation Therapy and Radiooncology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.

Dennis Sohn (D)

Laboratory of Molecular Radiooncology, Clinic and Policlinic for Radiation Therapy and Radiooncology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany. dennis.sohn@hhu.de.
ORCID: 0009-0004-1392-9609

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Combined inhibition of class 1-PI3K-alpha and...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Vieillissement › Vieillissement de la cellule › Combined inhibition of class 1-PI3K-alpha and...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines nucléaires › Protéines liant le poly-adp-ribose › Inhibiteur p21 de kinase cycline-dépendante › Combined inhibition of class 1-PI3K-alpha and...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Cellules HCT116 › Combined inhibition of class 1-PI3K-alpha and...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Complexes multienzymatiques › Proteasome endopeptidase complex › Combined inhibition of class 1-PI3K-alpha and...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Mort cellulaire › Mort cellulaire régulée › Apoptose › Combined inhibition of class 1-PI3K-alpha and...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs des phosphoinositide-3 kinases › Combined inhibition of class 1-PI3K-alpha and...
questionsmedicales.fr › Cellules › Cellules cultivées › Lignée cellulaire › Cellules MCF-7 › Combined inhibition of class 1-PI3K-alpha and...
questionsmedicales.fr › Métabolisme › Protéolyse › Combined inhibition of class 1-PI3K-alpha and...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules A549 › Combined inhibition of class 1-PI3K-alpha and...
questionsmedicales.fr › Composés polycycliques › Composés à cycles fusionnés › Stéroïdes › Androstanes › Androstènes › Androstadiènes › Wortmannine › Combined inhibition of class 1-PI3K-alpha and...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Sénothérapie › Combined inhibition of class 1-PI3K-alpha and...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Phosphatidylinositol 3-kinases › Phosphatidylinositol-4-phosphate 3-kinase › Phosphatidylinositol 3-kinases de classe I › Combined inhibition of class 1-PI3K-alpha and...
questionsmedicales.fr › Phénomènes génétiques › Altération de l'ADN › Combined inhibition of class 1-PI3K-alpha and...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pyrimidines › Combined inhibition of class 1-PI3K-alpha and...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Quinazolines › Combined inhibition of class 1-PI3K-alpha and...