Dual PI3K/HDAC Inhibitor BEBT-908 Exhibits Potent Efficacy as Monotherapy for Primary Central Nervous System Lymphoma.

Humans Mice Animals Histone Deacetylase Inhibitors / pharmacology Phosphatidylinositol 3-Kinases / metabolism Chromatography, Liquid Tandem Mass Spectrometry Phosphoinositide-3 Kinase Inhibitors Neoplasms Lymphoma, Non-Hodgkin Lymphoma / drug therapy Xenograft Model Antitumor Assays Hematologic Neoplasms Central Nervous System / metabolism Cell Line, Tumor

Journal

Targeted oncology
ISSN: 1776-260X
Titre abrégé: Target Oncol
Pays: France
ID NLM: 101270595

Informations de publication

Date de publication:
Nov 2023
Historique:
accepted: 02 10 2023
medline: 23 11 2023
pubmed: 19 10 2023
entrez: 19 10 2023
Statut: ppublish

Résumé

The efficacy of systemic treatment for primary central nervous system lymphoma (PCNSL) is limited because of the blood-brain barrier (BBB) and the ineffectiveness of chemotherapy. The dual PI3K/HDAC inhibitor BEBT-908 has exhibited favorable in vivo distribution and activity in various cancers. The aims of this study were to assess the efficacy of BEBT-908 in brain orthotopic mouse models of hematological malignancies, to investigate its pharmacologic properties, and to elucidate the underlying mechanism of action. We evaluated the anticancer activity of BEBT-908 in various hematological malignancies through cell viability assays. The impact of BEBT-908 on c-Myc expression and ferroptosis signaling pathways was assessed using Western blotting, qPCR, ROS detection, GSH/GSSG detection, and IHC. Pharmacokinetic and pharmacodynamic profiles were assessed through LC-MS/MS and Western blotting. The effects of BEBT-908 in vivo were examined using xenografts and brain orthotopic mouse models. Our findings demonstrate that BEBT-908 exhibits promising anti-tumor activity in vitro and in vivo across multiple subtypes of hematological malignancies. Furthermore, BEBT-908 exhibits excellent BBB penetration and inhibits tumor growth in a brain orthotopic lymphoma model with prolonged survival of host mice. Mechanistically, BEBT-908 downregulated c-Myc expression, which contributed to ferroptosis, ultimately leading to tumor shrinkage. Our study provides robust evidence for the dual PI3K/HDAC inhibitor BEBT-908 as an effective anti-cancer agent for PCNSL.

Sections du résumé

BACKGROUND BACKGROUND
The efficacy of systemic treatment for primary central nervous system lymphoma (PCNSL) is limited because of the blood-brain barrier (BBB) and the ineffectiveness of chemotherapy. The dual PI3K/HDAC inhibitor BEBT-908 has exhibited favorable in vivo distribution and activity in various cancers.
OBJECTIVES OBJECTIVE
The aims of this study were to assess the efficacy of BEBT-908 in brain orthotopic mouse models of hematological malignancies, to investigate its pharmacologic properties, and to elucidate the underlying mechanism of action.
METHODS METHODS
We evaluated the anticancer activity of BEBT-908 in various hematological malignancies through cell viability assays. The impact of BEBT-908 on c-Myc expression and ferroptosis signaling pathways was assessed using Western blotting, qPCR, ROS detection, GSH/GSSG detection, and IHC. Pharmacokinetic and pharmacodynamic profiles were assessed through LC-MS/MS and Western blotting. The effects of BEBT-908 in vivo were examined using xenografts and brain orthotopic mouse models.
RESULTS RESULTS
Our findings demonstrate that BEBT-908 exhibits promising anti-tumor activity in vitro and in vivo across multiple subtypes of hematological malignancies. Furthermore, BEBT-908 exhibits excellent BBB penetration and inhibits tumor growth in a brain orthotopic lymphoma model with prolonged survival of host mice. Mechanistically, BEBT-908 downregulated c-Myc expression, which contributed to ferroptosis, ultimately leading to tumor shrinkage.
CONCLUSION CONCLUSIONS
Our study provides robust evidence for the dual PI3K/HDAC inhibitor BEBT-908 as an effective anti-cancer agent for PCNSL.

Identifiants

DOI: 10.1007/s11523-023-01006-z PMID: 37855991
pubmed: 37855991
doi: 10.1007/s11523-023-01006-z
pii: 10.1007/s11523-023-01006-z
doi:

Substances chimiques

Histone Deacetylase Inhibitors 0
BEBT-908 0
Phosphatidylinositol 3-Kinases EC 2.7.1.-
Phosphoinositide-3 Kinase Inhibitors 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

941-952

Subventions

Organisme : National Science and Technology Major Project
ID : 2016ZX09101002
Organisme : Guangdong Provincial Pearl River Talents Program
ID : 2014ZT05Y232
Organisme : Guangzhou Municipal Science and Technology Project
ID : 201909020004

Informations de copyright

© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.

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Auteurs

Ning Wang (N)

Guangdong Provincial People's Hospital Affiliated to Southern Medical University, Guangdong Academy of Medical Sciences, No. 123 Huifu West Road, Guangzhou, 510080, Guangdong, China.
School of Medicine, South China University of Technology, Guangzhou, China.

Zhenxian Mo (Z)

Guangzhou BeBetter Med Inc., No. 25 Yayingshi Road, Guangzhou, 510660, Guangdong, China.
College of Life Science and Technology, Jinan University, 601 Huangpu Avenue West, Guangzhou, China.

Lu Pan (L)

Guangdong Provincial People's Hospital Affiliated to Southern Medical University, Guangdong Academy of Medical Sciences, No. 123 Huifu West Road, Guangzhou, 510080, Guangdong, China.
School of Medicine, South China University of Technology, Guangzhou, China.

Minhua Zhou (M)

Guangzhou BeBetter Med Inc., No. 25 Yayingshi Road, Guangzhou, 510660, Guangdong, China.

Xiaolan Ye (X)

Guangzhou BeBetter Med Inc., No. 25 Yayingshi Road, Guangzhou, 510660, Guangdong, China.

Xinjian Liu (X)

Guangzhou BeBetter Med Inc., No. 25 Yayingshi Road, Guangzhou, 510660, Guangdong, China.

Xiong Cai (X)

Guangzhou BeBetter Med Inc., No. 25 Yayingshi Road, Guangzhou, 510660, Guangdong, China.
Curis, Inc., Lexington, MA, USA.

Changgeng Qian (C)

Guangzhou BeBetter Med Inc., No. 25 Yayingshi Road, Guangzhou, 510660, Guangdong, China.
Curis, Inc., Lexington, MA, USA.

Feili Chen (F)

Guangdong Provincial People's Hospital Affiliated to Southern Medical University, Guangdong Academy of Medical Sciences, No. 123 Huifu West Road, Guangzhou, 510080, Guangdong, China.

Yan Xiong (Y)

Guangzhou BeBetter Med Inc., No. 25 Yayingshi Road, Guangzhou, 510660, Guangdong, China.

Fushun Fan (F)

College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, China. ffan@bebettermed.com.
Guangzhou BeBetter Med Inc., No. 25 Yayingshi Road, Guangzhou, 510660, Guangdong, China. ffan@bebettermed.com.

Wenyu Li (W)

Guangdong Provincial People's Hospital Affiliated to Southern Medical University, Guangdong Academy of Medical Sciences, No. 123 Huifu West Road, Guangzhou, 510080, Guangdong, China. lwy80411@163.com.
School of Medicine, South China University of Technology, Guangzhou, China. lwy80411@163.com.
ORCID: 0000-0002-6444-7149

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Dual PI3K/HDAC Inhibitor BEBT-908 Exhibits...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Dual PI3K/HDAC Inhibitor BEBT-908 Exhibits...
questionsmedicales.fr › Eucaryotes › Animaux › Dual PI3K/HDAC Inhibitor BEBT-908 Exhibits...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de désacétylase d'histone › Dual PI3K/HDAC Inhibitor BEBT-908 Exhibits...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Phosphatidylinositol 3-kinases › Dual PI3K/HDAC Inhibitor BEBT-908 Exhibits...
questionsmedicales.fr › Techniques d'investigation › Techniques de chimie analytique › Chromatographie › Chromatographie en phase liquide › Dual PI3K/HDAC Inhibitor BEBT-908 Exhibits...
questionsmedicales.fr › Techniques d'investigation › Techniques de chimie analytique › Spectrométrie de masse › Spectrométrie de masse en tandem › Dual PI3K/HDAC Inhibitor BEBT-908 Exhibits...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs des phosphoinositide-3 kinases › Dual PI3K/HDAC Inhibitor BEBT-908 Exhibits...
questionsmedicales.fr › Tumeurs › Dual PI3K/HDAC Inhibitor BEBT-908 Exhibits...
questionsmedicales.fr › Maladies du système immunitaire › Syndromes immunoprolifératifs › Syndromes lymphoprolifératifs › Lymphomes › Lymphome malin non hodgkinien › Dual PI3K/HDAC Inhibitor BEBT-908 Exhibits...
questionsmedicales.fr › Maladies du système immunitaire › Syndromes immunoprolifératifs › Syndromes lymphoprolifératifs › Lymphomes › Dual PI3K/HDAC Inhibitor BEBT-908 Exhibits...
questionsmedicales.fr › Techniques d'investigation › Transplantation tumorale › Tests d'activité antitumorale sur modèle de xénogreffe › Dual PI3K/HDAC Inhibitor BEBT-908 Exhibits...
questionsmedicales.fr › Hémopathies et maladies lymphatiques › Hémopathies › Tumeurs hématologiques › Dual PI3K/HDAC Inhibitor BEBT-908 Exhibits...
questionsmedicales.fr › Système nerveux › Système nerveux central › Dual PI3K/HDAC Inhibitor BEBT-908 Exhibits...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Dual PI3K/HDAC Inhibitor BEBT-908 Exhibits...