Preclinical investigations of the efficacy of the glutaminase inhibitor CB-839 alone and in combinations in chronic lymphocytic leukemia.
BTK - Bruton’s tyrosine kinase
Bcl-2 inhibitor
CLL - chronic lymphoblastic leukemia
Mcl-1 inhibitor
glutamine (Gln) metabolism
ibrutinib
venetoclax
Journal
Frontiers in oncology
ISSN: 2234-943X
Titre abrégé: Front Oncol
Pays: Switzerland
ID NLM: 101568867
Informations de publication
Date de publication:
2023
2023
Historique:
received:
08
02
2023
accepted:
18
04
2023
medline:
25
5
2023
pubmed:
25
5
2023
entrez:
25
5
2023
Statut:
epublish
Résumé
Chronic lymphocytic leukemia (CLL) cells are metabolically flexible and adapt to modern anticancer treatments. Bruton tyrosine kinase (BTK) and B-cell lymphoma-2 (BCL-2) inhibitors have been widely used to treat CLL, but CLL cells become resistant to these treatments over time. CB-839 is a small-molecule glutaminase-1 (GLS-1) inhibitor that impairs glutamine use, disrupts downstream energy metabolism, and impedes the elimination of reactive oxygen species. To investigate the We found that CB-839 caused dose-dependent decreases in GLS-1 activity and glutathione synthesis. CB-839-treated cells also showed increased mitochondrial superoxide metabolism and impaired energy metabolism, which were reflected in decreases in the oxygen consumption rate and depletion of the adenosine triphosphate pool and led to the inhibition of cell proliferation. In the cell lines, CB-839 combined with venetoclax or AZD-5991, but not with ibrutinib, demonstrated synergism with an increased apoptosis rate and cell proliferation inhibition. In the primary lymphocytes, no significant effects of CB-839 alone or in combination with venetoclax, ibrutinib, or AZD-5991 were observed. Our findings suggest that CB-839 has limited efficacy in CLL treatment and shows limited synergy in combination with widely used CLL drugs.
Identifiants
pubmed: 37228498
doi: 10.3389/fonc.2023.1161254
pmc: PMC10203524
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1161254Informations de copyright
Copyright © 2023 Timofeeva, Ayres, Baran, Santiago-O’Farrill, Bildik, Lu, Konopleva and Gandhi.
Déclaration de conflit d'intérêts
Previously, for other investigations, V.G. received research funding from AbbVie, Acerta, AstraZeneca, Clear Creek Bio., Gilead, Infinity, Loxo/Lilly Oncology, Pharmacyclics, and Sunesis. The remaining authors declare no competing financial interests.
Références
Nat Med. 2022 Aug;28(8):1662-1671
pubmed: 35953718
Blood Cancer J. 2018 Jan 24;8(1):13
pubmed: 29367649
Sci Signal. 2011 Apr 05;4(167):pe17
pubmed: 21467295
Blood. 2015 Sep 10;126(11):1346-56
pubmed: 26186940
Cell Metab. 2012 Jan 4;15(1):110-21
pubmed: 22225880
Oncotarget. 2017 May 30;8(22):35863-35876
pubmed: 28415782
Blood. 2014 Apr 24;123(17):2663-72
pubmed: 24553174
Cancer Cell. 2019 Oct 14;36(4):369-384.e13
pubmed: 31543463
Mitochondrion. 2016 Nov;31:33-39
pubmed: 27650502
Mol Cancer Res. 2017 Dec;15(12):1692-1703
pubmed: 28835371
Br J Cancer. 2017 Jan 17;116(2):149-155
pubmed: 27884017
Integr Med (Encinitas). 2014 Feb;13(1):8-12
pubmed: 26770075
Genomics. 1997 Jun 15;42(3):369-77
pubmed: 9205107
Mol Cancer Ther. 2014 Apr;13(4):890-901
pubmed: 24523301
Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):13075-80
pubmed: 20615965
Front Oncol. 2018 Sep 26;8:411
pubmed: 30319974
Curr Opin Investig Drugs. 2006 May;7(5):443-50
pubmed: 16729721
Cancer Cell. 2012 Mar 20;21(3):297-308
pubmed: 22439925
Nat Commun. 2022 May 19;13(1):2801
pubmed: 35589701
Front Physiol. 2021 Apr 23;12:627837
pubmed: 33967820
Leuk Res. 1999 Feb;23(2):127-36
pubmed: 10071128
Cancer Cell. 2007 Jul;12(1):9-22
pubmed: 17613433
Mol Syst Biol. 2013 Dec 03;9:712
pubmed: 24301801
Cell Cycle. 2012 Nov 15;11(22):4107-8
pubmed: 23095634
Cancer Lett. 2021 Apr 1;502:180-188
pubmed: 33450358
Oncotarget. 2016 Nov 29;7(48):79722-79735
pubmed: 27806325
Blood. 2005 Jun 1;105(11):4455-62
pubmed: 15718423
Cell Death Discov. 2020 Apr 16;6:20
pubmed: 32337072
J Surg Res. 2006 Mar;131(1):26-40
pubmed: 16154153
J Biol Chem. 2019 Jun 14;294(24):9342-9357
pubmed: 31040181
Leukemia. 2022 Aug;36(8):2009-2021
pubmed: 35672446
Cancer Res. 2010 Jan 15;70(2):440-6
pubmed: 20068163
Cell Death Differ. 2018 Jan;25(1):21-26
pubmed: 28984869
Biochem Soc Trans. 2003 Dec;31(Pt 6):1337-9
pubmed: 14641058
Mol Cancer Ther. 2019 Nov;18(11):1937-1946
pubmed: 31387889
Nat Commun. 2017 Aug 24;8(1):338
pubmed: 28835610
Proc Natl Acad Sci U S A. 2008 Apr 1;105(13):5166-71
pubmed: 18362358
Mol Cancer Ther. 2021 Nov;20(11):2207-2217
pubmed: 34518298
Oncotarget. 2018 May 18;9(38):24980-24991
pubmed: 29861847
J Clin Biochem Nutr. 2015 Jan;56(1):1-7
pubmed: 25834301
Bioinformatics. 2016 Sep 15;32(18):2866-8
pubmed: 27153664
J Mol Med (Berl). 1999 Feb;77(2):266-81
pubmed: 10023780
Mol Cell. 2012 Aug 10;47(3):349-58
pubmed: 22749528
Sci Transl Med. 2019 May 8;11(491):
pubmed: 31068440
PLoS One. 2021 Nov 3;16(11):e0259241
pubmed: 34731180
Leuk Lymphoma. 2004 Oct;45(10):2017-27
pubmed: 15370246