2. Academic Validation
  3. Canagliflozin synergises with serine restriction mediating anti-leukaemic effects in T-cell acute lymphoblastic leukaemia

Canagliflozin synergises with serine restriction mediating anti-leukaemic effects in T-cell acute lymphoblastic leukaemia

  • Mol Metab. 2025 Oct 19:102:102275. doi: 10.1016/j.molmet.2025.102275.
Fernando M Ponce-Garcia 1,  Yasmin R Jenkins 1,  Victoria D Assmann 2,  Silpita Paul 3,  Nitesh D Sharma 3,  Catherine Moore 1,  Eric H Ma 4,  Paraskevi Diamanti 5,  Marc Hennequart 6,  Julianna Blagih 7,  Le Le 8,  Benjamin J Jenkins 1,  Sophie Rouvray 1,  James G Cronin 1,  Russell G Jones 4,  Marc Mansour 9,  Allison Blair 5,  Christina Halsey 2,  Ksenia Matlawska-Wasowska 3,  Daniel Herranz 10,  Emma E Vincent 11,  Nicholas Jones 12
Affiliations

Affiliations

  • 1 Institute of Life Science, Swansea University Medical School, Swansea University, SA2 8PP, United Kingdom.
  • 2 Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
  • 3 Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 4 Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.
  • 5 Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, Bristol, BS8 1TD, United Kingdom; NHS Blood and Transplant, Filton, Bristol, BS34 7QH, United Kingdom.
  • 6 The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, United Kingdom; Namur Research Institute for Life Sciences (NARILIS), Molecular Physiology Unit (URPHYM), University of Namur, Namur, Belgium.
  • 7 The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, United Kingdom; University of Montreal, Maisonneuve-Rosemont Hospital Research Centre, 5414 Assomption Blvd, Montreal, H1T 2M4, Canada.
  • 8 Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA.
  • 9 Department of Haematology, Cancer Institute, University College London, London, United Kingdom.
  • 10 Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA; Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, USA; Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, USA.
  • 11 School of Translational Health Sciences, Dorothy Hodgkin Building, University of Bristol, Bristol, BS1 3NY, United Kingdom; Integrative Epidemiology Unit, School of Population Health Science, University of Bristol, Bristol, BS8 2BN, United Kingdom. Electronic address: emma.vincent@bristol.ac.uk.
  • 12 Institute of Life Science, Swansea University Medical School, Swansea University, SA2 8PP, United Kingdom. Electronic address: n.jones@swansea.ac.uk.
PMID: 41120088 DOI: 10.1016/j.molmet.2025.102275
Abstract

T-cell acute lymphoblastic leukaemia (T-ALL) is a haematological malignancy commonly driven by NOTCH1 activating mutations. A concomitant feature associated with NOTCH1 mutations is heightened oxidative metabolism enabling the exponential proliferation of T-ALL blasts. As such, targeting Mitochondrial Metabolism in T-ALL is an attractive therapeutic avenue. Related to this, canagliflozin (cana), is an FDA-approved sodium glucose co-transporter 2 inhibitor with known off-target effects on complex I and glutamate dehydrogenase, but its potential anti-leukaemic effects remain unexplored. Here, we show that cana possesses potent anti-leukaemic effects underpinned by proliferative defects, cell cycle disruption and Apoptosis. These anti-leukaemic effects driven by cana, are attributed to a perturbed tricarboxylic acid (TCA) cycle and Mitochondrial Metabolism, and elevated mitochondrial ROS. Proteomic analysis revealed that cana treatment resulted in a compensatory increase in the expression of ATF4 targets, including upregulation of serine biosynthesis pathway and one-carbon metabolism Enzymes. As such, restriction of serine and glycine synergized with cana treatment, further enhancing its anti-leukaemic effects. Collectively, our study reveals a cana-driven metabolic vulnerability that can be further exploited via dietary manipulation to treat T-ALL.

Keywords

Canagliflozin; Glycine; Leukaemia; Metabolism; Serine; T-ALL.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z