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

Garcia, Fernando Ponce; Jenkins, Yasmin; Assmann, Victoria D.; Paul, Silpita; Sharma, Nitesh D.; Moore, Catherine; Ma, Eric H.; Diamanti, Paraskevi; Hennequart, Marc; Blagih, Julianna; Le, Le; Jenkins, Benjamin; Rouvray, Sophie; Cronin, James; Jones, Russell G.; Mansour, Marc; Blair, Allison; Halsey, Christina; Matlawska-Wasowska, Ksenia; Herranz, Daniel; Vincent, Emma E.; Jones, Nick

doi:10.1016/j.molmet.2025.102275

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

Fernando Ponce Garcia

, Yasmin Jenkins, Victoria D. Assmann, Silpita Paul, Nitesh D. Sharma, Catherine Moore, Eric H. Ma, Paraskevi Diamanti, Marc Hennequart, Julianna Blagih, Le Le, Benjamin Jenkins, Sophie Rouvray, James Cronin

, Russell G. Jones, Marc Mansour, Allison Blair, Christina Halsey, Ksenia Matlawska-Wasowska, Daniel Herranz, Emma E. Vincent, Nick Jones

Molecular Metabolism, Volume: 102, Start page: 102275

Swansea University Authors: Fernando Ponce Garcia , Yasmin Jenkins, Catherine Moore, Benjamin Jenkins, Sophie Rouvray, James Cronin , Nick Jones

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DOI (Published version): 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 mitochondri...

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Published in:	Molecular Metabolism
ISSN:	2212-8778
Published:	Elsevier BV 2025
Online Access:	Check full text
URI:	https://cronfa.swan.ac.uk/Record/cronfa70760

first_indexed	2025-10-23T13:04:18Z
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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.</abstract><type>Journal Article</type><journal>Molecular Metabolism</journal><volume>102</volume><journalNumber/><paginationStart>102275</paginationStart><paginationEnd/><publisher>Elsevier BV</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>2212-8778</issnPrint><issnElectronic/><keywords>eukaemia; Serine; Glycine; Metabolism; T-ALL; Canagliflozin</keywords><publishedDay>1</publishedDay><publishedMonth>12</publishedMonth><publishedYear>2025</publishedYear><publishedDate>2025-12-01</publishedDate><doi>10.1016/j.molmet.2025.102275</doi><url/><notes/><college>COLLEGE NANME</college><department>Medical School</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>MEDS</DepartmentCode><institution>Swansea University</institution><apcterm>External research funder(s) paid the OA fee (includes OA grants disbursed by the Library)</apcterm><funders>This research was funded by The Little Princess Trust in partnership with Children's Cancer and Leukaemia Group (CCLG) awarded to NJ (CCLGA 2021 05) and a Research Wales Innovation Fund (RWIF) Collaboration Booster Fund Project funded by HEFCW. N.J. is supported by an MRC New Investigator Research Grant (MR/X000095/1). E.E.V is supported by an MRC Research Grant (MR/Z505651/1) and by Cancer Research UK (C18281/A29019). KM-W was supported by grants from the National Cancer Institute (NCI) at the National Institutes of Health, including R01 CA237165 and R01 CA282701. DH was supported by The Leukemia & Lymphoma Society Scholar Award 1386-23. YRJ is funded by a Swansea University Research Excellence Scholarship. 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spelling	2025-11-13T11:17:25.7644450 v2 70760 2025-10-23 Canagliflozin synergises with serine restriction mediating anti-leukaemic effects in T-cell acute lymphoblastic leukaemia 255a64f4bf43b5a1e83000de40e9f41c 0000-0003-0651-2704 Fernando Ponce Garcia Fernando Ponce Garcia true false b274a45a4bc6afb86b4111ad27f544d5 Yasmin Jenkins Yasmin Jenkins true false 9fcd33e8d666364c7755d29e74c24351 Catherine Moore Catherine Moore true false 90f7cfd66781feba615436189178a528 Benjamin Jenkins Benjamin Jenkins true false c2f08519ea0083f12e2888b6b055d1bf Sophie Rouvray Sophie Rouvray true false 9cfd17551c0d1f7438895121e4fbb6e8 0000-0002-0590-9462 James Cronin James Cronin true false 0fce0f7ddbdbfeb968f4e2f1e3f86744 0000-0003-4846-5117 Nick Jones Nick Jones true false 2025-10-23 MEDS 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. Journal Article Molecular Metabolism 102 102275 Elsevier BV 2212-8778 eukaemia; Serine; Glycine; Metabolism; T-ALL; Canagliflozin 1 12 2025 2025-12-01 10.1016/j.molmet.2025.102275 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University External research funder(s) paid the OA fee (includes OA grants disbursed by the Library) This research was funded by The Little Princess Trust in partnership with Children's Cancer and Leukaemia Group (CCLG) awarded to NJ (CCLGA 2021 05) and a Research Wales Innovation Fund (RWIF) Collaboration Booster Fund Project funded by HEFCW. N.J. is supported by an MRC New Investigator Research Grant (MR/X000095/1). E.E.V is supported by an MRC Research Grant (MR/Z505651/1) and by Cancer Research UK (C18281/A29019). KM-W was supported by grants from the National Cancer Institute (NCI) at the National Institutes of Health, including R01 CA237165 and R01 CA282701. DH was supported by The Leukemia & Lymphoma Society Scholar Award 1386-23. YRJ is funded by a Swansea University Research Excellence Scholarship. VDA was supported by a Scotland Centre Cancer Research UK Non-Clinical Training Award (CANCTA-2022/100006) and CH by a Cancer Research UK Programme Foundation Award (DRCPFA-Nov21∖100001). 2025-11-13T11:17:25.7644450 2025-10-23T13:59:45.5940415 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Fernando Ponce Garcia 0000-0003-0651-2704 1 Yasmin Jenkins 2 Victoria D. Assmann 3 Silpita Paul 4 Nitesh D. Sharma 5 Catherine Moore 6 Eric H. Ma 7 Paraskevi Diamanti 8 Marc Hennequart 9 Julianna Blagih 10 Le Le 11 Benjamin Jenkins 12 Sophie Rouvray 13 James Cronin 0000-0002-0590-9462 14 Russell G. Jones 15 Marc Mansour 16 Allison Blair 17 Christina Halsey 18 Ksenia Matlawska-Wasowska 19 Daniel Herranz 20 Emma E. Vincent 21 Nick Jones 0000-0003-4846-5117 22 70760__35615__474ce327ac174804a3423a8fedfa73de.pdf 70760.VoR.pdf 2025-11-13T11:14:53.6084455 Output 4575565 application/pdf Version of Record true ©2025 The Author(s). This is an open access article under the CC BY license. true eng http://creativecommons.org/licenses/by/4.0/)
title	Canagliflozin synergises with serine restriction mediating anti-leukaemic effects in T-cell acute lymphoblastic leukaemia
spellingShingle	Canagliflozin synergises with serine restriction mediating anti-leukaemic effects in T-cell acute lymphoblastic leukaemia Fernando Ponce Garcia Yasmin Jenkins Catherine Moore Benjamin Jenkins Sophie Rouvray James Cronin Nick Jones
title_short	Canagliflozin synergises with serine restriction mediating anti-leukaemic effects in T-cell acute lymphoblastic leukaemia
title_full	Canagliflozin synergises with serine restriction mediating anti-leukaemic effects in T-cell acute lymphoblastic leukaemia
title_fullStr	Canagliflozin synergises with serine restriction mediating anti-leukaemic effects in T-cell acute lymphoblastic leukaemia
title_full_unstemmed	Canagliflozin synergises with serine restriction mediating anti-leukaemic effects in T-cell acute lymphoblastic leukaemia
title_sort	Canagliflozin synergises with serine restriction mediating anti-leukaemic effects in T-cell acute lymphoblastic leukaemia
author_id_str_mv	255a64f4bf43b5a1e83000de40e9f41c b274a45a4bc6afb86b4111ad27f544d5 9fcd33e8d666364c7755d29e74c24351 90f7cfd66781feba615436189178a528 c2f08519ea0083f12e2888b6b055d1bf 9cfd17551c0d1f7438895121e4fbb6e8 0fce0f7ddbdbfeb968f4e2f1e3f86744
author_id_fullname_str_mv	255a64f4bf43b5a1e83000de40e9f41c_*_Fernando Ponce Garcia b274a45a4bc6afb86b4111ad27f544d5__Yasmin Jenkins 9fcd33e8d666364c7755d29e74c24351__Catherine Moore 90f7cfd66781feba615436189178a528__Benjamin Jenkins c2f08519ea0083f12e2888b6b055d1bf__Sophie Rouvray 9cfd17551c0d1f7438895121e4fbb6e8__James Cronin 0fce0f7ddbdbfeb968f4e2f1e3f86744_**_Nick Jones
author	Fernando Ponce Garcia Yasmin Jenkins Catherine Moore Benjamin Jenkins Sophie Rouvray James Cronin Nick Jones
author2	Fernando Ponce Garcia Yasmin Jenkins Victoria D. Assmann Silpita Paul Nitesh D. Sharma Catherine Moore Eric H. Ma Paraskevi Diamanti Marc Hennequart Julianna Blagih Le Le Benjamin Jenkins Sophie Rouvray James Cronin Russell G. Jones Marc Mansour Allison Blair Christina Halsey Ksenia Matlawska-Wasowska Daniel Herranz Emma E. Vincent Nick Jones
format	Journal article
container_title	Molecular Metabolism
container_volume	102
container_start_page	102275
publishDate	2025
institution	Swansea University
issn	2212-8778
doi_str_mv	10.1016/j.molmet.2025.102275
publisher	Elsevier BV
college_str	Faculty of Medicine, Health and Life Sciences
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hierarchy_top_title	Faculty of Medicine, Health and Life Sciences
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hierarchy_parent_title	Faculty of Medicine, Health and Life Sciences
department_str	Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
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description	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.
published_date	2025-12-01T05:31:37Z
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Canagliflozin synergises with serine restriction mediating anti-leukaemic effects in T-cell acute lymphoblastic leukaemia

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