Simultaneous targeting of glycolysis and oxidative phosphorylation as a therapeutic strategy to treat diffuse large B-cell lymphoma
© 2022. The Author(s)..
BACKGROUND: We evaluated the therapeutic potential of combining the monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 with the mitochondrial respiratory Complex I inhibitor IACS-010759, for the treatment of diffuse large B-cell lymphoma (DLBCL), a potential clinically actionable strategy to target tumour metabolism.
METHODS: AZD3965 and IACS-010759 sensitivity were determined in DLBCL cell lines and tumour xenograft models. Lactate concentrations, oxygen consumption rate and metabolomics were examined as mechanistic endpoints. In vivo plasma concentrations of IACS-010759 in mice were determined by LC-MS to select a dose that reflected clinically attainable concentrations.
RESULTS: In vitro, the combination of AZD3965 and IACS-010759 is synergistic and induces DLBCL cell death, whereas monotherapy treatments induce a cytostatic response. Significant anti-tumour activity was evident in Toledo and Farage models when the two inhibitors were administered concurrently despite limited or no effect on the growth of DLBCL xenografts as monotherapies.
CONCLUSIONS: This is the first study to examine a combination of two distinct approaches to targeting tumour metabolism in DLBCL xenografts. Whilst nanomolar concentrations of either AZD3965 or IACS-010759 monotherapy demonstrate anti-proliferative activity against DLBCL cell lines in vitro, appreciable clinical activity in DLBCL patients may only be realised through their combined use.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:127 |
|---|---|
| Enthalten in: |
British journal of cancer - 127(2022), 5 vom: 26. Sept., Seite 937-947 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Noble, Richard A [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Journal Article |
|---|
| Anmerkungen: |
Date Completed 02.09.2022 Date Revised 13.11.2022 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1038/s41416-022-01848-w |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM341411183 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM341411183 | ||
| 003 | DE-627 | ||
| 005 | 20231226011719.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41416-022-01848-w |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1137.xml |
| 035 | |a (DE-627)NLM341411183 | ||
| 035 | |a (NLM)35618788 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Noble, Richard A |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Simultaneous targeting of glycolysis and oxidative phosphorylation as a therapeutic strategy to treat diffuse large B-cell lymphoma |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 02.09.2022 | ||
| 500 | |a Date Revised 13.11.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022. The Author(s). | ||
| 520 | |a BACKGROUND: We evaluated the therapeutic potential of combining the monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 with the mitochondrial respiratory Complex I inhibitor IACS-010759, for the treatment of diffuse large B-cell lymphoma (DLBCL), a potential clinically actionable strategy to target tumour metabolism | ||
| 520 | |a METHODS: AZD3965 and IACS-010759 sensitivity were determined in DLBCL cell lines and tumour xenograft models. Lactate concentrations, oxygen consumption rate and metabolomics were examined as mechanistic endpoints. In vivo plasma concentrations of IACS-010759 in mice were determined by LC-MS to select a dose that reflected clinically attainable concentrations | ||
| 520 | |a RESULTS: In vitro, the combination of AZD3965 and IACS-010759 is synergistic and induces DLBCL cell death, whereas monotherapy treatments induce a cytostatic response. Significant anti-tumour activity was evident in Toledo and Farage models when the two inhibitors were administered concurrently despite limited or no effect on the growth of DLBCL xenografts as monotherapies | ||
| 520 | |a CONCLUSIONS: This is the first study to examine a combination of two distinct approaches to targeting tumour metabolism in DLBCL xenografts. Whilst nanomolar concentrations of either AZD3965 or IACS-010759 monotherapy demonstrate anti-proliferative activity against DLBCL cell lines in vitro, appreciable clinical activity in DLBCL patients may only be realised through their combined use | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Monocarboxylic Acid Transporters |2 NLM | |
| 650 | 7 | |a Symporters |2 NLM | |
| 700 | 1 | |a Thomas, Huw |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Herendi, Lili |e verfasserin |4 aut | |
| 700 | 1 | |a Howarth, Rachel |e verfasserin |4 aut | |
| 700 | 1 | |a Dragoni, Ilaria |e verfasserin |4 aut | |
| 700 | 1 | |a Keun, Hector C |e verfasserin |4 aut | |
| 700 | 1 | |a Vellano, Christopher P |e verfasserin |4 aut | |
| 700 | 1 | |a Marszalek, Joseph R |e verfasserin |4 aut | |
| 700 | 1 | |a Wedge, Stephen R |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t British journal of cancer |d 1947 |g 127(2022), 5 vom: 26. Sept., Seite 937-947 |w (DE-627)NLM000027537 |x 1532-1827 |7 nnns |
| 773 | 1 | 8 | |g volume:127 |g year:2022 |g number:5 |g day:26 |g month:09 |g pages:937-947 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41416-022-01848-w |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 127 |j 2022 |e 5 |b 26 |c 09 |h 937-947 | ||