Format

Send to

Choose Destination
Haematologica. 2017 Jul;102(7):1247-1257. doi: 10.3324/haematol.2016.163030. Epub 2017 Apr 6.

Inhibition of monocarboxyate transporter 1 by AZD3965 as a novel therapeutic approach for diffuse large B-cell lymphoma and Burkitt lymphoma.

Author information

1
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne.
2
Division of Cancer, Imperial College London.
3
Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne.
4
Cellular Pathology, Newcastle upon Tyne Hospitals NHS Foundation Trust.
5
MRC/EPSRC Newcastle Molecular Pathology Node, Newcastle upon Tyne.
6
Department of Pediatric and Adolescent Hematology and Oncology, Newcastle upon Tyne Hospitals NHS Foundation Trust.
7
AstraZeneca, Cambridge, UK.
8
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne steve.wedge@ncl.ac.uk.

Abstract

Inhibition of monocarboxylate transporter 1 has been proposed as a therapeutic approach to perturb lactate shuttling in tumor cells that lack monocarboxylate transporter 4. We examined the monocarboxylate transporter 1 inhibitor AZD3965, currently in phase I clinical studies, as a potential therapy for diffuse large B-cell lymphoma and Burkitt lymphoma. Whilst extensive monocarboxylate transporter 1 protein was found in 120 diffuse large B-cell lymphoma and 10 Burkitt lymphoma patients' tumors, monocarboxylate transporter 4 protein expression was undetectable in 73% of the diffuse large B-cell lymphoma samples and undetectable or negligible in each Burkitt lymphoma sample. AZD3965 treatment led to a rapid accumulation of intracellular lactate in a panel of lymphoma cell lines with low monocarboxylate transporter 4 protein expression and potently inhibited their proliferation. Metabolic changes induced by AZD3965 in lymphoma cells were consistent with a feedback inhibition of glycolysis. A profound cytostatic response was also observed in vivo: daily oral AZD3965 treatment for 24 days inhibited CA46 Burkitt lymphoma growth by 99%. Continuous exposure of CA46 cells to AZD3965 for 7 weeks in vitro resulted in a greater dependency upon oxidative phosphorylation. Combining AZD3965 with an inhibitor of mitochondrial complex I (central to oxidative phosphorylation) induced significant lymphoma cell death in vitro and reduced CA46 disease burden in vivo These data support clinical examination of AZD3965 in Burkitt lymphoma and diffuse large B-cell lymphoma patients with low tumor monocarboxylate transporter 4 expression and highlight the potential of combination strategies to optimally target the metabolic phenotype of tumors.

PMID:
28385782
PMCID:
PMC5566036
DOI:
10.3324/haematol.2016.163030
[Indexed for MEDLINE]
Free PMC Article

Publication type, MeSH terms, Substances, Grant support

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center