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Inhibition of monocarboxyate transporter 1 by AZD3965 as a novel therapeutic approach for diffuse large B-cell lymphoma and Burkitt lymphoma
- Source :
- Haematologica
- Publication Year :
- 2017
- Publisher :
- Ferrata Storti Foundation (Haematologica), 2017.
-
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.
- Subjects :
- Monocarboxylic Acid Transporters
0301 basic medicine
medicine.medical_specialty
Monocarboxylate Transporter 1 Inhibitor AZD3965
Programmed cell death
Non-Hodgkin Lymphoma
Muscle Proteins
Antineoplastic Agents
Pyrimidinones
Thiophenes
Article
Oxidative Phosphorylation
03 medical and health sciences
0302 clinical medicine
immune system diseases
Cell Line, Tumor
hemic and lymphatic diseases
Internal medicine
medicine
Humans
Lactic Acid
Electron Transport Complex I
Cell Death
Symporters
biology
business.industry
Transporter
Hematology
medicine.disease
Burkitt Lymphoma
Mitochondria
3. Good health
Lymphoma
030104 developmental biology
Endocrinology
Monocarboxylate transporter 1
Drug Resistance, Neoplasm
Cell culture
030220 oncology & carcinogenesis
Monocarboxylate transporter 4
biology.protein
Cancer research
Lymphoma, Large B-Cell, Diffuse
Energy Metabolism
business
Diffuse large B-cell lymphoma
Biomarkers
Subjects
Details
- ISSN :
- 15928721 and 03906078
- Volume :
- 102
- Database :
- OpenAIRE
- Journal :
- Haematologica
- Accession number :
- edsair.doi.dedup.....f1529ca2ef9fc0fa71d0167d88fb5f63