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Inhibition of the hyaluronan matrix enhances metabolic anticancer therapy by dichloroacetate in vitro and in vivo
- Source :
- British Journal of Pharmacology
- Publication Year :
- 2019
- Publisher :
- Wiley, 2019.
-
Abstract
- Background and purpose Aerobic glycolysis is a unique feature of tumour cells that entails several advantages for cancer progression such as resistance to apoptosis. The low MW compound, dichloroacetate, is a pyruvate dehydrogenase kinase inhibitor, which restores oxidative phosphorylation and induces apoptosis in a variety of cancer entities. However, its therapeutic effectiveness is limited by resistance mechanisms. This study aimed to examine the role of the anti-apoptotic hyaluronan (HA) matrix in this context and to identify a potential add-on treatment option to overcome this limitation. Experimental approach The metabolic connection between dichloroacetate treatment and HA matrix augmentation was analysed in vitro by quantitative PCR and affinity cytochemistry. Metabolic pathways were analysed using Seahorse, HPLC, fluorophore-assisted carbohydrate electrophoresis, colourimetry, immunoblots, and immunochemistry. The effects of combining dichloroacetate with the HA synthesis inhibitor 4-methylumbelliferone was evaluated in 2D and 3D cell cultures and in a nude mouse tumour xenograft regression model by immunoblot, immunochemistry, and FACS analysis. Key results Mitochondrial reactivation induced by dichloroacetate metabolically activated HA synthesis by augmenting precursors as well as O-GlcNAcylation. This process was blocked by 4-methylumbelliferone, resulting in enhanced anti-tumour efficacy in 2D and 3D cell culture and in a nude mouse tumour xenograft regression model. Conclusions and implications The HA rich tumour micro-environment represents a metabolic factor contributing to chemotherapy resistance. HA synthesis inhibition exhibited pronounced synergistic actions with dichloroacetate treatment on oesophageal tumour cell proliferation and survival in vitro and in vivo suggesting the combination of these two strategies is an effective anticancer therapy.
- Subjects :
- Male
0301 basic medicine
Pyruvate dehydrogenase kinase
Esophageal Neoplasms
Mice, Nude
Antineoplastic Agents
Apoptosis
Mice
Structure-Activity Relationship
03 medical and health sciences
0302 clinical medicine
Nude mouse
In vivo
Immunochemistry
Tumor Cells, Cultured
Animals
Humans
Hyaluronic Acid
Cell Proliferation
Pharmacology
Dichloroacetic Acid
Dose-Response Relationship, Drug
Molecular Structure
biology
Chemistry
Cell growth
Neoplasms, Experimental
biology.organism_classification
Research Papers
Extracellular Matrix
Mitochondria
Disease Models, Animal
030104 developmental biology
Anaerobic glycolysis
Cell culture
Cancer research
Regression Analysis
Esophageal Squamous Cell Carcinoma
Drug Screening Assays, Antitumor
Hymecromone
030217 neurology & neurosurgery
Research Paper
Subjects
Details
- ISSN :
- 14765381 and 00071188
- Volume :
- 176
- Database :
- OpenAIRE
- Journal :
- British Journal of Pharmacology
- Accession number :
- edsair.doi.dedup.....939195a14ae916474c90e8249899212b