Bicarbonate and dichloroacetate: Evaluating pH altering therapies in a mouse model for metastatic breast cancer

Persistent Link:
http://hdl.handle.net/10150/610344
Title:
Bicarbonate and dichloroacetate: Evaluating pH altering therapies in a mouse model for metastatic breast cancer
Author:
Robey, Ian; Martin, Natasha
Affiliation:
Arizona Respiratory Center, University of Arizona, Tucson Arizona, USA; Centre for Mathematical Biology, Mathematical Institute, Oxford University, 24-29 St Giles', Oxford, OX1 3LB, UK; Department of Social Medicine, University of Bristol, Canynge Hall, 29 Whatley Road, Bristol, BS8 2PS, UK
Issue Date:
2011
Publisher:
BioMed Central
Citation:
Robey and Martin BMC Cancer 2011, 11:235 http://www.biomedcentral.com/1471-2407/11/235
Journal:
BMC Cancer
Rights:
© 2011 Robey and Martin; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0)
Collection Information:
This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.
Abstract:
BACKGROUND:The glycolytic nature of malignant tumors contributes to high levels of extracellular acidity in the tumor microenvironment. Tumor acidity is a driving force in invasion and metastases. Recently, it has been shown that buffering of extracellular acidity through systemic administration of oral bicarbonate can inhibit the spread of metastases in a mouse model for metastatic breast cancer. While these findings are compelling, recent assessments into the use of oral bicarbonate as a cancer intervention reveal limitations.METHODS:We posited that safety and efficacy of bicarbonate could be enhanced by dichloroacetate (DCA), a drug that selectively targets tumor cells and reduces extracellular acidity through inhibition of glycolysis. Using our mouse model for metastatic breast cancer (MDA-MB-231), we designed an interventional survival study where tumor bearing mice received bicarbonate, DCA, or DCA-bicarbonate (DB) therapies chronically.RESULTS:Dichloroacetate alone or in combination with bicarbonate did not increase systemic alkalosis in mice. Survival was longest in mice administered bicarbonate-based therapies. Primary tumor re-occurrence after surgeries is associated with survival rates. Although DB therapy did not significantly enhance oral bicarbonate, we did observe reduced pulmonary lesion diameters in this cohort. The DCA monotherapy was not effective in reducing tumor size or metastases or improving survival time. We provide in vitro evidence to suggest this outcome may be a function of hypoxia in the tumor microenvironment.CONCLUSIONS:DB combination therapy did not appear to enhance the effect of chronic oral bicarbonate. The anti-tumor effect of DCA may be dependent on the cancer model. Our studies suggest DCA efficacy is unpredictable as a cancer therapy and further studies are necessary to determine the role of this agent in the tumor microenvironment.
EISSN:
 1471-2407
DOI:
10.1186/1471-2407-11-235
Keywords:
Tumor; pH; Acidity; Dichloroacetate; Sodium bicarbonate
Version:
Final published version
Additional Links:
http://www.biomedcentral.com/1471-2407/11/235

Full metadata record

DC FieldValue Language
dc.contributor.authorRobey, Ianen
dc.contributor.authorMartin, Natashaen
dc.date.accessioned2016-05-20T09:04:43Z-
dc.date.available2016-05-20T09:04:43Z-
dc.date.issued2011en
dc.identifier.citationRobey and Martin BMC Cancer 2011, 11:235 http://www.biomedcentral.com/1471-2407/11/235en
dc.identifier.doi10.1186/1471-2407-11-235en
dc.identifier.urihttp://hdl.handle.net/10150/610344-
dc.description.abstractBACKGROUND:The glycolytic nature of malignant tumors contributes to high levels of extracellular acidity in the tumor microenvironment. Tumor acidity is a driving force in invasion and metastases. Recently, it has been shown that buffering of extracellular acidity through systemic administration of oral bicarbonate can inhibit the spread of metastases in a mouse model for metastatic breast cancer. While these findings are compelling, recent assessments into the use of oral bicarbonate as a cancer intervention reveal limitations.METHODS:We posited that safety and efficacy of bicarbonate could be enhanced by dichloroacetate (DCA), a drug that selectively targets tumor cells and reduces extracellular acidity through inhibition of glycolysis. Using our mouse model for metastatic breast cancer (MDA-MB-231), we designed an interventional survival study where tumor bearing mice received bicarbonate, DCA, or DCA-bicarbonate (DB) therapies chronically.RESULTS:Dichloroacetate alone or in combination with bicarbonate did not increase systemic alkalosis in mice. Survival was longest in mice administered bicarbonate-based therapies. Primary tumor re-occurrence after surgeries is associated with survival rates. Although DB therapy did not significantly enhance oral bicarbonate, we did observe reduced pulmonary lesion diameters in this cohort. The DCA monotherapy was not effective in reducing tumor size or metastases or improving survival time. We provide in vitro evidence to suggest this outcome may be a function of hypoxia in the tumor microenvironment.CONCLUSIONS:DB combination therapy did not appear to enhance the effect of chronic oral bicarbonate. The anti-tumor effect of DCA may be dependent on the cancer model. Our studies suggest DCA efficacy is unpredictable as a cancer therapy and further studies are necessary to determine the role of this agent in the tumor microenvironment.en
dc.language.isoenen
dc.publisherBioMed Centralen
dc.relation.urlhttp://www.biomedcentral.com/1471-2407/11/235en
dc.rights© 2011 Robey and Martin; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0)en
dc.subjectTumoren
dc.subjectpHen
dc.subjectAcidityen
dc.subjectDichloroacetateen
dc.subjectSodium bicarbonateen
dc.titleBicarbonate and dichloroacetate: Evaluating pH altering therapies in a mouse model for metastatic breast canceren
dc.typeArticleen
dc.identifier.eissn 1471-2407en
dc.contributor.departmentArizona Respiratory Center, University of Arizona, Tucson Arizona, USAen
dc.contributor.departmentCentre for Mathematical Biology, Mathematical Institute, Oxford University, 24-29 St Giles', Oxford, OX1 3LB, UKen
dc.contributor.departmentDepartment of Social Medicine, University of Bristol, Canynge Hall, 29 Whatley Road, Bristol, BS8 2PS, UKen
dc.identifier.journalBMC Canceren
dc.description.collectioninformationThis item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
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