Enhancing the efficacy of glycolytic blockade in cancer cells via RAD51 inhibition

Targeting the early steps of the glycolysis pathway in cancers is a well-established therapeutic strategy; however, the doses required to elicit a therapeutic effect on the cancer can be toxic to the patient. Consequently, numerous preclinical and clinical studies have combined glycolytic blockade w...

Full description

Saved in:

Bibliographic Details
Published in:	Cancer biology & therapy Vol. 20; no. 2; pp. 169 - 182
Main Authors:	Wilson, John J., Chow, Kin-hoe, Labrie, Nathan J., Branca, Jane A., Sproule, Thomas J., Perkins, Bryant R. A., Wolf, Elise E., Costa, Mauro, Stafford, Grace, Rosales, Christine, Mills, Kevin D., Roopenian, Derry C., Hasham, Muneer G.
Format:	Journal Article
Language:	English
Published:	United States Taylor & Francis 01-02-2019
Subjects:	4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid - administration & dosage 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid - pharmacology AID Animals Antineoplastic Combined Chemotherapy Protocols - pharmacology cancer Cell Line, Tumor Deoxyglucose - administration & dosage Deoxyglucose - pharmacology Drug Synergism Female glycolysis Glycolysis - drug effects Humans Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy Leukemia, Lymphocytic, Chronic, B-Cell - metabolism Lung Neoplasms - drug therapy Lung Neoplasms - metabolism Mice Mice, Inbred C57BL Mice, Inbred NOD Neoplasms - drug therapy Neoplasms - metabolism RAD51 Rad51 Recombinase - antagonists & inhibitors Rad51 Recombinase - metabolism Research Paper xenograft Xenograft Model Antitumor Assays cancer RAD51 xenograft AID glycolysis
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Targeting the early steps of the glycolysis pathway in cancers is a well-established therapeutic strategy; however, the doses required to elicit a therapeutic effect on the cancer can be toxic to the patient. Consequently, numerous preclinical and clinical studies have combined glycolytic blockade with other therapies. However, most of these other therapies do not specifically target cancer cells, and thus adversely affect normal tissue. Here we first show that a diverse number of cancer models - spontaneous, patient-derived xenografted tumor samples, and xenografted human cancer cells - can be efficiently targeted by 2-deoxy-D-Glucose (2DG), a well-known glycolytic inhibitor. Next, we tested the cancer-cell specificity of a therapeutic compound using the MEC1 cell line, a chronic lymphocytic leukemia (CLL) cell line that expresses activation induced cytidine deaminase (AID). We show that MEC1 cells, are susceptible to 4,4ʹ-Diisothiocyano-2,2ʹ-stilbenedisulfonic acid (DIDS), a specific RAD51 inhibitor. We then combine 2DG and DIDS, each at a lower dose and demonstrate that this combination is more efficacious than fludarabine, the current standard- of- care treatment for CLL. This suggests that the therapeutic blockade of glycolysis together with the therapeutic inhibition of RAD51-dependent homologous recombination can be a potentially beneficial combination for targeting AID positive cancer cells with minimal adverse effects on normal tissue. Implications: Combination therapy targeting glycolysis and specific RAD51 function shows increased efficacy as compared to standard of care treatments in leukemias.
Bibliography:	Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/kcbt.
ISSN:	1538-4047 1555-8576
DOI:	10.1080/15384047.2018.1507666