Enhancing the efficacy of glycolytic blockade in cancer cells via RAD51 inhibition
John J Wilson1, Kin-Hoe Chow1, Nathan J Labrie1
1a Research Department , The Jackson Laboratory , Bar Harbor , Maine , USA.
Abstract:
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 4,4'-Diisothiocyano-2,2'-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.
Insights
Combining glycolysis inhibition with RAD51 inhibition offers a potent new strategy for targeting AID-positive cancer cells, showing greater efficacy than current treatments with fewer side effects.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Targeting cancer cell glycolysis is a known strategy, but high doses cause patient toxicity.
- Existing combination therapies often lack cancer-cell specificity, affecting normal tissues.
- Activation induced cytidine deaminase (AID) is present in certain cancer cells, including chronic lymphocytic leukemia (CLL).
Purpose of the Study:
- To evaluate the efficacy of combining glycolysis inhibition with RAD51 inhibition in cancer models.
- To assess the cancer-cell specificity of this combination therapy.
- To compare the efficacy of the combination therapy against standard treatments for CLL.
Main Methods:
- Utilized diverse cancer models including spontaneous, patient-derived xenografts, and xenografted human cancer cells.
- Tested 2-deoxy-D-Glucose (2DG) as a glycolytic inhibitor and 4,4'-Diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS) as a RAD51 inhibitor.
- Administered a combination of lower doses of 2DG and DIDS to MEC1 CLL cells and compared outcomes to fludarabine.
Main Results:
- 2-deoxy-D-Glucose (2DG) effectively targeted various cancer models.
- MEC1 cells expressing AID were susceptible to the RAD51 inhibitor DIDS.
- The combination of 2DG and DIDS demonstrated superior efficacy compared to fludarabine in MEC1 cells.
Conclusions:
- Combining glycolysis blockade with RAD51 inhibition is a promising therapeutic strategy for AID-positive cancers.
- This combination therapy shows potential for targeting cancer cells specifically, minimizing adverse effects on normal tissues.
- The 2DG and DIDS combination therapy represents a potentially beneficial alternative to current standard-of-care treatments for leukemias.
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