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A Drug Repositioning Approach Identifies a Combination of Compounds as a Potential Regimen for Chronic Lymphocytic Leukemia Treatment
- Source :
- Frontiers in Oncology, Vol 11 (2021), Frontiers in Oncology
- Publication Year :
- 2021
- Publisher :
- Frontiers Media SA, 2021.
-
Abstract
- Drug repositioning is a promising and powerful innovative strategy in the field of drug discovery. In this study, we screened a compound-library containing 800 Food and Drug Administration approved drugs for their anti-leukemic effect. All screening activities made use of human peripheral blood mononuclear cells (PBMCs), isolated from healthy or leukemic donors. Compounds with confirmed cytotoxicity were selected and classified in three groups: i) anti-neoplastic compounds which are drugs used in leukemia treatment, ii) compounds known to have an anti-cancer effect and iii) compounds demonstrating an anti-leukemic potential for the first time. The latter group was the most interesting from a drug repositioning perspective and yielded a single compound, namely Isoprenaline which is a non-selective β-adrenergic agonist. Analysis of the cytotoxic effect of this drug indicated that it induces sustainable intracellular ATP depletion leading, over time, to necrotic cell death. We exploited the Isoprenaline-induced intracellular ATP depletion to sensitize primary leukemic cells to fludarabine (purine analogue) and Ibrutinib (Bruton’s tyrosine kinase inhibitor) treatment. In-vitro treatment of primary leukemic cells with a combination of Isoprenaline/fludarabine or Isoprenaline/Ibrutinib showed a very high synergistic effect. These combinations could constitute a new efficient regimen for CLL treatment following successful evaluation in animal models and clinical trials.
- Subjects :
- ATP depletion
Cancer Research
medicine.drug_class
Chronic lymphocytic leukemia
Purine analogue
Pharmacology
Tyrosine-kinase inhibitor
chemistry.chemical_compound
synergistic effect
Isoprenaline
medicine
RC254-282
Original Research
Drug discovery
business.industry
Ibrutinib
fludarabine
BTKi
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
medicine.disease
Fludarabine
Leukemia
Drug repositioning
Oncology
chemistry
business
CLL
medicine.drug
Subjects
Details
- ISSN :
- 2234943X
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Frontiers in Oncology
- Accession number :
- edsair.doi.dedup.....fc746d3e8403c0c365658be4ba2bfc7a
- Full Text :
- https://doi.org/10.3389/fonc.2021.579488