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.
Highlights
Drug repositioning, known as drug re-tasking, drug rescuing, therapeutic switching, drug recycling, drug repurposing or drug re-profiling, constitutes an alternative approach to the traditional methods of drug discovery, which, in addition to being extremely costly and time consuming, is a high-risk process
The single compound concentration High Throughput Screening (HTS) (10mM; 48h incubation) of the 800 compounds in the Food and Drug Administration (FDA) approved drugs in primary cancer cells obtained from leukemic patients, led to the identification of 31 compounds that satisfied the criteria for progression
We showed in this study by phenotypic screening that treatment of CLL primary cells (CPCs) with the b-adrenergic agonist Isoprenaline sensitizes the CPCs to the purine analogue chemotherapeutic drug fludarabine
Summary
Known as drug re-tasking, drug rescuing, therapeutic switching, drug recycling, drug repurposing or drug re-profiling, constitutes an alternative approach to the traditional methods of drug discovery, which, in addition to being extremely costly and time consuming, is a high-risk process. The situation is even more challenging with the approval rate for new drugs at least 50% lower than for other indications [3]. Efficacy and toxicity of these drugs have been extensively investigated resulting in FDA approval, identifying an additional use for these drugs offers the potential to accelerate the drug discovery process, thereby saving time and money [4, 5]. The cost of the drug repositioning approach could be ten-fold lower than developing a new drug which is estimated at $1.6 billion [6] which offers many countries an opportunity to develop drugs with reduced investment. Additional advantages of the drug repositioning approach is the 30% approval rate compared to 10% for de-novo drug discovery [5]
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