Pyrvinium Pamoate Use in a B cell Acute Lymphoblastic Leukemia Model of the Bone Tumor Microenvironment
| Autor: | Stephanie L. Rellick, Karen H. Martin, Debbie Piktel, Patrick Thomas, Quincy A. Hathaway, Laura F. Gibson, John M. Hollander, Pushkar Saralkar, Werner J. Geldenhuys, Rajesh R. Nair |
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| Rok vydání: | 2020 |
| Předmět: |
Programmed cell death
Drug Compounding Cell Pharmaceutical Science Antineoplastic Agents 02 engineering and technology 030226 pharmacology & pharmacy Article Bone and Bones Pyrvinium Compounds 03 medical and health sciences 0302 clinical medicine Immune system Nanocapsules Cell Line Tumor Precursor B-Cell Lymphoblastic Leukemia-Lymphoma Tumor Microenvironment medicine Humans Pharmacology (medical) Phosphorylation Cell Proliferation Pharmacology Tumor microenvironment Cell Death Chemistry Cell growth Organic Chemistry 021001 nanoscience & nanotechnology medicine.disease Drug Liberation Leukemia medicine.anatomical_structure Cell culture Drug delivery Cancer research Molecular Medicine 0210 nano-technology Signal Transduction Biotechnology |
| Zdroj: | Pharm Res |
| ISSN: | 1573-904X 0724-8741 |
| Popis: | PURPOSE: Pyrvinium pamoate (PP) is an anthelmintic drug that has been found to have anti-cancer activity in several cancer types. In the present study, we evaluated PP for potential anti-leukemic activity in B-cell acute lymphoblastic leukemia (ALL) cell lines, in an effort to evaluate the repurposing potential of this drug in leukemia. METHODS: ALL cells were treated with PP at various concentrations to determine its effect on cell proliferation. Metabolic function was tested by evaluating Extracellular Acidification Rate (ECAR) and Oxygen Consumption Rate (OCR). Lastly, 3D spheroids were grown, and PP was reformulated into nanoparticles to evaluate distribution effectiveness. RESULTS: PP was found to inhibit ALL proliferation, with varied selectivity to different ALL cell subtypes. We also found that PP’s cell death activity was specific for leukemic cells, as primary normal immune cells were resistant to PP-mediated cell death. Metabolic studies indicated that PP, in part, inhibits mitochondrial oxidative phosphorylation. To increase the targeting of PP to a hypoxic bone tumor microenvironment (BTME) niche, we successfully encapsulated PP in a nanoparticle drug delivery system and demonstrated that it retained its anti-leukemic activity in a hemosphere assay. CONCLUSION: We have demonstrated that PP is a novel therapeutic lead compound that counteracts the respiratory reprogramming found in refractory ALL cells and can be effectively formulated into a nanoparticle delivery system to target the BTME. |
| Databáze: | OpenAIRE |
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