Abstract
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.
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Abbreviations
- 2-DG:
-
2-deoxyglucose
- ALL:
-
B cell acute lymphoblastic leukemia
- ATP:
-
Adenosine triphosphate
- BM:
-
Bone marrow
- BMSC:
-
Bone marrow stromal cells
- BTME:
-
Bone tumor microenvironment
- ECAR:
-
Extracellular acidification rate
- ETC:
-
Electron transport chain
- FBS:
-
Fetal bovine serum
- FCCP:
-
Carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone
- HK2:
-
Hexokinase II
- HOB:
-
Human osteoblasts
- IPA:
-
Ingenuity Pathway Analysis
- M:
-
Monoculture
- MRD:
-
Minimal residual disease
- NP:
-
Nanoparticles
- OCR:
-
Oxygen consumption rate
- OXPHOS:
-
Oxidative phosphorylation
- PD:
-
Phase dim, buried co-culture ALL cells
- PP:
-
Pyrvinium pamoate
- TBS:
-
Tris-buffered saline
- S:
-
Co-culture ALL cells in suspension
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ACKNOWLEDGMENTS AND DISCLOSURES
The authors would like to acknowledge Kathleen Brundage, director of the WVU Flow Cytometry & Single Cell Core Facility, for her assistance in acquisition of the flow cytometry data and Aniello Infante, lead bioinformatician with the WVU Genomics Core Facility, for his assistance with gene expression analysis. This work was supported by the Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program, Community Foundation for the Ohio Valley Whipkey Trust, NIH grants U54GM104942, P30GM103488, P20GM103434, RO1HL128485, S10OD016165, R42AR074812, R44CA221554, R41NS110070 and P20 GM109098; and AHA grant 17PRE33660333. The authors declare that they have no conflicts of interest with the contents of this manuscript.
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Nair, R.R., Piktel, D., Hathaway, Q.A. et al. Pyrvinium Pamoate Use in a B cell Acute Lymphoblastic Leukemia Model of the Bone Tumor Microenvironment. Pharm Res 37, 43 (2020). https://doi.org/10.1007/s11095-020-2767-4
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DOI: https://doi.org/10.1007/s11095-020-2767-4