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Pyrvinium Pamoate Use in a B cell Acute Lymphoblastic Leukemia Model of the Bone Tumor Microenvironment

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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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Author notes

  1. Rajesh R. Nair and Debbie Piktel contributed equally to this work.

Authors and Affiliations

  1. Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia, USA

    Rajesh R. Nair, Karen H. Martin & Laura F. Gibson

  2. West Virginia University Cancer Institute, Robert C. Byrd Health Sciences Center, West Virginia University, PO Box 9104, Morgantown, West Virginia, 26506, USA

    Debbie Piktel, Patrick Thomas, Karen H. Martin & Laura F. Gibson

  3. Division of Exercise Physiology, West Virginia University School of Medicine, Morgantown, West Virginia, USA

    Quincy A. Hathaway & John M. Hollander

  4. Mitochondria, Metabolism and Bioenergetics Working Group, West Virginia University School of Medicine, Morgantown, West Virginia, USA

    Quincy A. Hathaway, Werner J. Geldenhuys & John M. Hollander

  5. Department of Physiology and Pharmacology, West Virginia University School of Medicine, Morgantown, West Virginia, USA

    Stephanie L. Rellick

  6. Department of Pharmaceutical Sciences, West Virginia University School of Pharmacy, Morgantown, West Virginia, USA

    Pushkar Saralkar & Werner J. Geldenhuys

  7. Department of Neuroscience, West Virginia University School of Medicine, Morgantown, West Virginia, USA

    Werner J. Geldenhuys

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  1. Rajesh R. Nair
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Correspondence to Laura F. Gibson.

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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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