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Clinical Cancer Drugs

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ISSN (Print): 2212-697X
ISSN (Online): 2212-6988

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Research Article

The Antimalarial Drug Pyronaridine Inhibits Topoisomerase II in Breast Cancer Cells and Hinders Tumor Progression In Vivo

Author(s): Paulina J. Villanueva, Denisse A Gutierrez, Lisett Contreras, Karla Parra, Aldo Segura-Cabrera, Armando Varela-Ramirez and Renato J Aguilera*

Volume 8, Issue 1, 2021

Published on: 19 February, 2021

Article ID: e301221191585 Pages: 7

DOI: 10.2174/2212697X08666210219101023

Price: $65

Abstract

Background: Breast cancer is the most frequently diagnosed cancer in women worldwide. Pyronaridine (PND), an antimalarial drug, was shown to exert anticancer activity on seventeen different human cancer cells, seven from female breast tissue. Additionally, PND induced apoptosis via mitochondrial depolarization, alteration of cell cycle progression, and DNA intercalation. However, the molecular target of PND in cells was not elucidated.

Objective: Here, we have further investigated PND's mode of action by using transcriptome analysis. Preclinical studies were also performed to determine whether PND could affect tumor progression in a human breast cancer xenograft in mice. Moreover, we assessed the combined efficacy of PND with well-known anticancer drugs.

Methods: Transcriptome analyses of PND-treated cancer cells were performed. Topoisomerase II activity was evaluated by an in vitro assay. In addition, daily oral administration of PND was given to mice with human breast cancer xenografts. The differential nuclear staining assay measured in- -vitro cell toxicity.

Results: The transcriptome signatures suggested that PND might act as a topoisomerase II inhibitor. Thus, topoisomerase inhibition assays were performed, providing evidence that PND is a bona fide topoisomerase II inhibitor. Also, in-vivo studies suggest that PND hinders tumor progression. Besides, combination studies of PND with anticancer drugs cisplatin and gemcitabine revealed higher cytotoxicity against cancer cells than individual drug administration.

Conclusion: The findings provide evidence that PND is a topoisomerase II inhibitor and can hinder cancer progression in an animal model, further demonstrating PND's favorable characteristics as a repurposed anticancer drug.

Keywords: Anticancer, anticancer drug combination, breast cancer, drug discovery, drug repurposing, in-vivo tumor, multidrugresistance, topoisomerase.

Graphical Abstract

[1]
Pushpakom S, Iorio F, Eyers PA, et al. Drug repurposing: Progress, challenges and recommendations. Nat Rev Drug Discov 2019; 18(1): 41-58.
[http://dx.doi.org/10.1038/nrd.2018.168] [PMID: 30310233]
[2]
Vasan N, Baselga J, Hyman DM. A view on drug resistance in cancer. Nature 2019; 575(7782): 299-309.
[http://dx.doi.org/10.1038/s41586-019-1730-1] [PMID: 31723286]
[3]
Nath J, Paul R, Ghosh SK, Paul J, Singha B, Debnath N. Drug repurposing and relabeling for cancer therapy: Emerging benzimidazole antihelminthics with potent anticancer effects. Life Sci 2020; 258: 118189.
[http://dx.doi.org/10.1016/j.lfs.2020.118189] [PMID: 32781060]
[4]
Bertolini F, Sukhatme VP, Bouche G. Drug repurposing in oncology--patient and health systems opportunities. Nat Rev Clin Oncol 2015; 12(12): 732-42.
[http://dx.doi.org/10.1038/nrclinonc.2015.169] [PMID: 26483297]
[5]
Villanueva PJ, Martinez A, Baca ST, et al. Pyronaridine exerts potent cytotoxicity on human breast and hematological cancer cells through induction of apoptosis. PLoS One 2018; 13(11): e0206467.
[http://dx.doi.org/10.1371/journal.pone.0206467] [PMID: 30395606]
[6]
Worldwide cancer data. 2019.https://www.wcrf.org/dietandcancer/cancer-trends/worldwide-cancer-data
[7]
Breast Cancer Facts & Figures 2019-2020. 2019.https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-cancer-facts-and-figures/breast-cancer-facts-and-figures-2019-2020.pdf
[8]
Harbeck N, Gnant M. Breast cancer. Lancet 2017; 389(10074): 1134-50.
[http://dx.doi.org/10.1016/S0140-6736(16)31891-8] [PMID: 27865536]
[9]
Kumar B, Chand V, Ram A, et al. Oncogenic mutations in tumorigenesis and targeted therapy in breast cancer. Curr Mol Bio Rep 2020; 6: 116-25. https://0-doi-org.lib.utep.edu/10.1007/s40610- 020-00136-x
[10]
Mansoori B, Mohammadi A, Davudian S, Shirjang S, Baradaran B. The different mechanisms of cancer drug resistance: A brief review. Adv Pharm Bull 2017; 7(3): 339-48.
[http://dx.doi.org/10.15171/apb.2017.041] [PMID: 29071215]
[11]
Croft SL, Duparc S, Arbe-Barnes SJ, et al. Review of pyronaridine anti-malarial properties and product characteristics. Malar J 2012; 11: 270.
[http://dx.doi.org/10.1186/1475-2875-11-270] [PMID: 22877082]
[12]
Munoz R, Man S, Shaked Y, et al. Highly efficacious nontoxic preclinical treatment for advanced metastatic breast cancer using combination oral UFT-cyclophosphamide metronomic chemotherapy. Cancer Res 2006; 66(7): 3386-91.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-4411] [PMID: 16585158]
[13]
Contreras L, Calderon RI, Varela-Ramirez A, et al. Induction of apoptosis via proteasome inhibition in leukemia/lymphoma cells by two potent piperidones. Cell Oncol (Dordr) 2018; 41(6): 623-36.
[http://dx.doi.org/10.1007/s13402-018-0397-1] [PMID: 30088262]
[14]
CLUE. Available from: https://clue.io/
[15]
Subramanian A, Narayan R, Corsello SM, et al. A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles. Cell 2017; 171(6): 1437-1452.e17.
[http://dx.doi.org/10.1016/j.cell.2017.10.049] [PMID: 29195078]
[16]
Lamb J. The Connectivity Map: A new tool for biomedical research. Nat Rev Cancer 2007; 7(1): 54-60.
[http://dx.doi.org/10.1038/nrc2044] [PMID: 17186018]
[17]
Chavalitshewinkoon P, Wilairat P, Gamage S, Denny W, Figgitt D, Ralph R. Structure-activity relationships and modes of action of 9-anilinoacridines against chloroquine-resistant Plasmodium falciparum in vitro. Antimicrob Agents Chemother 1993; 37(3): 403-6.
[http://dx.doi.org/10.1128/AAC.37.3.403] [PMID: 8384810]
[18]
Parra K, Valenzuela P, Lerma N, et al. Impact of CTLA-4 blockade in conjunction with metronomic chemotherapy on preclinical breast cancer growth. Br J Cancer 2017; 116(3): 324-34.
[http://dx.doi.org/10.1038/bjc.2016.429] [PMID: 28056464]
[19]
Lema C, Varela-Ramirez A, Aguilera RJ. Differential nuclear staining assay for high-throughput screening to identify cytotoxic compounds. Curr Cell Biochem 2011; 1(1): 1-14.
[PMID: 27042697]
[20]
Morán-Santibañez K, Vasquez AH, Varela-Ramirez A, et al. Larrea tridentata Extract Mitigates Oxidative Stress-Induced Cytotoxicity in Human Neuroblastoma SH-SY5Y Cells. Antioxidants 2019; 8(10): 427.
[http://dx.doi.org/10.3390/antiox8100427] [PMID: 31557847]
[21]
Zheng X. Studies of new antimalarial '7351. Shanghai: Chinese Academy of Medical Sciences 1972; pp. 165-73.
[22]
Sun W, Sanderson PE, Zheng W. Drug combination therapy increases successful drug repositioning. Drug Discov Today 2016; 21(7): 1189-95.
[http://dx.doi.org/10.1016/j.drudis.2016.05.015] [PMID: 27240777]

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