Villanueva Paulina J, Gutierrez Denisse A, Contreras Lisett, Parra Karla, Segura-Cabrera Aldo, Varela-Ramirez Armando, Aguilera Renato J
The Cellular Characterization and Biorepository (CCB) Core Facility, Border Biomedical Research Center, Department of Biological Sciences, the University of Texas at El Paso, 500 West University Avenue, El Paso, TX79968-0519, USA.
Current address: Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
Clin Cancer Drugs. 2021 Mar;8(1):50-56. doi: 10.2174/2212697x08666210219101023. Epub 2021 Feb 19.
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 mitochondrial depolarization, alteration of cell cycle progression, and DNA intercalation. However, the molecular target of PND in cells was not elucidated.
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.
Transcriptome analyses of PND-treated cancer cells were performed. Topoisomerase II activity was evaluated by an assay. In addition, daily oral administration of PND was given to mice with human breast cancer xenografts. The differential nuclear staining assay measured cell toxicity.
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, 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.
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.
乳腺癌是全球女性中最常被诊断出的癌症。咯萘啶（PND）是一种抗疟药物，已显示对17种不同的人类癌细胞具有抗癌活性，其中7种来自女性乳腺组织。此外，PND可诱导细胞凋亡、线粒体去极化、细胞周期进程改变以及DNA嵌入。然而，PND在细胞中的分子靶点尚未阐明。
在此，我们通过转录组分析进一步研究了PND的作用方式。还进行了临床前研究，以确定PND是否会影响小鼠人乳腺癌异种移植瘤的肿瘤进展。此外，我们评估了PND与知名抗癌药物联合使用的疗效。
对经PND处理的癌细胞进行转录组分析。通过一种检测方法评估拓扑异构酶II活性。此外，对患有人类乳腺癌异种移植瘤的小鼠每日口服给予PND。差异核染色检测测量细胞毒性。
转录组特征表明PND可能作为拓扑异构酶II抑制剂发挥作用。因此，进行了拓扑异构酶抑制检测，提供了PND是一种真正的拓扑异构酶II抑制剂的证据。同时，研究表明PND会阻碍肿瘤进展。此外，PND与抗癌药物顺铂和吉西他滨的联合研究显示，与单独给药相比，对癌细胞具有更高的细胞毒性。
这些发现提供了证据，表明PND是一种拓扑异构酶II抑制剂，并且可以在动物模型中阻碍癌症进展，进一步证明了PND作为一种重新利用的抗癌药物的良好特性。
