Pre-clinical safety and therapeutic efficacy of a plant-based alkaloid in a human colon cancer xenograft model
Title
Pre-clinical safety and therapeutic efficacy of a plant-based alkaloid in a human colon cancer xenograft model
Date
2022
Publisher
Springer Science and Business Media LLC
Subject
Drug development
Drug safety
Drug safety
Language
English
Abstract
A high-throughput drug screen revealed that veratridine (VTD), a natural plant alkaloid, induces expression of the anti-cancer protein UBXN2A in colon cancer cells. UBXN2A suppresses mortalin, a heat shock protein, with dominant roles in cancer development including epithelial-mesenchymal transition (EMT), cancer cell stemness, drug resistance, and apoptosis. VTD-dependent expression of UBXN2A leads to the deactivation of mortalin in colon cancer cells, making VTD a potential targeted therapy in malignant tumors with high levels of mortalin. VTD was used clinically for the treatment of hypertension in decades past. However, the discovery of newer antihypertensive drugs and concerns over potential neuro- and cardiotoxicity ended the use of VTD for this purpose. The current study aims to determine the safety and efficacy of VTD at doses sufficient to induce UBXN2A expression in a mouse model. A set of flow-cytometry experiments confirmed that VTD induces both early and late apoptosis in a dose-dependent manner. In vivo intraperitoneal (IP) administration of VTD at 0.1 mg/kg every other day (QOD) for 4 weeks effectively induced expression of UBXN2A in the small and large intestines of mice. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays on tissues collected from VTD-treated animals demonstrated VTD concentrations in the low pg/mg range. To address concerns regarding neuro- and cardiotoxicity, a comprehensive set of behavioral and cardiovascular assessments performed on C57BL/6NHsd mice revealed that VTD generates no detectable neurotoxicity or cardiotoxicity in animals receiving 0.1 mg/kg VTD QOD for 30 days. Finally, mouse xenograft experiments in athymic nude mice showed that VTD can suppress tumor growth. The main causes for the failure of experimental oncologic drug candidates are lack of sufficient safety and efficacy. The results achieved in this study support the potential utility of VTD as a safe and efficacious anti-cancer molecule.
Source
Cell Death Discovery, Volume 8, Issue 1, March 2022
Rights
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third-party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Format
PDF
Type
Text
Identifier
Bibliographic Citation
Freeling, J. L., Scholl, J. L., Eikanger, M., Knoblich, C., Potts, R. A., Anderson, D. J., Rower, J. E., Farjoo, M. H., Zhao, H., Pillatzki, A., & Rezvani, K. (2022). Pre-clinical safety and therapeutic efficacy of a plant-based alkaloid in a human colon cancer xenograft model. In Cell Death Discovery (Vol. 8, Issue 1). Springer Science and Business Media LLC. https://doi.org/10.1038/s41420-022-00936-3
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Citation
Freeling, J. L., Scholl, J. L., Eikanger, M., Knoblich, C., Potts, R. A., Anderson, D. J., Rower, J. E., Farjoo, M. H., Zhao, H., Pillatzki, A., & Rezvani, K., Pre-clinical safety and therapeutic efficacy of a plant-based alkaloid in a human colon cancer xenograft model. Cell Death Discovery, Volume 8, Issue 1, March 2022, New York Tech Institutional Repository, accessed April 27, 2024, https://repository.nyitlibrary.org/items/show/3787
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