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PloS one2020; 15(11); e0241448; doi: 10.1371/journal.pone.0241448

In vitro assessment of triterpenoids NVX-207 and betulinyl-bis-sulfamate as a topical treatment for equine skin cancer.

Abstract: Equine sarcoid (ES) is the most prevalent skin tumor in equids worldwide. Additionally, aging grey horses frequently suffer from equine malignant melanoma (EMM). Current local therapies targeting these skin tumors remain challenging. Therefore, more feasible topical treatment options should be considered. In order to develop a topical therapy against ES and EMM, betulinyl-bis-sulfamate and NVX-207, derivatives of the naturally occurring betulin and betulinic acid, respectively, were evaluated for their antiproliferative (crystal violet staining assay), cytotoxic (MTS assay) and apoptotic (AnnexinV staining, cell cycle investigations) effects on primary ES cells, EMM cells and equine dermal fibroblasts in vitro. The more potent derivative was assessed for its in vitro penetration and permeation on isolated equine skin within 30 min and 24 h using Franz-type diffusion cells and HPLC analysis. Betulinyl-bis-sulfamate and NVX-207 inhibited the proliferation and metabolism in ES cells, EMM cells and fibroblasts significantly (p < 0.001) in a time- and dose-dependent manner. NVX-207 had superior anticancer effects compared to betulinyl-bis-sulfamate. Both compounds led to the externalization of phosphatidylserines on the cell membrane and DNA fragmentation, demonstrating that the effective mode of action was apoptosis. After 48 h of treatment with NVX-207, the number of necrotic cells was less than 2% in all cell types. Detected amounts of NVX-207 in the different skin layers exceeded the half-maximal inhibitory concentrations calculated by far. Even though data obtained in vitro are auspicious, the results are not unconditionally applicable to the clinical situation. Consequently, in vivo studies are required to address the antitumoral effects of topically applied NVX-207 in ES and EMM patients.
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Publication Date: 2020-11-05 PubMed ID: 33151949PubMed Central: PMC7643960DOI: 10.1371/journal.pone.0241448Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research evaluates two triterpenoids, NVX-207 and betulinyl-bis-sulfamate, as potential topical treatments for the most common skin tumors in horses: equine sarcoid and equine malignant melanoma. The study was conducted in a laboratory setting and tested the compounds’ abilities to inhibit cell proliferation, induce cell death, and penetrate equine skin.

Research Context and Purpose

  • Equine sarcoid (ES) and equine malignant melanoma (EMM) are the most common skin cancers in horses. Current treatment options for these tumors are limited and present challenges, thus necessitating the exploration of more feasible solutions.
  • The study aimed to develop a suitable topical treatment for ES and EMM. For this purpose, NVX-207 and betulinyl-bis-sulfamate were chosen for evaluation. These two substances are derivatives of betulin and betulinic acid, respectively, which occur naturally.
  • The research assessed the compounds’ abilities to affect cell proliferation, to cause cell death (cytotoxicity), and to induce programmed cell death (apoptosis) in ES cells, EMM cells, and equine dermal fibroblasts in an in vitro setting.

Methodology and Results

  • The research utilized different assays to measure the effects of the compounds on cell proliferation, cytotoxicity, and apoptosis. Findings showed that both NVX-207 and betulinyl-bis-sulfamate significantly inhibited the proliferation and metabolism of ES cells, EMM cells, and fibroblasts in a time- and dose-dependent manner.
  • NVX-207 was found to be more effective at inhibiting cancer cells compared to betulinyl-bis-sulfamate.
  • Both compounds caused changes to cell membranes and DNA fragmentation, an indication that they induce apoptosis as a primary mode of action.
  • Moreover, necrotic cells, which are cells that have died from injury or disease, accounted for less than 2% of all cells after 48 hours of treatment with NVX-207, suggesting minimal collateral damage.
  • The research also examined the potential skin penetration and permeation of NVX-207 using Franz-type diffusion cells and HPLC analysis. It was found that NVX-207 penetrated the different skin layers more than necessary, based on the calculated half-maximal inhibitory concentrations.

Implications

  • While the in vitro data shows promising potential for NVX-207 as a topical treatment for ES and EMM, these results are not immediately applicable to a clinical scenario. Further in vivo research is needed to assess the actual anticancer effects of NVX-207 when applied directly on ES and EMM in horses.
  • If successful, this research may pave the way for more effective, easy-to-use topical treatments for equine skin cancer, improving the quality of life of affected equines and making the work of veterinarians easier.

Cite This Article

APA
Weber LA, Funtan A, Paschke R, Delarocque J, Kalbitz J, Meißner J, Feige K, Kietzmann M, Cavalleri JV. (2020). In vitro assessment of triterpenoids NVX-207 and betulinyl-bis-sulfamate as a topical treatment for equine skin cancer. PLoS One, 15(11), e0241448. https://doi.org/10.1371/journal.pone.0241448

Publication

PloS one
ISSN: 1932-6203
NlmUniqueID: 101285081
Country: United States
Language: English
Volume: 15
Issue: 11
Pages: e0241448
PII: e0241448

Researcher Affiliations

Weber, Lisa Annabel
  • Clinic for Horses, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany.
Funtan, Anne
  • Biozentrum, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.
Paschke, Reinhard
  • Biozentrum, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.
Delarocque, Julien
  • Clinic for Horses, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany.
Kalbitz, Jutta
  • BioSolutions Halle GmbH, Halle (Saale), Germany.
Meißner, Jessica
  • Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany.
Feige, Karsten
  • Clinic for Horses, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany.
Kietzmann, Manfred
  • Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany.
Cavalleri, Jessika-Maximiliane V
  • Equine Internal Medicine, University Equine Clinic, University of Veterinary Medicine Vienna, Vienna, Austria.

MeSH Terms

  • Administration, Topical
  • Animals
  • Apoptosis / drug effects
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dermis / pathology
  • Diffusion
  • Fibroblasts / drug effects
  • Fibroblasts / pathology
  • Horse Diseases / drug therapy
  • Horses
  • Inhibitory Concentration 50
  • Propanolamines / pharmacology
  • Propanolamines / therapeutic use
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / veterinary
  • Sulfonic Acids / pharmacology
  • Sulfonic Acids / therapeutic use
  • Triterpenes / administration & dosage
  • Triterpenes / pharmacology
  • Triterpenes / therapeutic use

Conflict of Interest Statement

The authors declare that no competing interests exist. The affiliation "BioSolutions Halle GmbH” of Dr. Jutta Kalbitz does not alter our adherence to PLOS ONE policies on sharing data and materials. As described in the Funding Statement, BioSolutions Halle GmbH is not a commercial funder, but an equal partner in the TopiDrugHorse project.

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Citations

This article has been cited 5 times.
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