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.
Highlights
The skin is the organ in horses most frequently affected by tumors [1]
The antiproliferative and cytotoxic effects of NVX-207 and BBS on equine sarcoid (ES) cells, equine malignant melanoma (EMM) cells and equine dermal fibroblasts were assessed by the crystal violet staining assay (CVS) and MTS assay
Both compounds had significant inhibitory effects on cell proliferation (p < 0.001 in CVS assay for every cell type) and cell viability (p < 0.001 in MTS assay for every cell type) compared to untreated controls
Summary
With a reported occurrence ranging from 35 to 90% of all cutaneous neoplasms [2,3,4], the equine sarcoid (ES) is the most prevalent skin cancer in equids worldwide [5,6,7]. The pathogenesis of this coat-color independent tumor of the fibroblasts has been linked to an infection with the bovine papillomavirus type 1 and 2 [8,9,10], trauma [11, 12], and a genetic predisposition [13, 14]. The development of a novel topical treatment approach for ES should be considered to take advantage of the benefits of topical therapies
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