Effects of Para-Toluenesulfonamide on Canine Melanoma Xenotransplants in a BALB/c Nude Mouse Model

SIMPLE SUMMARY: Canine melanomas are malignant neoplasms, and primary melanomas arise at the footpad, nail bed, gastrointestinal tract, mucocutaneous junction, and eyes. Para-toluenesulfonamide (PTS) is a small molecule that acts against several cancers (hepatocellular carcinoma, nonsmall-cell lung cancer, and tongue squamous cell carcinoma). The pharmacological pathway of PTS has the potential to exert anti-inflammatory and antithrombotic functions. We established canine melanoma xenografts in mice and randomized the animals into four treatment groups: saline, cisplatin, PTS, and PTS combined with cisplatin. The findings indicated that compared with the control mice, mice treated with PTS and the combination of PTS and cisplatin showed retarded tumor growth; increased tumor apoptosis through the upregulation of caspase 3 and extracellular signal-regulated kinase phosphorylation; decreased inflammation levels of cytokines, such as interleukin-1β, tumor necrosis factor-α, and interleukin-6; reduced inflammation-related factors, such as the cyclooxygenase-2 protein and nuclear factor-κB mRNA; enhanced anti-inflammation-related factors; and inhibition of the metastasis-related factors transforming growth factor β, CD44, epidermal growth factor receptor, and vascular endothelial growth factor. Combining cisplatin with PTS has a stronger effect than PTS alone. These findings may prove useful in further explorations of the application of PTS or PTS combined with cisplatin to the treatment of canine melanoma in general. ABSTRACT: The pharmacological pathway of para-toluenesulfonamide (PTS) restricts the kinase activity of the mammalian target of rapamycin, potentially leading to reductions in cell division, cell growth, cell proliferation, and inflammation. These pathways have a critical effect on tumorigenesis. We aimed to examine the antitumor effect of PTS or PTS combined with cisplatin on canine melanoma implanted in BALB/c nude mice by estimating tumor growth, apoptosis expression, inflammation, and metastasis. The mice were randomly divided into four groups: control, cisplatin, PTS, and PTS combined with cisplatin. Mice treated with PTS or PTS combined with cisplatin had retarded tumor growth and increased tumor apoptosis through the enhanced expression of cleaved caspase 3 and extracellular signal-regulated kinase phosphorylation, decreased inflammatory cytokine levels, reduced inflammation-related factors, enhanced anti-inflammation-related factors, and inhibition of metastasis-related factors. Mice treated with PTS combined with cisplatin exhibited significantly retarded tumor growth, reduced tumor size, and increased tumor inhibition compared with those treated with cisplatin or PTS alone. PTS or PTS combined with cisplatin could retard canine melanoma growth and inhibit tumorigenesis. PTS and cisplatin were found to have an obvious synergistic tumor-inhibiting effect on canine melanoma. PTS alone and PTS combined with cisplatin may be antitumor agents for canine melanoma treatment.