Tenovin-6 induces the SIRT-independent cell growth suppression and blocks autophagy flux in canine hemangiosarcoma cell lines.

Canine hemangiosarcoma (HSA) is a commonly occurring aggressive tumor stemming from the vascular endothelial cells and is considered to be a good model for a similar disease in humans, called angiosarcoma. In this study, we reviewed drug libraries to identify new signal transduction inhibitors that can suppress the cell growth of canine HSA in vitro. We observed that tenovin-6, a sirtuin (SIRT) inhibitor, inhibited cell proliferation and induced cell death in three canine HSA cell lines (JuB4, Re12, and Ud6). These effects were induced through G1 cell cycle arrest and caspase-3 activation. Although tenovin-6 is known as an inhibitor of SIRT1 and SIRT2, knockout (KO) of genes encoding SIRT1 and/or SIRT2 had no apparent impact on cell proliferation in canine HSA. In addition, tenovin-6 showed cell growth inhibition in SIRT KO cells, as well as parental cells. These results indicated the cytotoxicity of tenovin-6 was a SIRT-independent event. Instead, we found that tenovin-6 inhibited autophagy flux in canine HSA cells, as evidenced by the suppression of lysosomal proteolysis. These results suggested that tenovin-6 induces cell growth suppression in canine HSA cells by impairing the lysosomal function. Therefore, tenovin-6 could be used in a new therapeutic strategy to treat canine HSA.

Combination Therapy with Reovirus and ATM Inhibitor Enhances Cell Death and Virus Replication in Canine Melanoma.

Oncolytic virotherapy using reovirus is a promising new anti-cancer treatment with potential for use in humans and dogs. Because reovirus monotherapy shows limited efficacy in human and canine cancer patients, the clinical development of a combination therapy is necessary. To identify candidate components of such a combination, we screened a 285-compound drug library for those that enhanced reovirus cytotoxicity in a canine melanoma cell line. Here, we show that exposure to an inhibitor of the ataxia telangiectasia mutated protein (ATM) enhances the oncolytic potential of reovirus in five of six tested canine melanoma cell lines. Specifically, the ATM inhibitor potentiated reovirus replication in cancer cells along with promoting the lysosomal activity, resulting in an increased proportion of caspase-dependent apoptosis and cell cycle arrest at G2/M compared to those observed with reovirus alone. Overall, our study suggests that the combination of reovirus and the ATM inhibitor may be an attractive option in cancer therapy.

Anti-tumour activity of oncolytic reovirus against canine histiocytic sarcoma cells.

Canine histiocytic sarcoma is an aggressive, fatal neoplastic disease with a poor prognosis. Lomustine is generally accepted as the first-line systemic therapy, although this compound does not provide complete regression. Therefore, research into a novel approach against canine histiocytic sarcoma is needed. However, anti-tumour effects of oncolytic therapy using reovirus against histiocytic sarcoma are unknown. Here, we showed that reovirus has oncolytic activity in canine histiocytic sarcoma cell lines in vitro and in vivo. We found that reovirus can replicate and induce caspase-dependent apoptosis in canine histiocytic sarcoma cell lines. A single intra-tumoural injection of reovirus completely suppressed the growth of subcutaneously grafted tumours in NOD/SCID mice. Additionally, we demonstrated that susceptibility to reovirus-induced cell death was attributable to the extent of expression of type I interferons induced by reovirus infection in vitro. In conclusion, oncolytic reovirus appears to be an effective treatment option for histiocytic sarcoma, and therefore warrants further investigation in early clinical trials.

Pancreatic Abscess in a cat due to Staphylococcus aureus infection.

A 16-year-old spayed female American Shorthair cat was presented with lethargy, anorexia, and wamble. Physical and blood examination did not reveal any remarkable findings. Abdominal ultrasonography identified the presence of a localized anechoic structure with a thick wall in contact with the small intestine and adjacent to the liver. Ultrasound-guided fine-needle aspiration of the structure revealed fluid containing numerous cocci and neutrophils. Two days after antibiotic treatment, exploratory laparotomy was performed and the content of the structure was removed before multiple lavages. The pathological and bacteriological examination results supported a confirmatory diagnosis of pancreatic abscess due to Staphylococcus aureus infection, making this the first such report in a cat. The cat remained healthy thereafter with no disease recurrence.