The long-acting COX-2 inhibitor mavacoxib (Trocoxil™) has anti-proliferative and pro-apoptotic effects on canine cancer cell lines and cancer stem cells in vitro

Abstract

BackgroundThe NSAID mavacoxib (Trocoxcil™) is a recently described selective COX-2 inhibitor used for the management of inflammatory disease in dogs. It has a long plasma half-life, requiring less frequent dosing and supporting increased owner compliance in treating their dogs. Although the use of NSAIDs has been described in cancer treatment in dogs, there are no studies to date that have examined the utility of mavacoxib specifically.ResultsIn this study we compared the in vitro activity of a short-acting non-selective COX inhibitor (carprofen) with mavacoxib, on cancer cell and cancer stem cell survival. We demonstrate that mavacoxib has a direct cell killing effect on cancer cells, increases apoptosis in cancer cells in a manner that may be independent of caspase activity, and has an inhibitory effect on cell migration. Importantly, we demonstrate that cancer stem cells derived from osteosarcoma cell lines are sensitive to the cytotoxic effect of mavacoxib.ConclusionsBoth NSAIDs can inhibit cancer cell proliferation and induce apoptosis in vitro. Importantly, cancer stem cells derived from an osteosarcoma cell line are sensitive to the cytotoxic effect of mavacoxib. Our results suggest that mavacoxib has anti-tumour effects and that this in vitro anti-cancer activity warrants further study.Electronic supplementary materialThe online version of this article (doi:10.1186/s12917-014-0184-9) contains supplementary material, which is available to authorized users.

The selective cyclooxygenase‐2 inhibitor mavacoxib (Trocoxil) exerts anti‐tumour effects in vitro independent of cyclooxygenase‐2 expression levels

“…Caspase‐independent cell death has been previously characterized, highlighting that caspase inhibitors do not prevent cell death through autophagy, necrosis and apoptosis‐like cell death . Previous studies have noted similar results with NSAIDs in cancer cell lines, with caspase‐independent and BAX‐independent apoptosis suggested as a possible explanation . We have previously shown that increased Bcl‐2 levels after COX‐2 inhibition may be the result of a mitochondrial‐independent apoptotic pathway .…”

“…The canine osteosarcoma cell lines, KTOSA5 and CSKOS (gifted from Chand Khanna [NIH]) were maintained in Dulbecco's modified Eagle's medium (DMEM) (ThermoFisher Scientific, Massachusetts). The human osteosarcoma cell line U2OS was grown in McCoys 5A modified medium (ThermoFisher Scientific).…”

“…There is limited research into the potential anti‐cancer effects of mavacoxib. We have previously shown that mavacoxib exhibits anti‐proliferative and pro‐apoptotic effects in a panel of canine cancer cell lines and cancer stem cells in vitro Here, we investigate the effects of mavacoxib on a panel of canine and human cancer cell lines. The cancers studied include osteosarcoma, mammary carcinoma and transitional cell carcinoma (TCC) of the urinary bladder, which exhibit cross species similarities.…”

“…The cancers studied include osteosarcoma, mammary carcinoma and transitional cell carcinoma (TCC) of the urinary bladder, which exhibit cross species similarities. COX‐2 has an important role in disease progression in these cancer types and in both species the use of NSAIDs has shown positive therapeutic effects . We aim to determine if mavacoxib is directly cytotoxic to, and is able to inhibit the migration of these particular cell lines.…”

Cyclooxygenase‐2: A Role in Cancer Stem Cell Survival and Repopulation of Cancer Cells during Therapy

“…Molecular dissection of the mechanisms by which PGE 2 exerts these effects on HSCs has identified in vivo evidence that PGE 2 enhances the activation of Wnt, a key regulator of stem cell self-renewal, during embryogenesis by stabilising β -catenin, and that Wnt-mediated regulation of HSC development is PGE 2 -dependent [67]. Given the stem-cell-enhancing activity of PGE 2 , and that PGE 2 activates general cell survival and proliferation pathways, it is unsurprising that upregulation of COX-2 is associated with populations of CSCs isolated from several cancer types, including breast [74–77], colon [78, 79], and bone cancer [13, 80]. COX-2 is coexpressed with CSC markers including CD44, CD133, Oct3/4, LGR5, SOX-2, and ALDH [75, 78, 81–84].…”