NK1 receptor antagonists and dexamethasone as anticancer agents in vitro and in a model of brain tumours secondary to breast cancer

Abstract

Emend, an NK1 antagonist, and dexamethasone are used to treat complications associated with metastatic brain tumours and their treatment. It has been suggested that these agents exert anticancer effects apart from their current use. The effects of the NK1 antagonists, Emend and N-acetyl-L-tryptophan, and dexamethasone on tumour growth were investigated in vitro and in vivo at clinically relevant doses. For animal experiments, a stereotaxic injection model of Walker 256 rat breast carcinoma cells into the striatum of Wistar rats was used. Emend treatment led to a decrease in tumour cell viability in vitro, although this effect was not replicated by N-acetyl-L-tryptophan. Dexamethasone did not decrease tumour cell viability in vitro but decreased tumour volume in vivo, likely to be through a reduction in tumour oedema, as indicated by the increase in tumour cell density. None of the agents investigated altered tumour cell replication or apoptosis in vivo. Inoculated animals showed increased glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1 immunoreactivity indicative of astrocytes and microglia in the peritumoral area, whereas treatment with Emend and dexamethasone reduced the labelling for both glial cells. These results do not support the hypothesis that NK1 antagonists or dexamethasone exert a cytotoxic action on tumour cells, although these conclusions may be specific to this model and cell line.

Differential effects of aprepitant, a clinically used neurokinin-1 receptor antagonist on the expression of conditioned psychostimulant versus opioid reward

“…Thus, the utility of NK1 directed therapeutics in the clinic is an area of interest in addiction field. Animal studies indicate therapeutic benefits of NK1R antagonists in treating stimulant abuse, depression and cancer (Gabrielian et al 2013; Gonzalez-Nicolini and McGinty 2002; Kramer et al 2004; Lewis et al 2013). Species differences exist with respect to response to non-peptide NK1R antagonists, and rats and mice have amino acid residue changes at antagonist binding sites relative to humans and guinea pigs (Olive 2015; Saria 1999).…”

Treatment with the NK1 Antagonist Emend Reduces Blood Brain Barrier Dysfunction and Edema Formation in an Experimental Model of Brain Tumors

“…As was observed in TBI, administration of a SP antagonist resulted in marked improvement in functional outcome following stroke [12]. Given its role in the development of edema following these insults to the CNS, and that SP expression is increased in a variety of human cancer cell lines including brain tumors [13]–[16], SP may also be a potential target for the treatment of metastatic brain tumor-associated edema [9]–[12].…”

Development and validation of a highly sensitive LC‐MS/MS method for the determination of dexamethasone in nude mice plasma and its application to a pharmacokinetic study

“…Dexamethasone (DEX, Fig. A), one of the most widely used synthetic glucocorticoids, has been demonstrated to have antitumor efficacy in the MCF‐7 xenograft nude mice model as well as in other tumor cell lines in vitro and in vivo (Bavaresco et al ., ; Gong et al ., ; Lewis et al ., ; Villeneuve et al ., ). These findings suggest that dexamethasone may have a promising future as an anticancer drug in both preclinical and clinical studies.…”