Limited short-term effects on human prostate cancer xenograft growth and epidermal growth factor receptor gene expression by the ghrelin receptor antagonist [D-Lys 3 ]-GHRP-6

Abstract

Purpose

The ghrelin axis regulates many physiological functions (including appetite, metabolism, and energy balance) and plays a role in disease processes. As ghrelin stimulates prostate cancer proliferation, the ghrelin receptor antagonist [D-Lys³]-GHRP-6 is a potential treatment for castrate-resistant prostate cancer and for preventing the metabolic consequences of androgen-targeted therapies. We therefore explored the effect of [D-Lys³]-GHRP-6 on PC3 prostate cancer xenograft growth.

Methods

NOD/SCID mice with PC3 prostate cancer xenografts were administered 20 nmoles/mouse [D-Lys³]-GHRP-6 daily by intraperitoneal injection for 14 days and tumour volume and weight were measured. RNA sequencing of tumours was conducted to investigate expression changes following [D-Lys³]-GHRP-6 treatment. A second experiment, extending treatment time to 18 days and including a higher dose of [D-Lys³]-GHRP-6 (200 nmoles/mouse/day), was undertaken to ensure repeatability.

Results

We demonstrate here that daily intraperitoneal injection of 20 nmoles/mouse [D-Lys³]-GHRP-6 reduces PC3 prostate cancer xenograft tumour volume and weight in NOD/SCID mice at two weeks post treatment initiation. RNA-sequencing revealed reduced expression of epidermal growth factor receptor (EGFR) in these tumours. Further experiments demonstrated that the effects of [D-Lys³]-GHRP-6 are transitory and lost after 18 days of treatment.

Conclusions

We show that [D-Lys³]-GHRP-6 has transitory effects on prostate xenograft tumours in mice, which rapidly develop an apparent resistance to the antagonist. Although further studies on [D-Lys³]-GHRP-6 are warranted, we suggest that daily treatment with the antagonist is not a suitable treatment for advanced prostate cancer.

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