Michelle L Maugham1,2,3,4, Inge Seim1,2,3,5, Patrick B Thomas1,2,3, Gabrielle J Crisp1,2,3, Esha T Shah1,2,3, Adrian C Herington1,2, Laura S Gregory4, Colleen C Nelson2, Penny L Jeffery1,2,3, Lisa K Chopin6,7,8. 1. Ghrelin Research Group, Institute of Health and Biomedical Innovation, Translational Research Institute and School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia. 2. Australian Prostate Cancer Research Centre - Queensland, Princess Alexandra Hospital, Institute of Health and Biomedical Innovation, Translational Research Institute, Queensland University of Technology, Brisbane, QLD, Australia. 3. Comparative and Endocrine Biology Laboratory, Institute of Health and Biomedical Innovation, Translational Research Institute, Queensland University of Technology, Brisbane, QLD, Australia. 4. Skeletal Biology and Forensic Anthropology Research Laboratory, Cancer Program, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Translational Research Institute, Queensland University of Technology, Brisbane, QLD, Australia. 5. Integrative Biology Laboratory, College of Life Sciences, Nanjing Normal University, Nanjing, Jiangsu, China. 6. Ghrelin Research Group, Institute of Health and Biomedical Innovation, Translational Research Institute and School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia. l.chopin@qut.edu.au. 7. Australian Prostate Cancer Research Centre - Queensland, Princess Alexandra Hospital, Institute of Health and Biomedical Innovation, Translational Research Institute, Queensland University of Technology, Brisbane, QLD, Australia. l.chopin@qut.edu.au. 8. Comparative and Endocrine Biology Laboratory, Institute of Health and Biomedical Innovation, Translational Research Institute, Queensland University of Technology, Brisbane, QLD, Australia. l.chopin@qut.edu.au.
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.
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/SCIDmice 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 PC3prostate cancer xenograft tumour volume and weight in NOD/SCIDmice 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.
Authors: Inge Seim; Amy A Lubik; Melanie L Lehman; Nadine Tomlinson; Eliza J Whiteside; Adrian C Herington; Colleen C Nelson; Lisa K Chopin Journal: J Mol Endocrinol Date: 2013-02-15 Impact factor: 5.098
Authors: Thomas Conway; Jeremy Wazny; Andrew Bromage; Martin Tymms; Dhanya Sooraj; Elizabeth D Williams; Bryan Beresford-Smith Journal: Bioinformatics Date: 2012-06-15 Impact factor: 6.937
Authors: Damian Szklarczyk; Andrea Franceschini; Stefan Wyder; Kristoffer Forslund; Davide Heller; Jaime Huerta-Cepas; Milan Simonovic; Alexander Roth; Alberto Santos; Kalliopi P Tsafou; Michael Kuhn; Peer Bork; Lars J Jensen; Christian von Mering Journal: Nucleic Acids Res Date: 2014-10-28 Impact factor: 16.971