Targeting hypoxic prostate tumours using the novel hypoxia-activated prodrug OCT1002 inhibits expression of genes associated with malignant progression

Heather Nesbitt, Niall Byrne, Louise Ming, Jenny Worthington, Rachel Errington, Laurence Patterson, Paul Smith, Stephanie McKeown, Declan McKenna

Research output: Contribution to journalArticle

Abstract

PurposeHypoxia is a common hallmark of the tumour microenvironment. Recently we have shown the anti-androgen bicalutamide induces profound hypoxia in prostate tumours in vivo. This resulted in the promotion of epithelial to mesenchymal transition. Here we target tumour hypoxia using a novel unidirectional hypoxia-activated prodrug OCT1002 to enhance the anti-tumour effect of bicalutamide. Experimental Design The effect of OCT1002 treatment on LNCaP-luc cells was measured in normoxia and hypoxia in vitro. In vivo, tumour growth and lung metastases were measured in mice treated with bicalutamide, OCT1002 or a combination. Dorsal skin fold chambers were used to image tumour vasculature in vivo. Longitudinal genetic changes in tumours were analysed using PCR.Results Reduction of OCT1002 to its active form (OCT1001) decreased LNCaP-luc cell viability. In LNCaP-luc spheroids, OCT1002 caused increased apoptosis and decreased clonogenicity. In vivo, treatment with OCT1002 alone or with bicalutamide, showed significantly greater tumour growth control and reduced lung metastases compared to controls. Re-establishment of the tumour vasculature following bicalutamide-induced vascular collapse is inhibited by OCT1002. Significantly, the up-regulation of RUNX2 and its targets caused by bicalutamide alone were also blocked by OCT1002. Conclusions OCT1002 selectively targets hypoxic tumour cells and enhances the anti-tumour efficacy of bicalutamide. Furthermore, bicalutamide causes changing genetic profiles during treatment, with development of a more malignant genotype; OCT1002 can block this effect. This study indicates that more attention should be attached to understanding genetic changes that may occur during treatment. Early targeting of hypoxic cells with OCT1002 can provide a means of inhibiting prostate tumour growth and malignant progression.
LanguageEnglish
Pages11-11
JournalUlster Medical Journal, The
Volume86
Issue number1
Publication statusAccepted/In press - 9 Sep 2016

Fingerprint

Prodrugs
Prostate
Gene Expression
Neoplasms
Growth
Hypoxia
Neoplasm Metastasis
Lung
Epithelial-Mesenchymal Transition
Tumor Microenvironment
bicalutamide
Androgens
Blood Vessels
Cell Survival
Research Design
Up-Regulation
Genotype
Apoptosis
Polymerase Chain Reaction
Skin

Keywords

  • OCT1002
  • hypoxia
  • bicalutamide
  • prostate cancer

Cite this

Nesbitt, Heather ; Byrne, Niall ; Ming, Louise ; Worthington, Jenny ; Errington, Rachel ; Patterson, Laurence ; Smith, Paul ; McKeown, Stephanie ; McKenna, Declan. / Targeting hypoxic prostate tumours using the novel hypoxia-activated prodrug OCT1002 inhibits expression of genes associated with malignant progression. In: Ulster Medical Journal, The. 2016 ; Vol. 86, No. 1. pp. 11-11.
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abstract = "PurposeHypoxia is a common hallmark of the tumour microenvironment. Recently we have shown the anti-androgen bicalutamide induces profound hypoxia in prostate tumours in vivo. This resulted in the promotion of epithelial to mesenchymal transition. Here we target tumour hypoxia using a novel unidirectional hypoxia-activated prodrug OCT1002 to enhance the anti-tumour effect of bicalutamide. Experimental Design The effect of OCT1002 treatment on LNCaP-luc cells was measured in normoxia and hypoxia in vitro. In vivo, tumour growth and lung metastases were measured in mice treated with bicalutamide, OCT1002 or a combination. Dorsal skin fold chambers were used to image tumour vasculature in vivo. Longitudinal genetic changes in tumours were analysed using PCR.Results Reduction of OCT1002 to its active form (OCT1001) decreased LNCaP-luc cell viability. In LNCaP-luc spheroids, OCT1002 caused increased apoptosis and decreased clonogenicity. In vivo, treatment with OCT1002 alone or with bicalutamide, showed significantly greater tumour growth control and reduced lung metastases compared to controls. Re-establishment of the tumour vasculature following bicalutamide-induced vascular collapse is inhibited by OCT1002. Significantly, the up-regulation of RUNX2 and its targets caused by bicalutamide alone were also blocked by OCT1002. Conclusions OCT1002 selectively targets hypoxic tumour cells and enhances the anti-tumour efficacy of bicalutamide. Furthermore, bicalutamide causes changing genetic profiles during treatment, with development of a more malignant genotype; OCT1002 can block this effect. This study indicates that more attention should be attached to understanding genetic changes that may occur during treatment. Early targeting of hypoxic cells with OCT1002 can provide a means of inhibiting prostate tumour growth and malignant progression.",
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Targeting hypoxic prostate tumours using the novel hypoxia-activated prodrug OCT1002 inhibits expression of genes associated with malignant progression. / Nesbitt, Heather; Byrne, Niall; Ming, Louise; Worthington, Jenny; Errington, Rachel; Patterson, Laurence; Smith, Paul; McKeown, Stephanie; McKenna, Declan.

In: Ulster Medical Journal, The, Vol. 86, No. 1, 09.09.2016, p. 11-11.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Targeting hypoxic prostate tumours using the novel hypoxia-activated prodrug OCT1002 inhibits expression of genes associated with malignant progression

AU - Nesbitt, Heather

AU - Byrne, Niall

AU - Ming, Louise

AU - Worthington, Jenny

AU - Errington, Rachel

AU - Patterson, Laurence

AU - Smith, Paul

AU - McKeown, Stephanie

AU - McKenna, Declan

PY - 2016/9/9

Y1 - 2016/9/9

N2 - PurposeHypoxia is a common hallmark of the tumour microenvironment. Recently we have shown the anti-androgen bicalutamide induces profound hypoxia in prostate tumours in vivo. This resulted in the promotion of epithelial to mesenchymal transition. Here we target tumour hypoxia using a novel unidirectional hypoxia-activated prodrug OCT1002 to enhance the anti-tumour effect of bicalutamide. Experimental Design The effect of OCT1002 treatment on LNCaP-luc cells was measured in normoxia and hypoxia in vitro. In vivo, tumour growth and lung metastases were measured in mice treated with bicalutamide, OCT1002 or a combination. Dorsal skin fold chambers were used to image tumour vasculature in vivo. Longitudinal genetic changes in tumours were analysed using PCR.Results Reduction of OCT1002 to its active form (OCT1001) decreased LNCaP-luc cell viability. In LNCaP-luc spheroids, OCT1002 caused increased apoptosis and decreased clonogenicity. In vivo, treatment with OCT1002 alone or with bicalutamide, showed significantly greater tumour growth control and reduced lung metastases compared to controls. Re-establishment of the tumour vasculature following bicalutamide-induced vascular collapse is inhibited by OCT1002. Significantly, the up-regulation of RUNX2 and its targets caused by bicalutamide alone were also blocked by OCT1002. Conclusions OCT1002 selectively targets hypoxic tumour cells and enhances the anti-tumour efficacy of bicalutamide. Furthermore, bicalutamide causes changing genetic profiles during treatment, with development of a more malignant genotype; OCT1002 can block this effect. This study indicates that more attention should be attached to understanding genetic changes that may occur during treatment. Early targeting of hypoxic cells with OCT1002 can provide a means of inhibiting prostate tumour growth and malignant progression.

AB - PurposeHypoxia is a common hallmark of the tumour microenvironment. Recently we have shown the anti-androgen bicalutamide induces profound hypoxia in prostate tumours in vivo. This resulted in the promotion of epithelial to mesenchymal transition. Here we target tumour hypoxia using a novel unidirectional hypoxia-activated prodrug OCT1002 to enhance the anti-tumour effect of bicalutamide. Experimental Design The effect of OCT1002 treatment on LNCaP-luc cells was measured in normoxia and hypoxia in vitro. In vivo, tumour growth and lung metastases were measured in mice treated with bicalutamide, OCT1002 or a combination. Dorsal skin fold chambers were used to image tumour vasculature in vivo. Longitudinal genetic changes in tumours were analysed using PCR.Results Reduction of OCT1002 to its active form (OCT1001) decreased LNCaP-luc cell viability. In LNCaP-luc spheroids, OCT1002 caused increased apoptosis and decreased clonogenicity. In vivo, treatment with OCT1002 alone or with bicalutamide, showed significantly greater tumour growth control and reduced lung metastases compared to controls. Re-establishment of the tumour vasculature following bicalutamide-induced vascular collapse is inhibited by OCT1002. Significantly, the up-regulation of RUNX2 and its targets caused by bicalutamide alone were also blocked by OCT1002. Conclusions OCT1002 selectively targets hypoxic tumour cells and enhances the anti-tumour efficacy of bicalutamide. Furthermore, bicalutamide causes changing genetic profiles during treatment, with development of a more malignant genotype; OCT1002 can block this effect. This study indicates that more attention should be attached to understanding genetic changes that may occur during treatment. Early targeting of hypoxic cells with OCT1002 can provide a means of inhibiting prostate tumour growth and malignant progression.

KW - OCT1002

KW - hypoxia

KW - bicalutamide

KW - prostate cancer

M3 - Article

VL - 86

SP - 11

EP - 11

JO - Ulster Medical Journal, The

T2 - Ulster Medical Journal, The

JF - Ulster Medical Journal, The

SN - 0041-6193

IS - 1

ER -