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Vasoactivity of Rucaparib, a PARP-1 Inhibitor, is a Complex Process that Involves Myosin Light Chain Kinase, P2 Receptors, and PARP Itself

Therapeutic inhibition of poly(ADP-ribose) polymerase (PARP), as monotherapy or to supplement the potencies of other agents, is a promising strategy in cancer treatment. We previously reported that the first PARP inhibitor to enter clinical trial, rucaparib (AG014699), induced vasodilation in vivo i...

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Autores principales: McCrudden, Cian M., O’Rourke, Martin G., Cherry, Kim E., Yuen, Hiu-Fung, O’Rourke, Declan, Babur, Muhammad, Telfer, Brian A., Thomas, Huw D., Keane, Patrick, Nambirajan, Thiagarajan, Hagan, Chris, O’Sullivan, Joe M., Shaw, Chris, Williams, Kaye J., Curtin, Nicola J., Hirst, David G., Robson, Tracy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4331495/
https://www.ncbi.nlm.nih.gov/pubmed/25689628
http://dx.doi.org/10.1371/journal.pone.0118187
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author McCrudden, Cian M.
O’Rourke, Martin G.
Cherry, Kim E.
Yuen, Hiu-Fung
O’Rourke, Declan
Babur, Muhammad
Telfer, Brian A.
Thomas, Huw D.
Keane, Patrick
Nambirajan, Thiagarajan
Hagan, Chris
O’Sullivan, Joe M.
Shaw, Chris
Williams, Kaye J.
Curtin, Nicola J.
Hirst, David G.
Robson, Tracy
author_facet McCrudden, Cian M.
O’Rourke, Martin G.
Cherry, Kim E.
Yuen, Hiu-Fung
O’Rourke, Declan
Babur, Muhammad
Telfer, Brian A.
Thomas, Huw D.
Keane, Patrick
Nambirajan, Thiagarajan
Hagan, Chris
O’Sullivan, Joe M.
Shaw, Chris
Williams, Kaye J.
Curtin, Nicola J.
Hirst, David G.
Robson, Tracy
author_sort McCrudden, Cian M.
collection PubMed
description Therapeutic inhibition of poly(ADP-ribose) polymerase (PARP), as monotherapy or to supplement the potencies of other agents, is a promising strategy in cancer treatment. We previously reported that the first PARP inhibitor to enter clinical trial, rucaparib (AG014699), induced vasodilation in vivo in xenografts, potentiating response to temozolomide. We now report that rucaparib inhibits the activity of the muscle contraction mediator myosin light chain kinase (MLCK) 10-fold more potently than its commercially available inhibitor ML-9. Moreover, rucaparib produces additive relaxation above the maximal degree achievable with ML-9, suggesting that MLCK inhibition is not solely responsible for dilation. Inhibition of nitric oxide synthesis using L-NMMA also failed to impact rucaparib’s activity. Rucaparib contains the nicotinamide pharmacophore, suggesting it may inhibit other NAD+-dependent processes. NAD(+) exerts P2 purinergic receptor-dependent inhibition of smooth muscle contraction. Indiscriminate blockade of the P2 purinergic receptors with suramin abrogated rucaparib-induced vasodilation in rat arterial tissue without affecting ML-9-evoked dilation, although the specific receptor subtypes responsible have not been unequivocally identified. Furthermore, dorsal window chamber and real time tumor vessel perfusion analyses in PARP-1(-/-) mice indicate a potential role for PARP in dilation of tumor-recruited vessels. Finally, rucaparib provoked relaxation in 70% of patient-derived tumor-associated vessels. These data provide tantalising evidence of the complexity of the mechanism underlying rucaparib-mediated vasodilation.
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spelling pubmed-43314952015-02-24 Vasoactivity of Rucaparib, a PARP-1 Inhibitor, is a Complex Process that Involves Myosin Light Chain Kinase, P2 Receptors, and PARP Itself McCrudden, Cian M. O’Rourke, Martin G. Cherry, Kim E. Yuen, Hiu-Fung O’Rourke, Declan Babur, Muhammad Telfer, Brian A. Thomas, Huw D. Keane, Patrick Nambirajan, Thiagarajan Hagan, Chris O’Sullivan, Joe M. Shaw, Chris Williams, Kaye J. Curtin, Nicola J. Hirst, David G. Robson, Tracy PLoS One Research Article Therapeutic inhibition of poly(ADP-ribose) polymerase (PARP), as monotherapy or to supplement the potencies of other agents, is a promising strategy in cancer treatment. We previously reported that the first PARP inhibitor to enter clinical trial, rucaparib (AG014699), induced vasodilation in vivo in xenografts, potentiating response to temozolomide. We now report that rucaparib inhibits the activity of the muscle contraction mediator myosin light chain kinase (MLCK) 10-fold more potently than its commercially available inhibitor ML-9. Moreover, rucaparib produces additive relaxation above the maximal degree achievable with ML-9, suggesting that MLCK inhibition is not solely responsible for dilation. Inhibition of nitric oxide synthesis using L-NMMA also failed to impact rucaparib’s activity. Rucaparib contains the nicotinamide pharmacophore, suggesting it may inhibit other NAD+-dependent processes. NAD(+) exerts P2 purinergic receptor-dependent inhibition of smooth muscle contraction. Indiscriminate blockade of the P2 purinergic receptors with suramin abrogated rucaparib-induced vasodilation in rat arterial tissue without affecting ML-9-evoked dilation, although the specific receptor subtypes responsible have not been unequivocally identified. Furthermore, dorsal window chamber and real time tumor vessel perfusion analyses in PARP-1(-/-) mice indicate a potential role for PARP in dilation of tumor-recruited vessels. Finally, rucaparib provoked relaxation in 70% of patient-derived tumor-associated vessels. These data provide tantalising evidence of the complexity of the mechanism underlying rucaparib-mediated vasodilation. Public Library of Science 2015-02-17 /pmc/articles/PMC4331495/ /pubmed/25689628 http://dx.doi.org/10.1371/journal.pone.0118187 Text en © 2015 McCrudden et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
McCrudden, Cian M.
O’Rourke, Martin G.
Cherry, Kim E.
Yuen, Hiu-Fung
O’Rourke, Declan
Babur, Muhammad
Telfer, Brian A.
Thomas, Huw D.
Keane, Patrick
Nambirajan, Thiagarajan
Hagan, Chris
O’Sullivan, Joe M.
Shaw, Chris
Williams, Kaye J.
Curtin, Nicola J.
Hirst, David G.
Robson, Tracy
Vasoactivity of Rucaparib, a PARP-1 Inhibitor, is a Complex Process that Involves Myosin Light Chain Kinase, P2 Receptors, and PARP Itself
title Vasoactivity of Rucaparib, a PARP-1 Inhibitor, is a Complex Process that Involves Myosin Light Chain Kinase, P2 Receptors, and PARP Itself
title_full Vasoactivity of Rucaparib, a PARP-1 Inhibitor, is a Complex Process that Involves Myosin Light Chain Kinase, P2 Receptors, and PARP Itself
title_fullStr Vasoactivity of Rucaparib, a PARP-1 Inhibitor, is a Complex Process that Involves Myosin Light Chain Kinase, P2 Receptors, and PARP Itself
title_full_unstemmed Vasoactivity of Rucaparib, a PARP-1 Inhibitor, is a Complex Process that Involves Myosin Light Chain Kinase, P2 Receptors, and PARP Itself
title_short Vasoactivity of Rucaparib, a PARP-1 Inhibitor, is a Complex Process that Involves Myosin Light Chain Kinase, P2 Receptors, and PARP Itself
title_sort vasoactivity of rucaparib, a parp-1 inhibitor, is a complex process that involves myosin light chain kinase, p2 receptors, and parp itself
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4331495/
https://www.ncbi.nlm.nih.gov/pubmed/25689628
http://dx.doi.org/10.1371/journal.pone.0118187
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