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 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2015 |
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| Erschienen: |
2015 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:10 |
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| Enthalten in: |
PloS one - 10(2015), 2 vom: 24., Seite e0118187 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
McCrudden, Cian M [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 08.01.2016 Date Revised 23.02.2019 published: Electronic-eCollection Citation Status MEDLINE |
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| doi: |
10.1371/journal.pone.0118187 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM246314230 |
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| 100 | 1 | |a McCrudden, Cian M |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Vasoactivity of rucaparib, a PARP-1 inhibitor, is a complex process that involves myosin light chain kinase, P2 receptors, and PARP itself |
| 264 | 1 | |c 2015 | |
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| 500 | |a Date Revised 23.02.2019 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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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| 700 | 1 | |a O'Rourke, Martin G |e verfasserin |4 aut | |
| 700 | 1 | |a Cherry, Kim E |e verfasserin |4 aut | |
| 700 | 1 | |a Yuen, Hiu-Fung |e verfasserin |4 aut | |
| 700 | 1 | |a O'Rourke, Declan |e verfasserin |4 aut | |
| 700 | 1 | |a Babur, Muhammad |e verfasserin |4 aut | |
| 700 | 1 | |a Telfer, Brian A |e verfasserin |4 aut | |
| 700 | 1 | |a Thomas, Huw D |e verfasserin |4 aut | |
| 700 | 1 | |a Keane, Patrick |e verfasserin |4 aut | |
| 700 | 1 | |a Nambirajan, Thiagarajan |e verfasserin |4 aut | |
| 700 | 1 | |a Hagan, Chris |e verfasserin |4 aut | |
| 700 | 1 | |a O'Sullivan, Joe M |e verfasserin |4 aut | |
| 700 | 1 | |a Shaw, Chris |e verfasserin |4 aut | |
| 700 | 1 | |a Williams, Kaye J |e verfasserin |4 aut | |
| 700 | 1 | |a Curtin, Nicola J |e verfasserin |4 aut | |
| 700 | 1 | |a Hirst, David G |e verfasserin |4 aut | |
| 700 | 1 | |a Robson, Tracy |e verfasserin |4 aut | |
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