title: Vasoactivity of rucaparib, a PARP-1 inhibitor, is a complex process that involves myosin light chain kinase, P2 receptors, and PARP itself.
abstract: 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.
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Cian M
authors.initials: CM
authors.lastname: McCrudden
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Martin G
authors.initials: MG
authors.lastname: O'Rourke
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Kim E
authors.initials: KE
authors.lastname: Cherry
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Hiu-Fung
authors.initials: HF
authors.lastname: Yuen
authors.affiliation: Belfast Health and Social Care Trust, Belfast, United Kingdom.
authors.forename: Declan
authors.initials: D
authors.lastname: O'Rourke
authors.affiliation: Manchester Pharmacy School, The University of Manchester, Manchester, United Kingdom.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Babur
authors.affiliation: Manchester Pharmacy School, The University of Manchester, Manchester, United Kingdom.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Telfer
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Huw D
authors.initials: HD
authors.lastname: Thomas
authors.affiliation: Belfast Health and Social Care Trust, Belfast, United Kingdom.
authors.forename: Patrick
authors.initials: P
authors.lastname: Keane
authors.affiliation: Belfast Health and Social Care Trust, Belfast, United Kingdom.
authors.forename: Thiagarajan
authors.initials: T
authors.lastname: Nambirajan
authors.affiliation: Belfast Health and Social Care Trust, Belfast, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Hagan
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom; Belfast Health and Social Care Trust, Belfast, United Kingdom.
authors.forename: Joe M
authors.initials: JM
authors.lastname: O'Sullivan
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Shaw
authors.affiliation: Manchester Pharmacy School, The University of Manchester, Manchester, United Kingdom.
authors.forename: Kaye J
authors.initials: KJ
authors.lastname: Williams
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Curtin
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: David G
authors.initials: DG
authors.lastname: Hirst
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Tracy
authors.initials: T
authors.lastname: Robson
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D002292:Carcinoma, Renal Cell / Q000098:blood supply; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000098:blood supply; D008297:Male; D051379:Mice; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D018048:Receptors, Purinergic P2; C531549:rucaparib; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D009219:Myosin-Light-Chain Kinase