title: Inhibition of Rho-associated coiled-coil-forming kinase increases efficacy of measles virotherapy.
abstract: RhoA and its downstream effector Rho-associated coiled-coil-forming kinase (ROCK) are known regulators of the formation of actin cytoskeleton in cells. Actin cytoskeleton is involved in paramyxovirus infection; we, therefore, examined the effect of ROCK inhibition on measles virus (MV) cytopathic effect and replication. Treatment with the ROCK inhibitor, Y27632, significantly increased syncytia size in tumor cell lines following MV infection, associated with cytoskeleton disruption as demonstrated by actin staining. Treatment of prostate cancer, breast cancer and glioblastoma tumor cell lines with Y27632 following MV infection resulted in increased cytopathic effect, as assessed by trypan blue exclusion assays. In addition, there was a significant increase in viral proliferation by at least one log or more as tested in one-step viral growth curves. Increased viral replication was also observed in athymic nude mice bearing MDA-MB-231 xenografts following combination treatment with MV and Y27632. In summary, inhibition of the ROCK kinase by Y27632 enhanced the oncolytic effect of MV and viral proliferation; this approach merits further translational investigation.
authors.affiliation: 1] Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA [2] Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: M
authors.initials: M
authors.lastname: Opyrchal
authors.forename: C
authors.initials: C
authors.lastname: Allen
authors.forename: P
authors.initials: P
authors.lastname: Msaouel
authors.forename: I
authors.initials: I
authors.lastname: Iankov
authors.forename: E
authors.initials: E
authors.lastname: Galanis
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000628:therapy* / Q000821:virology; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003131:Combined Modality Therapy; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D008459:Measles virus / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000628:therapy* / Q000821:virology; D011725:Pyridines / Q000494:pharmacology; D011897:Random Allocation; D014407:Tumor Cells, Cultured; D014709:Vero Cells; D023041:Xenograft Model Antitumor Assays; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D011725:Pyridines; C108830:Y 27632; D054460:rho-Associated Kinases