title: Time-dependent changes in the activation of RhoA/ROCK and ERM/p-ERM in the increased expression of intestinal P-glycoprotein by repeated oral treatment with etoposide.
abstract: Previously, we reported that repeated oral treatment with etoposide (ETP) increased ileal membrane localization of P-glycoprotein (P-gp) and that this was possibly mediated by increased expression of the ezrin/radixin/moesin (ERM)/phosphorylated ERM (p-ERM) via activation of RhoA/ROCK. These changes caused decreases in the analgesia of oral morphine (substrate drug for P-gp). However, there are no reports indicating the temporal changes in the above-mentioned factors after initiation and cessation of repeated treatment with the substrate drugs for P-gp including ETP. We examined the relationships between time-dependent changes in protein expressions of ileal P-gp and those of RhoA, ROCK, ERM, and p-ERM, and in oral morphine analgesia after initiation or cessation of repeated oral treatment with ETP. Ileal membrane localization of RhoA was increased 3 days after initiating ETP treatment; on 5 or 7 days, that of ROCK, ERM, and p-ERM was increased along with increments in P-gp expression, leading to decreases in oral morphine analgesia. All these changes returned toward normal levels 3 days after cessation. These data suggest that regulating the active state of the above-mentioned proteins during cancer chemotherapy or creating a timeframe of discontinuation a few days after cessation may enable effective palliative care using oral opioids.
authors.affiliation: Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, Kobe 650-8586, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Kobori
authors.forename: Shinichi
authors.initials: S
authors.lastname: Harada
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nakamoto
authors.forename: Shogo
authors.initials: S
authors.lastname: Tokuyama
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000032:analysis / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005047:Etoposide / Q000008:administration & dosage / Q000378:metabolism*; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins / Q000032:analysis / Q000378:metabolism*; D009020:Morphine / Q000008:administration & dosage; D054460:rho-Associated Kinases / Q000032:analysis / Q000378:metabolism*; D000099149:Ezrin
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D003598:Cytoskeletal Proteins; D005047:Etoposide; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009020:Morphine; D054460:rho-Associated Kinases; D000099149:Ezrin; C071058:moesin; C071776:radixin; C515854:Rock1 protein, mouse