title: In vitro moxifloxacin drug interaction with chemotherapeutics: implications for retinoblastoma management.
abstract: Retinoblastoma (RB) is a common malignant intraocular tumor primarily affecting children. Multidrug resistance (MDR) proteins (P-gp and MRPs) mediated chemoresistance have been considered as a major cause of treatment failure in treatment of RB. Ocular cells have shown good tolerability against moxifloxacin (MFX). Hence, the aim of present study was to investigate the effect of moxifloxacin on the functionality of MDR proteins. Furthermore, we have also examined an interaction of MFX with anticancer agents (Topotecan, etoposide and vinblastine) for RB treatment. For interaction of MFX with efflux transporter, model cell lines transfected with the efflux transporters (MDCK-MDR1 and MDCK-MRP2) were used to perform uptake and bi-directional transport experiments. Modulation of anticancer induced cell cytotoxicity, pro-inflammatory cytokines (IL-6 and IL-8) release and caspase-3 enzyme activity in presence of MFX was also evaluated. Result indicates that MFX is a substrate of both MDR1 and MRP2 efflux transporters. Furthermore elevation of anticancer uptake and bi-directional transport, reduction in IC50 cytotoxic value and modulation of antiproliferative and cytokines release in presence of MFX by anticancer agents was observed. Our results demonstrate that MFX may not only modulate the permeability of anticancer agents at efflux sites but it may also potentiate antiproliferative activity of anticancer agents in retinoblastoma cells. This study may be further extended to explore in vivo outcome of this finding.
authors.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri - Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA.
authors.forename: Megha
authors.initials: M
authors.lastname: Barot
authors.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri - Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA.
authors.forename: Mitan R
authors.initials: MR
authors.lastname: Gokulgandhi
authors.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri - Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA.
authors.forename: Dhananjay
authors.initials: D
authors.lastname: Pal
authors.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri - Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA. Electronic address: mitraa@umkc.edu.
authors.forename: Ashim K
authors.initials: AK
authors.lastname: Mitra
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001372:Aza Compounds / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002648:Child; D004347:Drug Interactions; D024841:Fluoroquinolones; D006801:Humans; D000077266:Moxifloxacin; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D011804:Quinolines / Q000627:therapeutic use*; D019572:Retinal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012175:Retinoblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D000077266:Moxifloxacin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011804:Quinolines
keywords: anticancer agents; moxifloxacin; multidrug resistant (MDR); retinoblastoma