title: Non-toxic melanoma therapy by a novel tubulin-binding agent.
abstract: (S)-3-((R)-9-bromo-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquino-lin-5-yl)-6,7-dimethoxyisobenzofuran-1(3H)-one (EM011) is a tubulin-binding agent with significant anticancer activity. Here we show that EM011 modulates microtubule dynamics at concentrations that do not alter the total polymer mass of tubulin. In particular, EM011 decreases the transition frequencies between growth and shortening phases and increases the duration microtubules spend in an idle 'pause' state. Using B16LS9 murine melanoma cells, we show that EM011 briefly arrests cell-cycle progression at the G2/M phase by formation of multiple aster spindles. An aberrant mitotic exit without cytokinesis then occurs, leading to the accumulation of abnormal multinucleated cells prior to apoptosis. Our pharmacokinetic studies conformed to a linear dose-response relationship upto 150 mg/kg. However, non-linearity was observed at 300 mg/kg. In a syngeneic murine model of subcutaneous melanoma, better antitumor responses were seen at 150 mg/kg compared to 300 mg/kg of EM011. Unlike currently available chemotherapeutics, EM011 is non-toxic to normal tissues and most importantly, does not cause any immunosuppression and neurotoxicity. Our data thus warrant a clinical evaluation of EM011 for melanoma therapy.
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA 30303, USA. raneja@gsu.edu
authors.forename: Ritu
authors.initials: R
authors.lastname: Aneja
authors.forename: Seneshaw
authors.initials: S
authors.lastname: Asress
authors.forename: Neerupma
authors.initials: N
authors.lastname: Dhiman
authors.forename: Anshumali
authors.initials: A
authors.lastname: Awasthi
authors.forename: Padmashree C G
authors.initials: PC
authors.lastname: Rida
authors.forename: Sudarshan K
authors.initials: SK
authors.lastname: Arora
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Glass
authors.forename: Harish C
authors.initials: HC
authors.lastname: Joshi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use*; D004149:Dioxoles / Q000378:metabolism*; D005260:Female; D007150:Immunohistochemistry; D007546:Isoquinolines / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D014404:Tubulin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D004149:Dioxoles; C510553:EM011 compound; D007546:Isoquinolines; D014404:Tubulin