title: N-alkylated isatins evade P-gp mediated efflux and retain potency in MDR cancer cell lines.
abstract: The search for novel anticancer therapeutics with the ability to overcome multi-drug resistance (MDR) mechanisms is of high priority. A class of molecules that show potential in overcoming MDR are the N-alkylated isatins. In particular 5,7-dibromo-N-alkylisatins are potent microtubule destabilizing agents that act to depolymerize microtubules, induce apoptosis and inhibit primary tumor growth in vivo. In this study we evaluated the ability of four dibrominated N-alkylisatin derivatives and the parent compound, 5,7-dibromoisatin, to circumvent MDR. All of the isatin-based compounds examined retained potency against the MDR cell lines; U937VbR and MES-SA/Dx5 and displayed bioequivalent dose-dependent cytotoxicity to that of the parental control cell lines. We show that one mechanism by which the isatin-based compounds overcome MDR is by circumventing P-glycoprotein (P-gp) mediated drug efflux. Thus, as the isatin-based compounds are not susceptible to extrusion from P-gp overexpressing tumor cells, they represent a promising alternative strategy as a stand-alone or combination therapy for treating MDR cancer.
authors.affiliation: Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australia; Centre for Medical and Molecular Bioscience, University of Wollongong, Wollongong, Australia; School of Biological Sciences, University of Wollongong, Wollongong, Australia.
authors.forename: Kara L
authors.initials: KL
authors.lastname: Vine
authors.affiliation: Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australia; Centre for Medical and Molecular Bioscience, University of Wollongong, Wollongong, Australia; School of Biological Sciences, University of Wollongong, Wollongong, Australia.
authors.forename: Lisa
authors.initials: L
authors.lastname: Belfiore
authors.affiliation: Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australia; Centre for Medical and Molecular Bioscience, University of Wollongong, Wollongong, Australia; School of Biological Sciences, University of Wollongong, Wollongong, Australia.
authors.forename: Luke
authors.initials: L
authors.lastname: Jones
authors.affiliation: Intelligent Polymer Research Institute, University of Wollongong, Wollongong, Australia; Australian Institute for Innovative Materials, University of Wollongong, Wollongong, Australia.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Locke
authors.affiliation: Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australia; Centre for Medical and Molecular Bioscience, University of Wollongong, Wollongong, Australia; School of Biological Sciences, University of Wollongong, Wollongong, Australia.
authors.forename: Samantha
authors.initials: S
authors.lastname: Wade
authors.affiliation: Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australia; Centre for Medical and Molecular Bioscience, University of Wollongong, Wollongong, Australia; School of Biological Sciences, University of Wollongong, Wollongong, Australia.
authors.forename: Elahe
authors.initials: E
authors.lastname: Minaei
authors.affiliation: Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australia; Centre for Medical and Molecular Bioscience, University of Wollongong, Wollongong, Australia; School of Biological Sciences, University of Wollongong, Wollongong, Australia.
authors.forename: Marie
authors.initials: M
authors.lastname: Ranson
keywords: Cancer treatment; Cell biology; Medicinal chemistry