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N-alkylated isatins evade P-gp mediated efflux and retain potency in MDR cancer cell lines

Journal Article


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


  •   Vine, Kara L.
  •   Belfiore, Lisa (external author)
  •   Jones, Luke A. (external author)
  •   Locke, Julie M. (external author)
  •   Wade, Samantha (external author)
  •   Minaei, Elahe
  •   Ranson, Marie

Publication Date


  • 2016

Citation


  • Vine, K. L., Belfiore, L., Jones, L., Locke, J. M., Wade, S., Minaei, E. & Ranson, M. (2016). N-alkylated isatins evade P-gp mediated efflux and retain potency in MDR cancer cell lines. Heliyon, 2 (1), e00060-1-e00060-23.

Scopus Eid


  • 2-s2.0-84956685832

Start Page


  • e00060-1

End Page


  • e00060-23

Volume


  • 2

Issue


  • 1

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


  •   Vine, Kara L.
  •   Belfiore, Lisa (external author)
  •   Jones, Luke A. (external author)
  •   Locke, Julie M. (external author)
  •   Wade, Samantha (external author)
  •   Minaei, Elahe
  •   Ranson, Marie

Publication Date


  • 2016

Citation


  • Vine, K. L., Belfiore, L., Jones, L., Locke, J. M., Wade, S., Minaei, E. & Ranson, M. (2016). N-alkylated isatins evade P-gp mediated efflux and retain potency in MDR cancer cell lines. Heliyon, 2 (1), e00060-1-e00060-23.

Scopus Eid


  • 2-s2.0-84956685832

Start Page


  • e00060-1

End Page


  • e00060-23

Volume


  • 2

Issue


  • 1