N-alkylated isatins evade P-gp mediated efflux and retain potency in MDR cancer cell lines
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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2016-01-01
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| Series: | Heliyon |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S240584401530445X |
| _version_ | 1811269391922233344 |
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| author | Kara L. Vine Lisa Belfiore Luke Jones Julie M. Locke Samantha Wade Elahe Minaei Marie Ranson |
| author_facet | Kara L. Vine Lisa Belfiore Luke Jones Julie M. Locke Samantha Wade Elahe Minaei Marie Ranson |
| author_sort | Kara L. Vine |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T21:41:12Z |
| format | Article |
| id | doaj.art-85e6a5bd64de42fa9610062895bfa467 |
| institution | Directory Open Access Journal |
| issn | 2405-8440 |
| language | English |
| last_indexed | 2024-04-12T21:41:12Z |
| publishDate | 2016-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj.art-85e6a5bd64de42fa9610062895bfa4672022-12-22T03:15:46ZengElsevierHeliyon2405-84402016-01-012110.1016/j.heliyon.2015.e00060N-alkylated isatins evade P-gp mediated efflux and retain potency in MDR cancer cell linesKara L. Vine0Lisa Belfiore1Luke Jones2Julie M. Locke3Samantha Wade4Elahe Minaei5Marie Ranson6Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, AustraliaIllawarra Health and Medical Research Institute, University of Wollongong, Wollongong, AustraliaIllawarra Health and Medical Research Institute, University of Wollongong, Wollongong, AustraliaIntelligent Polymer Research Institute, University of Wollongong, Wollongong, AustraliaIllawarra Health and Medical Research Institute, University of Wollongong, Wollongong, AustraliaIllawarra Health and Medical Research Institute, University of Wollongong, Wollongong, AustraliaIllawarra Health and Medical Research Institute, University of Wollongong, Wollongong, AustraliaThe 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.http://www.sciencedirect.com/science/article/pii/S240584401530445XMedicinal chemistryCancer treatmentCell biology |
| spellingShingle | Kara L. Vine Lisa Belfiore Luke Jones Julie M. Locke Samantha Wade Elahe Minaei Marie Ranson N-alkylated isatins evade P-gp mediated efflux and retain potency in MDR cancer cell lines Heliyon Medicinal chemistry Cancer treatment Cell biology |
| title | N-alkylated isatins evade P-gp mediated efflux and retain potency in MDR cancer cell lines |
| title_full | N-alkylated isatins evade P-gp mediated efflux and retain potency in MDR cancer cell lines |
| title_fullStr | N-alkylated isatins evade P-gp mediated efflux and retain potency in MDR cancer cell lines |
| title_full_unstemmed | N-alkylated isatins evade P-gp mediated efflux and retain potency in MDR cancer cell lines |
| title_short | N-alkylated isatins evade P-gp mediated efflux and retain potency in MDR cancer cell lines |
| title_sort | n alkylated isatins evade p gp mediated efflux and retain potency in mdr cancer cell lines |
| topic | Medicinal chemistry Cancer treatment Cell biology |
| url | http://www.sciencedirect.com/science/article/pii/S240584401530445X |
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