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

Vine, Kara L.; Belfiore, Lisa; Jones, Luke; Locke, Julie M.; Wade, Samantha J.; Minaei, Elahe; Ranson, Marie

doi:10.1016/j.heliyon.2015.e00060

Cited by 19 publications

(14 citation statements)

References 36 publications

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“…Keywords: Chemotherapy, Multi-drug resistance, N-alkylisatin, P-glycoprotein, Neurotoxicity, Acute lymphoblastic leukemia uterine sarcoma and vinblastine resistant lymphoma cell lines [30]. While preliminary investigations into the potential binding site of the N-alkylisatins on tubulin have been performed, it remains unknown whether this class of molecules bind at a known site, or exploit a novel site on tubulin.…”

Section: Discussionmentioning

confidence: 99%

N-alkylisatin-based microtubule destabilizers bind to the colchicine site on tubulin and retain efficacy in drug resistant acute lymphoblastic leukemia cell lines with less in vitro neurotoxicity

et al. 2020

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Background: Drug resistance and chemotherapy-induced peripheral neuropathy continue to be significant problems in the successful treatment of acute lymphoblastic leukemia (ALL). 5,7-Dibromo-N-alkylisatins, a class of potent microtubule destabilizers, are a promising alternative to traditionally used antimitotics with previous demonstrated efficacy against solid tumours in vivo and ability to overcome P-glycoprotein (P-gp) mediated drug resistance in lymphoma and sarcoma cell lines in vitro. In this study, three di-brominated N-alkylisatins were assessed for their ability to retain potency in vincristine (VCR) and 2-methoxyestradiol (2ME2) resistant ALL cell lines. For the first time, in vitro neurotoxicity was also investigated in order to establish their suitability as candidate drugs for future use in ALL treatment. Methods: Vincristine resistant (CEM-VCR R) and 2-methoxyestradiol resistant (CEM/2ME2-28.8R) ALL cell lines were used to investigate the ability of N-alkylisatins to overcome chemoresistance. Interaction of N-alkylisatins with tubulin at the the colchicine-binding site was studied by competitive assay using the fluorescent colchicine analogue MTC. Human neuroblastoma SH-SY5Y cells differentiated into a morphological and functional dopaminergic-like neurotransmitter phenotype were used for neurotoxicity and neurofunctional assays. Two-way ANOVA followed by a Tukey's post hoc test or a two-tailed paired t test was used to determine statistical significance. Results: CEM-VCR R and CEM/2ME2-28.8R cells displayed resistance indices of > 100 to VCR and 2-ME2, respectively. CEM-VCR R cells additionally displayed a multi-drug resistant phenotype with significant cross resistance to vinblastine, 2ME2, colchicine and paclitaxel consistent with P-gp overexpression. Despite differences in resistance mechanisms observed between the two cell lines, the N-alkylisatins displayed bioequivalent dose-dependent cytotoxicity to that of the parental control cell line. The N-alkylisatins proved to be significantly less neurotoxic towards differentiated SH-SY5Y cells than VCR and vinblastine, evidenced by increased neurite length and number of neurite branch points. Neuronal cells treated with 5,7-dibromo-N-(p-hydroxymethylbenzyl)isatin showed significantly higher voltage-gated

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Section: Discussionmentioning

confidence: 99%

N-alkylisatin-based microtubule destabilizers bind to the colchicine site on tubulin and retain efficacy in drug resistant acute lymphoblastic leukemia cell lines with less in vitro neurotoxicity

et al. 2020

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“…Experiments were performed as described in [ 22 ] with the following modifications. Cells in complete medium in 96-well flat bottom plates (5 × 10 3 cells/100 μ L/well) were incubated overnight at 37°C/5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

N-Alkyl-Substituted Isatins Enhance P2X7 Receptor-Induced Interleukin-1βRelease from Murine Macrophages

Sluyter

Vine

2016

Mediators of Inflammation

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Extracellular adenosine 5′-triphosphate (ATP) activates the P2X7 receptor channel to induce the rapid release of the proinflammatory cytokine, interleukin- (IL-) 1β, from macrophages. Microtubule rearrangements are thought to be involved in this process. Some isatin derivatives alter microtubules and display anticancer activities. The current study investigated the effect of isatin and seven structurally diverse isatin derivatives on P2X7-mediated IL-1β release from murine J774 macrophages. ATP-induced IL-1β and lactate dehydrogenase (LDH) release were assessed by specific colorimetric assays. P2X7 activity was determined by flow cytometric measurements of ATP-induced cation dye uptake. Cytotoxicity of isatin derivatives was determined using a tetrazolium-based colorimetric assay. ATP caused rapid IL-1β release in a concentration-dependent manner, and this process was completely impaired by the P2X7 antagonist, AZ10606120. In contrast, 5,7-dibromo-N-(p-methoxybenzyl)isatin (NAI) and 3-{4-[5,7-dibromo-1-(4-methoxybenzyl)-2-oxoindolin-3-ylidenamino]phenyl}propanoic acid (NAI-imine) enhanced P2X7-induced IL-1β release by twofold compared to that of isatin and the parent molecule, 5,7-dibromoisatin. NAI and NAI-imine had minimal effect on P2X7-induced dye uptake and LDH release. In contrast, 24-hour incubation with NAI and NAI-imine (in the absence of exogenous ATP) induced macrophage death in a concentration-dependent manner. In conclusion, this study demonstrates that N-alkyl-substituted isatins enhance P2X7 receptor-induced IL-1β release from murine macrophages. Thus, in addition to direct anticancer effects, these compounds may also impact inflammatory and immune cells within the tumor microenvironment.

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“…has shown the potency of the N-alkyl isatin derivatives against the multidrug-resistant cell lines, viz., U937VbR and MES-SA/Dx5, and observed bioequivalent dose-dependent cytotoxicity to that of the parental control cell lines. 21 In vitro selective inhibition of aldehyde dehydrogenase has also been reported for the N-substituted isatin–piperazine derivative. 22 Many isatin derivatives have also been evaluated for their antimicrobial potential with isatin-β-thiosemicarbazones exhibiting minimum inhibitory concentration (MIC) of 0.78 and 0.39 mg/L against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus .…”

Section: Introductionmentioning

confidence: 91%

Synthesis and Preliminary Antimicrobial Analysis of Isatin–Ferrocene and Isatin–Ferrocenyl Chalcone Conjugates

et al. 2018

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In this study, we outline the synthesis of isatin–ferrocenyl chalcone and 1H-1,2,3-triazole-tethered isatin–ferrocene conjugates along with their antimicrobial evaluation against the human mucosal pathogen Trichomonas vaginalis. The introduction of a triazole ring among the synthesized conjugates improved the activity profiles with most of the compounds in the library, exhibiting 100% growth inhibition in a preliminary susceptibility screen at 100 μM. IC50 determination of the most potent compounds in the set revealed an inhibitory range between 2 and 13 μM. Normal flora microbiome are unaffected by these compounds, suggesting that these may be new chemical scaffolds for the discovery of new drugs against trichomonad infections.

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

Cited by 19 publications

References 36 publications

N-alkylisatin-based microtubule destabilizers bind to the colchicine site on tubulin and retain efficacy in drug resistant acute lymphoblastic leukemia cell lines with less in vitro neurotoxicity

N-alkylisatin-based microtubule destabilizers bind to the colchicine site on tubulin and retain efficacy in drug resistant acute lymphoblastic leukemia cell lines with less in vitro neurotoxicity

N-Alkyl-Substituted Isatins Enhance P2X7 Receptor-Induced Interleukin-1βRelease from Murine Macrophages

Synthesis and Preliminary Antimicrobial Analysis of Isatin–Ferrocene and Isatin–Ferrocenyl Chalcone Conjugates

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