Isopetasin and S-isopetasin as novel P-glycoprotein inhibitors against multidrug-resistant cancer cells

Abdelfatah, Sara; Böckers, Madeleine; Asensio, Maitane; Kadioglu, Onat; Klinger, Anette; Fleischer, Edmond; Efferth, Thomas

doi:10.1016/j.phymed.2020.153196

Cited by 33 publications

(23 citation statements)

References 45 publications

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“…The resazurin assay [ 40 ] was applied to assess the cytotoxicity of established chemotherapy drugs toward the transfected cell lines. We performed the assay as recently described [ 41 ]. For each compound, three independent repetitions were performed with 72 h treatment.…”

Section: Methodsmentioning

confidence: 99%

Identification of Novel Anthracycline Resistance Genes and Their Inhibitors

et al. 2021

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Differentially expressed genes have been previously identified by us in multidrug-resistant tumor cells mainly resistant to doxorubicin. In the present study, we exemplarily focused on some of these genes to investigate their causative relationship with drug resistance. HMOX1, NEIL2, and PRKCA were overexpressed by lentiviral-plasmid-based transfection of HEK293 cells. An in silico drug repurposing approach was applied using virtual screening and molecular docking of FDA-approved drugs to identify inhibitors of these new drug-resistant genes. Overexpression of the selected genes conferred resistance to doxorubicin and daunorubicin but not to vincristine, docetaxel, and cisplatin, indicating the involvement of these genes in resistance to anthracyclines but not to a broader MDR phenotype. Using virtual drug screening and molecular docking analyses, we identified FDA-approved compounds (conivaptan, bexarotene, and desloratadine) that were interacting with HMOX1 and PRKCA at even stronger binding affinities than 1-(adamantan-1-yl)-2-(1H-imidazol-1-yl)ethenone and ellagic acid as known inhibitors of HMOX1 and PRKCA, respectively. Conivaptan treatment increased doxorubicin sensitivity of both HMOX1- and PRKCA-transfected cell lines. Bexarotene treatment had a comparable doxorubicin-sensitizing effect in HMOX1-transfected cells and desloratadine in PRKCA-transfected cells. Novel drug resistance mechanisms independent of ABC transporters have been identified that contribute to anthracycline resistance in MDR cells.

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Section: Methodsmentioning

confidence: 99%

Identification of Novel Anthracycline Resistance Genes and Their Inhibitors

et al. 2021

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“…The P-gp modulation of artemisinin and its derivatives have been reviewed by Wang and co-authors ( Yulin Wang et al., 2019 ). Isopetasin and S -isopetasin, additional sesquiterpenes isolated from Petasites formosanus , have dual roles in anticancer therapy: P-gp inhibition and cytotoxicity ( Abdelfatah et al., 2020 ). Abdelfatah and co-workers have reported high affinity binding at key amino acids on the P-gp transporter in silico .…”

Section: P-gp Inhibitors Investigated For Chemosensitization In Mdr Bcmentioning

confidence: 99%

“…P-gp inhibition increases the mitochondrial workload, thus generating more ATP in the MDA-MB-231 cell line. The prolonged stress on the mitochondria leads to ROS production, thus eventually resulting in cell death ( Abdelfatah et al., 2020 ). Boswellic acid, a pentacyclic terpenoid, modulates the P-gp transporter ( Weber et al., 2006 ).…”

Section: P-gp Inhibitors Investigated For Chemosensitization In Mdr Bcmentioning

confidence: 99%

Exploring new Horizons in overcoming P-glycoprotein-mediated multidrug-resistant breast cancer via nanoscale drug delivery platforms

Famta

Shah

Chatterjee

et al. 2021

Current Research in Pharmacology and Drug Discovery

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The high probability (13%) of women developing breast cancer in their lifetimes in America is exacerbated by the emergence of multidrug resistance after exposure to first-line chemotherapeutic agents. Permeation glycoprotein (P-gp)-mediated drug efflux is widely recognized as the major driver of this resistance. Initial in vitro and in vivo investigations of the co-delivery of chemotherapeutic agents and P-gp inhibitors have yielded satisfactory results; however, these results have not translated to clinical settings. The systemic delivery of multiple agents causes adverse effects and drug–drug interactions, and diminishes patient compliance. Nanocarrier-based site-specific delivery has recently gained substantial attention among researchers for its promise in circumventing the pitfalls associated with conventional therapy. In this review article, we focus on nanocarrier-based co-delivery approaches encompassing a wide range of P-gp inhibitors along with chemotherapeutic agents. We discuss the contributions of active targeting and stimuli responsive systems in imparting site-specific cytotoxicity and reducing both the dose and adverse effects.

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“…The cytotoxic effects of compounds on drug-sensitive leukemia CCRF-CEM and multidrug-resistant P-glycoprotein-overexpressing CEM/ADR5000 cells were evaluated by the resazurin assay as previously described. [29][30][31][32][33] All compounds were first tested at a single concentration of 10 µM (Figure 2) against CCRF-CEM and CEM/ADR5000 cells. Compounds 3a, 3e, and 3b, which significantly inhibited cell viability (reduction to less than 10% growth) were further tested in a concentration range from 0.001 to 10 µM to determine the 50% inhibitory concentrations (for IC 50 ) in both, CCRF-CEM and CEM/ ADR5000 cell lines.…”

Section: Resazurin Reduction Assaymentioning

confidence: 99%

Synthesis and Cytotoxicity of Thieno[2,3-b]Pyridine Derivatives Toward Sensitive and Multidrug-Resistant Leukemia Cells

Al-Trawneh¹,

Taráwneh²,

Gadetskaya³

et al. 2021

ACSi

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A new series of substituted ethyl 7-cyclopropyl-2-(2-aryloxo)-3-nitro-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylates 3a–e were prepared by utilizing ethyl 2-chloro-7-cyclopropyl-3-nitro-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate (1) and replacing of the 2-chlorine with anions obtained from phenol (2a), salicylaldehyde derivatives 2b–d or thiophenol (2e), leading to the respective ethyl 7-cyclopropyl-2-(2-aryloxo)-3-nitro-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylates 3a–e. The new compounds were evaluated for their in vitro cytotoxicity towards sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 leukemia cells. The screening revealed that compounds 3a, 3b, and 3e inhibited the growth of both cell lines. Compound 3b, with a phenol moiety, exhibited the highest growth inhibitory activity against CEM/ADR5000 and CCRF-CEM cells with IC50 values 4.486 ± 0.286 and 2.580 ± 0.550 μM, respectively. Collectively, the presented results demonstrate that the synthesized thieno[2,3-b]pyridines warrant further exploration for potential use as anti-cancer agents.

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Isopetasin and S-isopetasin as novel P-glycoprotein inhibitors against multidrug-resistant cancer cells

Cited by 33 publications

References 45 publications

Identification of Novel Anthracycline Resistance Genes and Their Inhibitors

Identification of Novel Anthracycline Resistance Genes and Their Inhibitors

Exploring new Horizons in overcoming P-glycoprotein-mediated multidrug-resistant breast cancer via nanoscale drug delivery platforms

Synthesis and Cytotoxicity of Thieno[2,3-b]Pyridine Derivatives Toward Sensitive and Multidrug-Resistant Leukemia Cells

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