Novel Symmetrical Cage Compounds as Inhibitors of the Symmetrical MRP4-Efflux Pump for Anticancer Therapy

Within the last decades cancer treatment improved by the availability of more specifically acting drugs that address molecular target structures in cancer cells. However, those target-sensitive drugs suffer from ongoing resistances resulting from mutations and moreover they are affected by the cancer phenomenon of multidrug resistance. A multidrug resistant cancer can hardly be treated with the common drugs, so that there have been long efforts to develop drugs to combat that resistance. Transmembrane efflux pumps are the main cause of the multidrug resistance in cancer. Early inhibitors disappointed in cancer treatment without a proof of expression of a respective efflux pump. Recent studies in efflux pump expressing cancer show convincing effects of those inhibitors. Based on the molecular symmetry of the efflux pump multidrug resistant protein (MRP) 4 we synthesized symmetric inhibitors with varied substitution patterns. They were evaluated in a MRP4-overexpressing cancer cell line model to prove structure-dependent effects on the inhibition of the efflux pump activity in an uptake assay of a fluorescent MRP4 substrate. The most active compound was tested to resentisize the MRP4-overexpressing cell line towards a clinically relevant anticancer drug as proof-of-principle to encourage for further preclinical studies.

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Enhancing the Therapeutic Efficacy of Daunorubicin and Mitoxantrone with Bavachinin, Candidone, and Tephrosin

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/3291737 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Sina Darzi ◽

Seyed Abbas Mirzaei ◽

Fatemeh Elahian ◽

Sadegh Shirian ◽

Amir Peymani ◽

...

Keyword(s):

Multidrug Resistance ◽

Cancer Treatment ◽

Cell Line ◽

Cell Lines ◽

Cancer Cell Line ◽

Multidrug Resistant ◽

Resistant Cell ◽

Dependent Manner ◽

Expression Levels ◽

Treatment Research

The capability of flavonoids in sensitizing cancer cells was demonstrated in numerous works to chemotherapy and converse multidrug resistance by modulating efflux pumps and apoptosis mechanisms. Three flavonoids, namely, bavachinin, tephrosin, and candidone, have been recently introduced to cancer treatment research presenting various activities, such as antibacterial, immunomodulatory, cell death, and anticancer. Less information exists regarding the therapeutic significance of these flavonoids in cancer treatment, especially in overcoming multidrug resistance (MDR). Here, we tempted to investigate the potency of these agents in reversing MDR by analyzing their effects as chemosensitizers on cell cytotoxicity, P-gp and ABCG2 protein expression levels, and their function on two multidrug-resistant cell lines, P-gp-overexpressing human gastric adenocarcinoma cell line (EPG85.257RDB) and ABCG2-overexpressing human epithelial breast cancer cell line (MCF7/MX). The inhibitory concentration of 10% (IC10) of bavachinin, tephrosin, and candidone in EPG85.257RDB cells was 1588.7 ± 202.2, 264.8 ± 86.15, and 1338.6 ± 114.11 nM, respectively. Moreover, these values in MCF7/MX cell were 2406.4 ± 257.63, 38.8 ± 4.28, and 27.9 ± 5.59 nM, respectively. Expression levels of ABCG2 and P-gp were not significantly downregulated by these flavonoids. Maximum levels of daunorubicin and mitoxantrone accumulations and minimum rates of drug efflux in both cell lines were detected 48 hrs posttreatment with tephrosin and bavachinin, respectively. Chemosensitization to mitoxantrone and daunorubicin treatments was, respectively, achieved in MCF7/MX and EPG85.257RDB cells in response to IC10 of bavachinin and tephrosin, independently. These effects did not follow time-dependent manner, and each flavonoid had its cell-dependent patterns. Overall, bavachinin, tephrosin, and candidone showed potency to sensitize MDR cells to daunorubicin and mitoxantrone and could be considered as attractive MDR modulators for cancer treatment. However, their action was time and cell specific.

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Antimicrobial, Anticancer and Multidrug-Resistant Reversing Activity of Novel Oxygen-, Sulfur- and Selenoflavones and Bioisosteric Analogues

Pharmaceuticals ◽

10.3390/ph13120453 ◽

2020 ◽

Vol 13 (12) ◽

pp. 453

Author(s):

Małgorzata Anna Marć ◽

Annamária Kincses ◽

Bálint Rácz ◽

Muhammad Jawad Nasim ◽

Muhammad Sarfraz ◽

...

Keyword(s):

Multidrug Resistance ◽

Cancer Treatment ◽

Efflux Pump ◽

Multidrug Resistant ◽

Positive Control ◽

Biological Evaluation ◽

Glycoprotein P ◽

Drug Candidates ◽

P Glycoprotein ◽

Efflux Pump Inhibitors

Multidrug resistance of cancer cells to cytotoxic drugs still remains a major obstacle to the success of chemotherapy in cancer treatment. The development of new drug candidates which may serve as P-glycoprotein (P-gp) efflux pump inhibitors is a promising strategy. Selenium analogues of natural products, such as flavonoids, offer an interesting motif from the perspective of drug design. Herein, we report the biological evaluation of novel hybrid compounds, bearing both the flavone core (compounds 1–3) or a bioisosteric analogue core (compounds 4–6) and the triflyl functional group against Gram-positive and Gram-negative bacteria, yeasts, nematodes, and human colonic adenocarcinoma cells. Results show that these flavones and analogues of flavones inhibited the activity of multidrug resistance (MDR) efflux pump ABCB1 (P-glycoprotein, P-gp). Moreover, the results of the rhodamine 123 accumulation assay demonstrated a dose-dependent inhibition of the abovementioned efflux pump. Three compounds (4, 5, and 6) exhibited potent inhibitory activity, much stronger than the positive control, verapamil. Thus, these chalcogen bioisosteric analogues of flavones become an interesting class of compounds which could be considered as P-gp efflux pump inhibitors in the therapy of MDR cancer. Moreover, all the compounds served as promising adjuvants in the cancer treatment, since they exhibited the P-gp efflux pump modulating activity.

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Modulation of multidrug resistance by andrographolid in a HCT-8/5-FU multidrug-resistant colorectal cancer cell line

Chinese Journal of Digestive Diseases ◽

10.1111/j.1443-9573.2005.00197.x ◽

2005 ◽

Vol 6 (2) ◽

pp. 82-86 ◽

Cited By ~ 18

Author(s):

Ying HAN ◽

Li Min BU ◽

Xin JI ◽

Chun Yan LIU ◽

Zhi Hong WANG

Keyword(s):

Colorectal Cancer ◽

Multidrug Resistance ◽

Cell Line ◽

Cancer Cell ◽

Cancer Cell Line ◽

Multidrug Resistant ◽

Colorectal Cancer Cell ◽

Colorectal Cancer Cell Line

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Discovery of Novel Symmetrical 1,4-Dihydropyridines as Inhibitors of Multidrug-Resistant Protein (MRP4) Efflux Pump for Anticancer Therapy

Molecules ◽

10.3390/molecules26010018 ◽

2020 ◽

Vol 26 (1) ◽

pp. 18

Author(s):

Henry Döring ◽

David Kreutzer ◽

Christoph Ritter ◽

Andreas Hilgeroth

Keyword(s):

Cell Line ◽

Efflux Pump ◽

Metastatic Cancer ◽

Efflux Pumps ◽

Multidrug Resistant ◽

Clinical Settings ◽

Glycoprotein P ◽

P Glycoprotein ◽

Overexpressing Cell ◽

Molecular Framework

Despite the development of targeted therapies in cancer, the problem of multidrug resistance (MDR) is still unsolved. Most patients with metastatic cancer die from MDR. Transmembrane efflux pumps as the main cause of MDR have been addressed by developed inhibitors, but early inhibitors of the most prominent and longest known efflux pump P-glycoprotein (P-gp) were disappointing. Those inhibitors have been used without knowledge about the expression of P-gp by the treated tumor. Therefore the use of inhibitors of transmembrane efflux pumps in clinical settings is reconsidered as a promising strategy in the case of the respective efflux pump expression. We discovered novel symmetric inhibitors of the symmetric efflux pump MRP4 encoded by the ABCC4 gene. MRP4 is involved in many kinds of cancer with resistance to anticancer drugs. All compounds showed better activities than the best known MRP4 inhibitor MK571 in an MRP4-overexpressing cell line assay, and the activities could be related to the various substitution patterns of aromatic residues within the symmetric molecular framework. One of the best compounds was demonstrated to overcome the MRP4-mediated resistance in the cell line model to restore the anticancer drug sensitivity as a proof of concept.

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Hexasaccharide resin glycosides from the jalap roots as modulators of multidrug resistance in MCF-7 cancer cell line

Planta Medica ◽

10.1055/s-0034-1382493 ◽

2014 ◽

Vol 80 (10) ◽

Author(s):

E Bautista ◽

M Fragoso ◽

R Pereda-Miranda

Keyword(s):

Multidrug Resistance ◽

Cell Line ◽

Cancer Cell ◽

Cancer Cell Line ◽

Mcf 7

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Proteomic analysis of multidrug-resistance mechanisms in adriamycin-resistant variants of DLKP, a squamous lung cancer cell line

PROTEOMICS ◽

10.1002/pmic.200800633 ◽

2009 ◽

Vol 9 (6) ◽

pp. 1556-1566 ◽

Cited By ~ 35

Author(s):

Joanne Keenan ◽

Lisa Murphy ◽

Michael Henry ◽

Paula Meleady ◽

Martin Clynes

Keyword(s):

Lung Cancer ◽

Multidrug Resistance ◽

Cell Line ◽

Cancer Cell ◽

Proteomic Analysis ◽

Cancer Cell Line ◽

Resistance Mechanisms ◽

Lung Cancer Cell Line ◽

Lung Cancer Cell ◽

Squamous Lung Cancer

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Establishment and Characterization of a Novel Multidrug Resistant Human Ovarian Cancer Cell Line With Heterogenous MRP7 Overexpression

Frontiers in Oncology ◽

10.3389/fonc.2021.731260 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jing-Quan Wang ◽

Zhuo-Xun Wu ◽

Yuqi Yang ◽

Jin-Sui Li ◽

Dong-Hua Yang ◽

...

Keyword(s):

Ovarian Cancer ◽

Multidrug Resistance ◽

Cell Line ◽

Anticancer Drugs ◽

Cancer Cell ◽

Ovarian Cancer Cell ◽

Ovarian Cancer Cell Line ◽

Cancer Cell Line ◽

Chemotherapeutic Drugs ◽

Mesenchymal Transition

Ovarian cancer is one of the leading female malignancies which accounts for the highest mortality rate among gynecologic cancers. Surgical cytoreduction followed by chemotherapy is the mainstay of treatment. However, patients with recurrent ovarian cancer are likely to exhibit resistance to chemotherapy due to reduced sensitivity to chemotherapeutic drugs. Adenosine triphosphate (ATP)-binding cassette (ABC) transporters have been extensively studied as multidrug resistance (MDR) mediators since they are responsible for the efflux of various anticancer drugs. Multidrug resistance protein 7 (MRP7, or ABCC10) was discovered in 2001 and revealed to transport chemotherapeutic drugs. Till now, only limited knowledge was obtained regarding its roles in ovarian cancer. In this study, we established an MRP7-overexpressing ovarian cancer cell line SKOV3/MRP7 via transfecting recombinant MRP7 plasmids. The SKOV3/MRP7 cell line was resistant to multiple anticancer drugs including paclitaxel, docetaxel, vincristine and vinorelbine with a maximum of 8-fold resistance. Biological function of MRP7 protein was further determined by efflux-accumulation assays. Additionally, MTT results showed that the drug resistance of the SKOV3/MRP7 cells was reversed by cepharanthine, a known inhibitor of MRP7. Moreover, we also found that the overexpression of MRP7 enhanced the migration and epithelial-mesenchymal transition (EMT) induction. In conclusion, we established an in vitro model of MDR in ovarian cancer and suggested MRP7 overexpression as the leading mechanism of chemoresistance in this cell line. Our results demonstrated the potential relationship between MRP7 and ovarian cancer MDR.

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