scholarly journals Overcoming P-Glycoprotein-Mediated Doxorubicin Resistance

2021 ◽  
Author(s):  
Suree Jianmongkol
Keyword(s):  
Cancer Cells ◽  
Multi Drug Resistance ◽  
Therapeutic Success ◽  
Glycoprotein P ◽  
Target Delivery ◽  
Doxorubicin Treatment ◽  
Doxorubicin Resistance ◽  
P Glycoprotein ◽  
Strategic Approach ◽  
Effective Level

Intracellular concentration of doxorubicin in target cancer cells is a major determinant of therapeutic success of doxorubicin-based regimens. As known, doxorubicin is a substrate of P-glycoprotein (P-gp), the drug efflux transporter in the ABC superfamily. High expression level of P-gp in cancer cells can prevent intracellular accumulation of doxorubicin up to its effective level, leading to doxorubicin resistance and treatment failure. Moreover, these P-gp-overexpressed cells display multi-drug resistance (MDR) phenotype. Regarding this, application of P-gp modulators (suppressor of P-gp activity and expression) is likely to reverse MDR and restore cell sensitivity to doxorubicin treatment. In searching for potential chemo-sensitizer against resistant cancer, a number of phytochemicals or dietary compounds have been studied extensively for their P-gp modulating effects. Furthermore, combination between doxorubicin and P-gp modulators (e.g., plant-derived compounds, siRNA) given through specific target delivery platforms have been an effective strategic approach for MDR reversal and restore doxorubicin effectiveness for cancer treatment.

scholarly journals The Effects of TiO2 Nanoparticles on Cisplatin Cytotoxicity in Cancer Cell Lines

2020 ◽  
Vol 21 (2) ◽  
pp. 605 ◽  
Author(s):  
Basma Salama ◽  
El-Said El-Sherbini ◽  
Gehad El-Sayed ◽  
Mohamed El-Adl ◽  
Koki Kanehira ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cancer Cells ◽  
Hepg2 Cells ◽  
Titanium Dioxide Nanoparticles ◽  
Membrane Receptors ◽  
Multi Drug Resistance ◽  
A431 Cells ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Low Expression

There have been many studies on improving the efficacy of cisplatin and on identifying safe compounds that can overcome multi-drug resistance (MDR) acquired by cancer cells. Our previous research showed that polyethylene glycol-modified titanium dioxide nanoparticles (TiO2 PEG NPs) affect cell membrane receptors, resulting in their aggregation, altered localization and downregulation. TiO2 PEG NPs may affect P-glycoprotein (P-gp), a membrane efflux channel involved in MDR. In this study, we investigated the effect of TiO2 PEG NPs on cisplatin cytotoxicity. We used HepG2 cells, which highly express P-gp and A431 cells, which show low expression of P-gp. The results showed that 10 µg/mL 100 nm TiO2 PEG NPs increased intracellular cisplatin levels and cytotoxicity in HepG2 cells but not in A431 cells. TiO2 PEG NPs treatment decreased the expression level of P-gp in HepG2 cells. Our findings indicate that TiO2 PEG NPs enhance cisplatin cytotoxicity by down regulating P-gp and that TiO2 PEG NPs are promising candidates for inhibiting P-gp and reversing drug resistance acquired by cancer cells.

Unsymmetric dihydropyridines bearing 2-pyridyl methyl carboxylate as modulators of P-glycoprotein; synthesis and biological evaluation in resistant and non-resistant cancer cells

2019 ◽  
Vol 97 (8) ◽  
pp. 603-614
Author(s):  
Maryam Nejati ◽  
Hossein Sadeghpour ◽  
Sara Ranjbar ◽  
Katayoun Javidnia ◽  
Najmeh Edraki ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Human Cancer ◽  
Binding Mode ◽  
Biological Evaluation ◽  
Multi Drug Resistance ◽  
Glycoprotein P ◽  
Glycoprotein Synthesis ◽  
Human Cancer Cells ◽  
P Glycoprotein ◽  
Mdr Reversal

Multi-drug resistance (MDR) in cancer cells is often associated with overexpression of P-glycoprotein (P-gp or ABCB1 or MDR1); therefore, modulators of this transporter might be helpful in overcoming MDR. In this study, 16 novel unsymmetrical dihydropyridine (DHP) derivatives bearing 2-pyridyl methyl carboxylate at C3 and a nitroimidazole or nitrophenyl ring at C4 positions of the DHP ring were synthesized. Their cytotoxicity was tested against four human cancer cells by MTT assay. The reversal capacity of MDR was examined in P-gp overexpressing cells (MES-SA/DX5) by measuring the alteration of doxorubicin’s IC50 and performing flow cytometric determination of intracellular rhodamine 123 accumulation. The calcium channel blocking (CCB) activity, as a side effect of DHPs, was tested on the ileum of a guinea pig. Molecular docking was performed to explain the binding mode of compounds. Two derivatives, 4a and 4c, containing 4-nitrophenyl at C4 and possessing methyl (4a) and iso-propyl (4c) carboxylates at the C5 position of DHP core demonstrated superior cytotoxic and MDR reversal activities and lower CCB effect. Docking analysis confirmed the importance of the 4-nitrophenyl ring for P-gp inhibitory activity. Some of the synthesized DHP derivatives with considerable MDR reversal capacity could be promising compounds for further discovery of useful agents for management of drug resistant cancer.

DJ-1 is involved in the multidrug resistance of SGC7901 gastric cancer cells through PTEN/PI3K/Akt/Nrf2 pathway

2020 ◽  
Vol 52 (11) ◽  
pp. 1202-1214
Author(s):  
Lejia Qiu ◽  
Zhaoxia Ma ◽  
Xiaoran Li ◽  
Yizhang Deng ◽  
Guangling Duan ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Multidrug Resistance ◽  
Cancer Cells ◽  
Gastric Cancer Cells ◽  
Glycoprotein P ◽  
Nrf2 Pathway ◽  
P Glycoprotein ◽  
New Findings ◽  
Nrf2 Signaling Pathway ◽  
Common Malignancy

Abstract Gastric cancer is a common malignancy worldwide. The occurrence of multidrug resistance (MDR) is the major obstacle for effective gastric cancer chemotherapy. In this study, the in-depth molecular mechanism of the DJ-1-induced MDR in SGC7901 gastric cancer cells was investigated. The results showed that DJ-1 expression level was higher in MDR variant SGC7901/VCR cells than that in its parental SGC7901 cells. Moreover, DJ-1 overexpression conferred the MDR phenotype to SGC7901 cells, while DJ-1 knockdown in SGC7901/VCR cells induced re-sensitization to adriamycin, vincristine, cisplatin, and 5-fluorouracil. These results suggested that DJ-1 mediated the development of MDR in SGC7901 gastric cancer cells. Importantly, further data revealed that the activation of PI3k/Akt and Nrf2 signaling pathway were required for the DJ-1-induced MDR phenotype in SGC7901 gastric cancer cells. Meanwhile, we found that PI3k/Akt pathway was activated probably through DJ-1 directly binding to and negatively regulating PTEN, consequently resulting in Nrf2 phosphorylation and activation, and thereby inducing Nrf2-dependent P-glycoprotein (P-gp) and Bcl-2 expressions in the DJ-1-mediated MDR of SGC7901 gastric cancer cells. Overall, these results revealed that activating PTEN/PI3K/Akt/Nrf2 pathway and subsequently upregulating P-gp and Bcl-2 expression could be a critical mechanism by which DJ-1 mediates the development of MDR in SGC7901 gastric cancer cells. The new findings may be helpful for understanding the mechanisms of MDR in gastric cancer cells, prompting its further investigation as a molecular target to overcome MDR.

Transferrin receptor-targeted redox/pH-sensitive podophyllotoxin prodrug micelles for multidrug-resistant breast cancer therapy

2019 ◽  
Vol 7 (38) ◽  
pp. 5814-5824 ◽  
Author(s):  
Yongfei Li ◽  
Mie Chen ◽  
Bowen Yao ◽  
Xun Lu ◽  
Xiaoqing Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Therapy ◽  
Cancer Cells ◽  
Transferrin Receptor ◽  
Multidrug Resistant ◽  
Ph Sensitive ◽  
Breast Cancer Therapy ◽  
Glycoprotein P ◽  
P Glycoprotein

Podophyllotoxin (PPT), a toxic polyphenol extracted from the roots of Podophyllum species, showed remarkable activity against P-glycoprotein (P-gp) mediated multidrug resistant (MDR) cancer cells.

Cross-linking of S-nitrosothiolated AIEgen inside cancer cells to monitor NO release and reverse chemo-resistance

2021 ◽  
Author(s):  
Wen WU ◽  
Fan Ying ◽  
Luo Ting Rong ◽  
Yuchen Hu ◽  
Qingyu Zhang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Multidrug Resistance ◽  
Cancer Cells ◽  
Cross Linking ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
No Release

Nitric oxide (NO)-releasing platforms have been demonstrated as promising approaches for the reversal of multidrug resistance (MDR) in cancer cells due to the suppression of P-glycoprotein (P-gp). However, the non-specific...

scholarly journals Homology modelling of human P-glycoprotein

2015 ◽  
Vol 43 (5) ◽  
pp. 952-958 ◽  
Author(s):  
Laura Domicevica ◽  
Philip C. Biggin
Keyword(s):  
Structural Biology ◽  
Conformational Changes ◽  
Homology Modelling ◽  
Md Simulations ◽  
Multi Drug Resistance ◽  
Glycoprotein P ◽  
The Past ◽  
Atp Binding Cassette Transporter ◽  
P Glycoprotein ◽  
Great Progress

P-glycoprotein (P-gp) is an ATP-binding cassette transporter that exports a huge range of compounds out of cells and is thus one of the key proteins in conferring multi-drug resistance in cancer. Understanding how it achieves such a broad specificity and the series of conformational changes that allow export to occur form major, on-going, research objectives around the world. Much of our knowledge to date has been derived from mutagenesis and assay data. However, in recent years, there has also been great progress in structural biology and although the structure of human P-gp has not yet been solved, there are now a handful of related structures on which homology models can be built to aid in the interpretation of the vast amount of experimental data that currently exists. Many models for P-gp have been built with this aim, but the situation is complicated by the apparent flexibility of the system and by the fact that although many potential templates exist, there is large variation in the conformational state in which they have been crystallized. In this review, we summarize how homology modelling has been used in the past, how models are typically selected and finally illustrate how MD simulations can be used as a means to give more confidence about models that have been generated via this approach.

PKD2 mediates multi-drug resistance in breast cancer cells through modulation of P-glycoprotein expression

2011 ◽  
Vol 300 (1) ◽  
pp. 48-56 ◽  
Author(s):  
Jiao Chen ◽  
Libing Lu ◽  
Yun feng ◽  
Hui Wang ◽  
Lila Dai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Multi Drug Resistance ◽  
P Glycoprotein

scholarly journals Screening dietary flavonoids for the reversal of P-glycoprotein-mediated multidrug resistance in cancer

2016 ◽  
Vol 12 (8) ◽  
pp. 2458-2470 ◽  
Author(s):  
S. Mohana ◽  
M. Ganesan ◽  
B. Agilan ◽  
R. Karthikeyan ◽  
G. Srithar ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Cells ◽  
Therapeutic Target ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Dietary Flavonoids

P-Glycoprotein (P-gp) serves as a therapeutic target for the development of inhibitors to overcome multidrug resistance in cancer cells.

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