Cordycepin re-sensitizes multidrug resistance cancer cells to chemotherapeutic agents through modulating P-glycoprotein expression and ATPase function

2016 ◽  
Vol 26 ◽  
pp. 681-690 ◽  
Author(s):  
Yu-Ning Teng ◽  
Chih-Shiang Chang ◽  
Tsui-Er Lee ◽  
Chin-Chuan Hung
Keyword(s):  
Multidrug Resistance ◽  
Cancer Cells ◽  
Chemotherapeutic Agents ◽  
P Glycoprotein

scholarly journals Tetrandrine Interaction with ABCB1 Reverses Multidrug Resistance in Cancer Cells Through Competition with Anti-Cancer Drugs Followed by Downregulation of ABCB1 Expression

Molecules ◽  
2019 ◽  
Vol 24 (23) ◽  
pp. 4383 ◽  
Author(s):  
Dan Liao ◽  
Wei Zhang ◽  
Pranav Gupta ◽  
Zi-Ning Lei ◽  
Jing-Quan Wang ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Cells ◽  
Anticancer Drugs ◽  
Cellular Localization ◽  
Treatment Time ◽  
Mrna Level ◽  
Chemotherapeutic Agents ◽  
Mdr1 Gene ◽  
P Glycoprotein ◽  
Abcb1 Transporter

The overexpression of ABC transporters induced by anticancer drugs has been found to be the main cause of multidrug resistance. It is actually also a strategy by which cancer cells escape being killed. Tetrandrine is a natural product extracted from the stem of Tinospora crispa. In this study, tetrandrine showed synergistic cytotoxic activity in combinational use with chemotherapeutic drugs, such as Doxorubicin, Vincristine, and Paclitaxel, in both drug-induced and MDR1 gene-transfected cancer cells that over-expressed ABCB1/P-glycoprotein. Tetrandrine stimulated P-glycoprotein ATPase activity, decreased the efflux of [3H]-Paclitaxel and increased the intracellular accumulation of [3H]-Paclitaxel in KB-C2 cells. Furthermore, SW620/Ad300 and KB-C2 cells pretreated with 1 μM tetrandrine for 72 h decreased P-glycoprotein expression without changing its cellular localization. This was demonstrated through Western blotting and immunofluorescence analysis. Interestingly, down-regulation of P-glycoprotein expression was not correlated with gene transcription, as the MDR1 mRNA level exhibited a slight fluctuation in SW620/Ad300 and KB-C2 cells at 0, 24, 48, and 72 h treatment time points. In addition, molecular docking analysis predicted that tetrandrine had inhibitory potential with the ABCB1 transporter. Our results suggested that tetrandrine can antagonize MDR in both drug-selected and MDR1 gene-transfected cancer cells by down regulating the expression of the ABCB1 transporter, followed by increasing the intracellular concentration of chemotherapeutic agents. The combinational therapy using tetrandrine and other anticancer drugs could promote the treatment efficiency of drugs that are substrates of ABCB1.

scholarly journals Euryops pectinatus L. Flower Extract Inhibits P-glycoprotein and Reverses Multi-Drug Resistance in Cancer Cells: A Mechanistic Study

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 647 ◽  
Author(s):  
Wafaa M. Elkady ◽  
Iriny M. Ayoub ◽  
Yousra Abdel-Mottaleb ◽  
Mohamed F. ElShafie ◽  
Michael Wink
Keyword(s):  
Molecular Docking ◽  
Multidrug Resistance ◽  
Cancer Cells ◽  
Inhibitory Activity ◽  
In Silico ◽  
Chemotherapeutic Agents ◽  
Selective Cytotoxicity ◽  
Flower Extract ◽  
P Glycoprotein ◽  
In Silico Molecular Docking

Euryops pectinatus is a South African ornamental plant belonging to family Asteraceae. The present work evaluates the cytotoxic activity and phytochemical profile of the flower extract. Metabolite profiling was performed using HPLC-PDA-ESI-MS/MS. Total phenolics and flavonoids content were assessed. Cytotoxicity was evaluated against 6 different cancer cell lines using MTT assay. The possible underlying mechanism was proposed. We analyzed whether the extract could overcome the resistance of multidrug-resistant cancer cells for doxorubicin. The effect of combination of E. pectinatus with doxorubicin was also studied. Additionally, the potential inhibitory activity of the identified phytochemicals to PB1 protein was analyzed using in silico molecular docking. Twenty-five compounds were tentatively identified. Total phenolic and flavonoid contents represented 49.41 ± 0.66 and 23.37 ± 0.23 µg/mg dried flower extract, respectively. The extract showed selective cytotoxicity against Caco2 cells but its main effect goes beyond mere cytotoxicity. It showed strong inhibition of P-glycoprotein, which helps to overcome multidrug resistance to classical chemotherapeutic agents. In silico molecular docking showed that dicaffeoyl quinic acid, kaempferol-O-rutinoside, rutin, and isorhamnetin-O-rutinoside exhibited the most potent inhibitory activity to PB1 involved in tumor progression. Euryops pectinatus flower heads could have promising selective cytotoxicity alone or in combination with other chemotherapeutic agents to counteract multidrug resistance.

scholarly journals Taxifolin Resensitizes Multidrug Resistance Cancer Cells via Uncompetitive Inhibition of P-Glycoprotein Function

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3055 ◽  
Author(s):  
Hsiu-Ju Chen ◽  
Yun-Lung Chung ◽  
Chia-Ying Li ◽  
Ying-Tzu Chang ◽  
Charles Wang ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Cells ◽  
Cell Line ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Chemotherapeutic Agents ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Uncompetitive Inhibition ◽  
P Glycoprotein

P-glycoprotein (P-gp) effluxes lots of chemotherapeutic agents and leads to multidrug resistance (MDR) in cancer treatments. The development of P-gp inhibitors from natural products provide a potential strategy for the beneficial clinical outcomes. This study aimed to evaluate the effects of the natural flavonoid taxifolin, luteolin, (−)-gallocatechin, and (−)-catechin on human P-gp activity. The kinetic interactions and underlying mechanisms of taxifolin-mediated transporter inhibition were further investigated. The transporter inhibition ability was evaluated in human P-gp stable expression cells (ABCB1/Flp-InTM-293) by calcein-AM uptake assays. The kinetics study for P-gp inhibition was evaluated by doxorubicin and rhodamine123 efflux assays. The MDR reversal ability of taxifolin were performed by SRB assays to detect the cell viability in sensitive cancer cell line (HeLaS3), and resistant cancer cell line (KB-vin). Cell cycle analysis and ABCB1 real-time RT-PCR were used for mechanical exploration. The results demonstrated that taxifolin decreased ABCB1 expression in a concentration-dependent manner. The function of P-gp was inhibited by taxifolin through uncompetitive inhibition of rhodamine 123 and doxorubicin efflux. The combination of taxifolin significantly resensitized MDR cancer cells to chemotherapeutic agents. These results suggested that taxifolin may be considered as a potential P-gp modulator for synergistic treatment of MDR cancers.

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.

scholarly journals Multidrug resistance-associated ABC transporters – too much of one thing, good for nothing

2012 ◽  
Vol 3 (4) ◽  
pp. 319-331 ◽  
Author(s):  
Jirina Prochazkova ◽  
Martina Lanova ◽  
Jiri Pachernik
Keyword(s):  
Multidrug Resistance ◽  
Cancer Cells ◽  
Abc Transporters ◽  
Family Members ◽  
Atp Binding ◽  
Detailed Mechanism ◽  
P Glycoprotein ◽  
The Future ◽  
Good For

AbstractOverexpression of ATP-binding cassette (ABC) transporters in cancer cells results in multidrug resistance (MDR) which leads to unsuccessful chemotherapy. The most important MDR-associated members of ABC superfamily are ABC B1/P-glycoprotein/MDR1, ABC C1/multidrug resistance associated protein 1 (MRP1), and ABC G2/BCRP. This study is not only focused on function, substrates, and localization of these popular proteins but also on other ABC C family members such as ABC C2–6/MRP2-6 and ABC C7/CFTR. Current research is mainly oriented on the cancer-promoting role of these proteins, but important lessons could also be learned from the physiological roles of these proteins or from polymorphisms affecting their function. Thorough knowledge of structure and detailed mechanism of efflux can aid in the discovery of new chemotherapy targets in the future. Although the best way on how to deal with MDR would be to prevent its development, we describe some new promising strategies on how to conquer both inherited and induced MDRs.

scholarly journals P-glycoprotein-mediated acquired multidrug resistance of human lung cancer cells in vivo

1996 ◽  
Vol 74 (12) ◽  
pp. 1929-1934 ◽  
Author(s):  
Y Abe ◽  
Y Ohnishi ◽  
M Yoshimura ◽  
E Ota ◽  
Y Ozeki ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Multidrug Resistance ◽  
Cancer Cells ◽  
Human Lung ◽  
Lung Cancer Cells ◽  
Human Lung Cancer ◽  
P Glycoprotein ◽  
Human Lung Cancer Cells

scholarly journals Thyroid Hormone and P-Glycoprotein in Tumor Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Paul J. Davis ◽  
Sandra Incerpi ◽  
Hung-Yun Lin ◽  
Heng-Yuan Tang ◽  
Thangirala Sudha ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Molecular Mechanisms ◽  
Efflux Pump ◽  
Inhibitory Effect ◽  
Chemotherapeutic Agents ◽  
Cell Surface Receptor ◽  
P Glycoprotein ◽  
Surface Receptor

P-glycoprotein (P-gp; multidrug resistance pump 1, MDR1; ABCB1) is a plasma membrane efflux pump that when activated in cancer cells exports chemotherapeutic agents. Transcription of the P-gp gene (MDR1) and activity of the P-gp protein are known to be affected by thyroid hormone. A cell surface receptor for thyroid hormone on integrinαvβ3 also binds tetraiodothyroacetic acid (tetrac), a derivative of L-thyroxine (T4) that blocks nongenomic actions of T4and of 3,5,3′-triiodo-L-thyronine (T3) atαvβ3. Covalently bound to a nanoparticle, tetrac as nanotetrac acts at the integrin to increase intracellular residence time of chemotherapeutic agents such as doxorubicin and etoposide that are substrates of P-gp. This action chemosensitizes cancer cells. In this review, we examine possible molecular mechanisms for the inhibitory effect of nanotetrac on P-gp activity. Mechanisms for consideration include cancer cell acidification via action of tetrac/nanotetrac on the Na+/H+exchanger (NHE1) and hormone analogue effects on calmodulin-dependent processes and on interactions of P-gp with epidermal growth factor (EGF) and osteopontin (OPN), apparently viaαvβ3. Intracellular acidification and decreased H+efflux induced by tetrac/nanotetrac via NHE1 is the most attractive explanation for the actions on P-gp and consequent increase in cancer cell retention of chemotherapeutic agent-ligands of MDR1 protein.

Overcoming multidrug resistance via simultaneous delivery of cytostatic drug and P-glycoprotein inhibitor to cancer cells by HPMA copolymer conjugate

Biomaterials ◽  
2017 ◽  
Vol 115 ◽  
pp. 65-80 ◽  
Author(s):  
Ladislav Sivak ◽  
Vladimir Subr ◽  
Jakub Tomala ◽  
Blanka Rihova ◽  
Jiri Strohalm ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Cells ◽  
Cytostatic Drug ◽  
Hpma Copolymer ◽  
P Glycoprotein ◽  
Simultaneous Delivery
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