scholarly journals Meloxicam increases intracellular accumulation of doxorubicin via downregulation of multidrug resistance-associated protein 1 (MRP1) in A549 cells

2015 ◽  
Vol 14 (4) ◽  
pp. 14548-14560 ◽  
Author(s):  
S.F. Chen ◽  
Z.Y. Zhang ◽  
J.L. Zhang
Keyword(s):  
Multidrug Resistance ◽  
A549 Cells ◽  
Intracellular Accumulation

scholarly journals The Multidrug Resistance-Reversing Activity of a Novel Antimicrobial Peptide

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1963
Author(s):  
Qiu-Xu Teng ◽  
Xiaofang Luo ◽  
Zi-Ning Lei ◽  
Jing-Quan Wang ◽  
John Wurpel ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Antimicrobial Peptides ◽  
Anticancer Drugs ◽  
Anticancer Agents ◽  
Abc Transporters ◽  
Intracellular Accumulation ◽  
The Past ◽  
Novel Strategy ◽  
New Generation ◽  
Abcb1 Transporter

The overexpression of ATP-binding cassette (ABC) transporters is a common cause of multidrug resistance (MDR) in cancers. The intracellular drug concentration of cancer cells can be decreased relative to their normal cell counterparts due to increased expression of ABC transporters acting as efflux pumps of anticancer drugs. Over the past decades, antimicrobial peptides have been investigated as a new generation of anticancer drugs and some of them were reported to have interactions with ABC transporters. In this article, we investigated several novel antimicrobial peptides to see if they could sensitize ABCB1-overexpressing cells to the anticancer drugs paclitaxel and doxorubicin, which are transported by ABCB1. It was found that peptide XH-14C increased the intracellular accumulation of ABCB1 substrate paclitaxel, which demonstrated that XH-14C could reverse ABCB1-mediated MDR. Furthermore, XH-14C could stimulate the ATPase activity of ABCB1 and the molecular dynamic simulation revealed a stable binding pose of XH-14C-ABCB1 complex. There was no change on the expression level or the location of ABCB1 transporter with the treatment of XH-14C. Our results suggest that XH-14C in combination with conventional anticancer agents could be used as a novel strategy for cancer treatment.

scholarly journals Decrease in Multidrug Resistance-associated Protein 2 Activities by Knockdown of Phosphatidylinositol 4-phosphate 5-kinase in Hepatocytes and Cancer Cells

2019 ◽  
Vol 22 ◽  
pp. 576-584 ◽  
Author(s):  
Atsushi Kawase ◽  
Yuta Inoue ◽  
Miho Hirosoko ◽  
Yuka Sugihara ◽  
Hiroaki Shimada ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Multidrug Resistance ◽  
Cancer Cells ◽  
Hepg2 Cells ◽  
Carcinoma Cells ◽  
Efflux Transporters ◽  
Membrane Localization ◽  
Intracellular Accumulation ◽  
Primary Hepatocytes ◽  
Phosphatidylinositol 4

Purpose: The plasma membrane localization and transport activity of multidrug resistance-associated protein 2 (MRP2/ABCC2) and P-glycoprotein (P-gp/ABCB1) efflux transporters are governed by transporter-associated proteins. Phosphatidylinositol 4,5-bisphosphate (PIP2) formed by phosphatidylinositol 4-phosphate 5-kinase type 1 (PIP5K1) activates the linker function of radixin for efflux transporters. Radixin is involved in the plasma membrane localization of efflux transporters. We examined whether PIP5K1 could be a target for the modulation of transporter activities in hepatocytes and cancer cells. Methods: The effects of PIP5K1 depletion by siRNA in mouse primary hepatocytes, PANC1 human pancreatic carcinoma cells, and HepG2 human hepatocellular carcinoma cells on the intracellular accumulation of MRP2 and P-gp substrates were examined. Results: PIP5K1A depletion resulted in increased intracellular accumulation of carboxydichlorofluorescein, a MRP2 fluorescent substrate, in mouse primary hepatocytes, PANC1 cells, and HepG2 cells. In PANC1 and HepG2 cells, the transport activities of MRP2 were significantly decreased by PIP5K1C depletion. However, the transport activities of P-gp were unchanged by PIP5K1 depletion. PIP2 levels were unchanged between control and PIP5K1A- or PIP5K1C-depleted HepG2 cells. MRP2 mRNA levels showed few changes in HepG2 cells following PIP5K1A or PIP5K1C depletion. The expression of phosphorylated radixin was decreased by PIP5K1A and PIP5K1C depletion, although total radixin levels were unchanged. Conclusions: These data suggest that PIP5K1A and PIP5K1C could be target proteins for modulating MRP2 function, partly because of the resulting changes of the linker function of radixin.

Contribution of multidrug resistance-associated proteins (MRPs) to the release of prostanoids from A549 cells

2013 ◽  
Vol 106 ◽  
pp. 37-44 ◽  
Author(s):  
Ayako Furugen ◽  
Hiroaki Yamaguchi ◽  
Nobuaki Tanaka ◽  
Narumi Shiida ◽  
Jiro Ogura ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
A549 Cells ◽  
Associated Proteins

Reversal of P-glycoprotein-medicated multidrug resistance by LBM-A5 in vitro and a study of its pharmacokinetics in vivo

2015 ◽  
Vol 93 (1) ◽  
pp. 33-38 ◽  
Author(s):  
Tianxiao Zhao ◽  
Yun Song ◽  
Baomin Liu ◽  
Qianqian Qiu ◽  
Lei Jiao ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Chemotherapy ◽  
Anticancer Agents ◽  
Efflux Pump ◽  
Therapeutic Index ◽  
Intracellular Accumulation ◽  
P Glycoprotein ◽  
Reversal Mechanism

The overexpression of P-glycoprotein (P-gp) in tumors leads to multidrug resistance (MDR), which is a significant obstacle in clinical cancer chemotherapy. The co-administration of anticancer drugs and MDR modulators is a promising strategy for overcoming this problem. Our study aimed to explore the reversal mechanism and safety of the MDR modulator LBM-A5 in vitro, and evaluate its pharmacokinetics and effects on doxorubicin metabolism in vivo. We evaluated an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay of anticancer agents mediated by LBM-A5, the effect of LBM-A5 on rhodamine123 intracellular accumulation, and the efflux in K562/DOX cells to investigate the reversal mechanisms of LBM-A5. The results showed that LBM-A5 inhibits rhodamine123 efflux and increases intracellular accumulation by inhibiting the efflux pump function of P-gp. Furthermore, the therapeutic index and CYP3A4 activity analysis in vitro suggested that LBM-A5 is reasonably safe to use. Also, LBM-A5 (10 mg/kg body mass) achieved the required plasma concentration in sufficient time to reverse MDR in vivo. Importantly, the LBM-A5 treatment group shared similar doxorubicin (DOX) pharmacokinetics with the free DOX group. Our results suggest that LBM-A5 effectively reverses MDR (EC50 = 483.6 ± 81.7 nmol·L−1) by inhibiting the function of P-gp, with relatively ideal pharmacokinetics and in a safe manner, and so may be a promising candidate for cancer chemotherapy research.

scholarly journals Survivin Suppression Strengthens BZML-induced Mitotic Catastrophe to Overcome Multidrug Resistance by Removing Senescent A549/Taxol Cells

2020 ◽  
Author(s):  
Zhaoshi Bai ◽  
Yiran Zhou ◽  
Xinyue Ye ◽  
Qi Guan ◽  
Weige Zhang ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cellular Senescence ◽  
A549 Cells ◽  
Nuclear Accumulation ◽  
Mitotic Catastrophe ◽  
Death Process ◽  
Protein Synthesis Inhibitor ◽  
Apoptosis Resistance ◽  
Hoechst 33342 ◽  
Cellular Death

Abstract Background: Mitotic catastrophe (MC) of cancer cells induced by BZML, a novel colchicine-binding site inhibitor, exerts a significant advantage in overcoming multidrug resistance (MDR) in NSCLC. However, the long cellular death process resulting from MC is not beneficial for anticancer treatment. Here, we study the mechanisms underlying MC occurrence and development to promote the development of anticancer therapies based on drug-induced MC.Methods: Cellular senescence was confirmed by morphological features, SA-β-Gal and C12FDG staining. Cell cycle analysis and Hoechst 33342 staining were used to detect MC. Relevant signal transduction pathways and protein location were detected by qRT-PCR, westren blot and immunofluorescence. The half-life of proteins was evaluated using the protein synthesis inhibitor cycloheximide. Flow cytometry, MTT assay, crystal violet staining, Hoechst 33342 staining and cell division detection were performed to determine the effects of BZML and/or YM155 on cell fate. Results: We found that BZML induced p53-dependent cellular senescence in A549/Taxol cells, but not in A549, H1299 and MDA-MB-231 cells. Interestingly, BZML-induced senescence was a secondary effect of MC. In addition, the destruction of the protein-degradation system induced by BZML contributed not only to an increase in p53 protein but also to the accumulation of survivin in the nucleus of A549/Taxol cells. However, in A549 cells, the overexpression of survivin had no effect on apoptosis resistance against BZML and failed to promote BZML-induced MC. The inhibition of survivin did not prevent MC occurrence. Unexpectedly, targeting survivin with YM155 accelerated the death of the MC cells by eliminating senescent cells and strengthening the efficiency of BZML in overcoming the MDR of A549/Taxol cells.Conclusions: Our data suggest that nuclear accumulation of survivin can delay cellular death during MC by promoting the survival of senescent BZML-treated A549/Taxol cells. Further, depending on the dose sequence, combination therapy with YM155 to inhibit survivin might be a new strategy for potentiating BZML-induced MC to overcome MDR during cancer treatment.

scholarly journals Venetoclax, a BCL-2 Inhibitor, Enhances the Efficacy of Chemotherapeutic Agents in Wild-Type ABCG2-Overexpression-Mediated MDR Cancer Cells

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 466 ◽  
Author(s):  
Jing-Quan Wang ◽  
Jonathan Y. Li ◽  
Qiu-Xu Teng ◽  
Zi-Ning Lei ◽  
Ning Ji ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Multidrug Resistance ◽  
Chronic Lymphocytic Leukemia ◽  
Combination Therapy ◽  
Atpase Activity ◽  
Chemotherapeutic Agents ◽  
Lymphocytic Leukemia ◽  
Wild Type ◽  
Intracellular Accumulation ◽  
Toxic Concentration

Previous studies have shown that small-molecule BCL-2 inhibitors can have a synergistic interaction with ABCG2 substrates in chemotherapy. Venetoclax is a potent and selective BCL-2 inhibitor, approved by the FDA in 2016 for the treatment of patients with chronic lymphocytic leukemia (CLL). This study showed that, at a non-toxic concentration, venetoclax at 10 µM significantly reversed multidrug resistance (MDR) mediated by wild-type ABCG2, without significantly affecting MDR mediated by mutated ABCG2 (R482G and R482T) and ABCB1, while moderate or no reversal effects were observed at lower concentrations (0.5 to 1 µM). The results showed that venetoclax increased the intracellular accumulation of chemotherapeutic agents, which was the result of directly blocking the wild-type ABCG2 efflux function and inhibiting the ATPase activity of ABCG2. Our study demonstrated that venetoclax potentiates the efficacy of wild-type ABCG2 substrate drugs. These findings may provide useful guidance in combination therapy against wild-type ABCG2-mediated MDR cancer in clinical practice.

Indole Curcumin Reverses Multidrug Resistance by Reducing the Expression of ABCB1 and COX2 in Induced Multidrug Resistant Human Lung Cancer Cells

2020 ◽  
Vol 17 (9) ◽  
pp. 1146-1154
Author(s):  
Sankar Pajaniradje ◽  
Kumaravel Mohankumar ◽  
Rakesh Radhakrishnan ◽  
Shamim Akhtar Sufi ◽  
Srividya Subramanian ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Drug Resistance ◽  
Multidrug Resistance ◽  
Human Lung ◽  
A549 Cells ◽  
Multidrug Resistant ◽  
Human Lung Cancer ◽  
Abcb1 Gene ◽  
Cox 2

Background: Drug resistance by the cancer cells towards current chemotherapeutic approaches poses a great challenge. In the present study, an indole analogue of a well-known plant derived anticancer molecule, curcumin, was tested for its Multidrug Resistance (MDR) reversing potential in induced multi drug resistant A549 cell line. Materials and Methods: Human lung cancer cell line A549 was made Multidrug Resistant (MDR) by prolonged treatment with low dosage of Docetaxel, an established anticancer drug. The MDR induction was confirmed by morphological evidence, Hoechst 33342 staining, MTT assay, Rhodamine123 staining and RT-PCR of ABCB1 gene. Protein expression studies were carried out using western blotting technique Results and Discussions: The induced MDR A549 cells exhibited significant increase in the gene expression of ABCB1 gene at the transcriptional level. Retention and efflux studies with Pglycoprotein (P-gp) substrate Rh123 indicated that indole curcumin inhibited P-gp mediated efflux of Rhodamine. Furthermore, treatment of MDR A549 cells with indole curcumin showed downregulation of gene expression of ABCB1 and COX 2. This was also confirmed from the decreased protein expression of COX 2. Conclusion: The results of the present study indicate that indole curcumin reverses multi drug resistance by downregulating the expression of ABCB1 and COX 2 genes. Thus, indole curcumin may act as a potent modulator for ABCB1 and COX 2 mediated MDR in lung cancer.

Reversing Multidrug Resistance in Chemo-resistant Human Lung Adenocarcinoma (A549/DOX) Cells by Algerian Propolis Through Direct Inhibiting the P-gp Efflux-pump, G0/G1 Cell Cycle Arrest and Apoptosis Induction

2019 ◽  
Vol 18 (9) ◽  
pp. 1330-1337 ◽  
Author(s):  
Wided Kebsa ◽  
Mesbah Lahouel ◽  
Hassiba Rouibah ◽  
Malek Zihlif ◽  
Mamoun Ahram ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Multidrug Resistance ◽  
Lung Adenocarcinoma ◽  
Cell Cycle Arrest ◽  
Efflux Pump ◽  
A549 Cells ◽  
Apoptosis Induction ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest ◽  
Resistant Cells

Background: Lung cancer is one of the most common malignancies with the highest incidence and mortality rate worldwide. Multidrug Resistance (MDR) continues to pose a major challenge for the clinicians and pharmacologists to effectively treat this disease. A new approach using natural substances with moderate or low cytotoxic properties become a promising hope for reversing multidrug resistance due to pgp- overexpression. Objective: This study aims to explore the efficacy of Algerian propolis in reversing multidrug resistance and sensitizing chemo-resistant lung cancer cells (A549/DOX) to chemotherapy with DOX. Methods: Resistant lung adenocarcinoma A549/DOX cell line was developed and used as in vitro model for MDR. Cell viability, Annexin V-PI apoptosis assay and cell cycle progression were tested to evaluate the reversal effect of propolis alone or in combination with DOX. Caspases 3, 8 and 9 assays were conducted to determine the type of apoptotic pathway. To investigate the mechanisms of MDR reversal agents, intracellular accumulation of DOX and P-gp-pump activity were investigated. Results: Our results showed that the obtained chemo-resistant cells were 13-fold more resistant to DOX than the parental A549 cells. Propolis showed dramatically cell growth inhibition on A549/DOX cells (The IC50 was 50.44± 0.07µg/ml). The killing effect of propolis was due to G0/G1 cell cycle arrest and apoptosis induction. After 24hours treatment, propolis at 100 µg/ml caused cells accumulation in G0/G1 phase and increased with 50, 65-fold the percentage of apoptotic population sub-G. Annexin V-PI assay showed that propolis induces apoptosis with 53.57-fold at 100 µg/ml. It induced intrinsic apoptotic pathway by increasing caspase-3 (22.15-fold) and caspase-9 (16.73-fold) activities. The direct approach to investigate the mechanisms of reversal agents is to detect the accumulation of P-gp substrates in resistant cells. Our results indicated that resistant cells poorly accumulated Doxorubicin and rhodamine 123 (7-fold lower) when compared to parental A549 cells, suggesting that chemo-resistant cells overexpress P-gp which pump DOX out of cells. Propolis inhibited in a concentration-dependent manner, the pgp efflux-pump, enhancing thereby the intracellular level of DOX with 5.48- fold against 3.33 fold obtained with verapamil, the conventional P-gp inhibitor. Conclusion: Taken together, Algerian propolis reverses multidrug resistance in resistant human lung adenocarcinoma cells through direct inhibiting the transport function of pgp-pump resulting in enhancing intracellular DOX-accumulation, G0/G1 cell cycle arrest and apoptosis induction. Thus, propolis could be developed as a chemotherapeutic agent for reversing multidrug resistance.

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