scholarly journals Homotype-Targeted Biogenic Nanoparticles to Kill Multidrug-Resistant Cancer Cells

Pharmaceutics ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 950
Author(s):  
Imran Shair Mohammad ◽  
Birendra Chaurasiya ◽  
Xuan Yang ◽  
Chuchu Lin ◽  
Hehui Rong ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Drug Delivery Systems ◽  
Multidrug Resistant ◽  
Hybrid Nanoparticles ◽  
Receptor Density ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Target Sites ◽  
Membrane Coating ◽  
Biogenic Nanoparticles

“Off-targeting” and receptor density expressed at the target sites always compromise the efficacy of the nanoparticle-based drug delivery systems. In this study, we isolated different cell membranes and constructed cell membrane-cloaked biogenic nanoparticles for co-delivery of antitumor paclitaxel (PTX) and multidrug resistance (MDR)-modulator disulfiram (DSF). Consequently, MDR cancer cell membrane (A549/T)-coated hybrid nanoparticles (A549/T CM-HNPs) selectively recognized the source cells and increased the uptake by ninefold via the homotypic binding mechanism. Moreover, the A549/T CM-HNPs sensitized MDR cells to PTX by suppressing P-glycoprotein (P-gp) activity by 3.2-fold and induced effective apoptosis (70%) in homologous A549/T cells. Cell-membrane coating based on the “homotypic binding” is promising in terms of promoting the accumulation of chemotherapeutics in MDR cells and killing them.

Expression of hamster P-glycoprotein and multidrug resistance in DNA-mediated transformants of mouse LTA cells

1987 ◽  
Vol 7 (2) ◽  
pp. 718-724
Author(s):  
K L Deuchars ◽  
R P Du ◽  
M Naik ◽  
D Evernden-Porelle ◽  
N Kartner ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Dna Sequences ◽  
Multidrug Resistant ◽  
Cross Resistance ◽  
Recipient Mouse ◽  
Strongly Correlated ◽  
Wild Type ◽  
Glycoprotein P ◽  
Single Drug ◽  
P Glycoprotein

The overexpression of a plasma membrane glycoprotein, P-glycoprotein, is strongly correlated with the expression of multidrug resistance. This phenotype (frequently observed in cell lines selected for resistance to a single drug) is characterized by cross resistance to many drugs, some of which are used in cancer chemotherapy. In the present study we showed that DNA-mediated transformants of mouse LTA cells with DNA from multidrug-resistant hamster cells acquired the multidrug resistance phenotype, that the transformants contained hamster P-glycoprotein DNA sequences, that these sequences were amplified whereas the recipient mouse P-glycoprotein sequences remained at wild-type levels, and that the overexpressed P-glycoprotein in these cells was of hamster origin. Furthermore, we showed that the hamster P-glycoprotein sequences were transfected independently of a group of genes that were originally coamplified and linked within a 1-megabase-pair region in the donor hamster genome. These data indicate that the high expression of P-glycoprotein is the only alteration required to mediate multidrug resistance.

Reversal of chemoresistance in malignant gliomas by calcium antagonists: correlation with the expression of multidrug-resistant p-glycoprotein

1994 ◽  
Vol 81 (4) ◽  
pp. 587-594 ◽  
Author(s):  
Jurgen Carl Walther Kiwit ◽  
Anja Hertel ◽  
Alexander E. Matuschek
Keyword(s):  
Calcium Antagonists ◽  
Malignant Gliomas ◽  
Multidrug Resistant ◽  
Chemotherapeutic Agents ◽  
Positive Staining ◽  
Glycoprotein P ◽  
Content Type ◽  
P Glycoprotein ◽  
Multiple Drugs

✓ Resistance to multiple drugs is often observed in malignant gliomas. The authors used a microtiter tetrazolium test to analyze primary in vitro chemoresistance and chemosensitivity of 15 early cultures of human malignant glioma exposed to 50 µg/ml (1,4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU), 50 µg/ml cisplatin, 1 µg/ml vincristine, or combinations of these chemotherapeutic agents. Primary chemoresistance was observed in 87% of tumors for ACNU, in 87% for cisplatin, and in 83% for vincristine. All tumors were examined for expression of multidrug-resistant p-glycoprotein, a transport protein of 170,000 D, by means of immunohistochemical staining with the JSB-1 antibody on paraffinized tumor sections. Eight of 15 specimens (53%) showed positive staining for the monoclonal antibody. Primary chemoresistance was overcome by addition of the calcium antagonists verapamil or nimodipine to the cultures if the original tumor expressed p-glycoprotein (p < 0.01 for verapamil, p < 0.05 for nimodipine). In tumors not expressing p-glycoprotein, addition of calcium antagonists to the cell cultures did not influence primary chemoresistance. It is concluded from these data that addition of calcium antagonists to the adjuvant chemotherapy of malignant gliomas might overcome primary chemoresistance in tumors expressing the multidrugresistant phenotype.

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.

P-glycoprotein in human sarcoma: evidence for multidrug resistance.

1987 ◽  
Vol 5 (9) ◽  
pp. 1452-1460 ◽  
Author(s):  
J H Gerlach ◽  
D R Bell ◽  
C Karakousis ◽  
H K Slocum ◽  
N Kartner ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Multidrug Resistant ◽  
Surface Glycoprotein ◽  
Glycoprotein P ◽  
Cell Surface Glycoprotein ◽  
P Glycoprotein ◽  
Drug Treatments ◽  
Tumor Types ◽  
Human Sarcoma

Overexpression of an immunologically conserved, cell-surface glycoprotein (P-glycoprotein) is consistently associated with multidrug resistance in cell lines in vitro. A preliminary survey of specimens from 12 solid tumor types in our laboratories indicates significant overexpression of P-glycoprotein in some sarcomas. When tested by immunoblotting with monoclonal antibodies directed against P-glycoprotein; tumors from six of 25 sarcoma patients displayed elevated levels of P-glycoprotein. Three of the sarcoma patients exhibiting P-glycoprotein had not previously been exposed to chemotherapy, implying that overexpression of this marker and possible concomitant multidrug resistance may not depend only on selection during prior drug treatments. The P-glycoprotein overexpression in the sarcoma specimens is evidence for the presence of multidrug resistant cells in these tumors; thus, our data suggest that this mode of resistance may have clinical significance in sarcoma patients.

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

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.

scholarly journals Expression of hamster P-glycoprotein and multidrug resistance in DNA-mediated transformants of mouse LTA cells.

1987 ◽  
Vol 7 (2) ◽  
pp. 718-724 ◽  
Author(s):  
K L Deuchars ◽  
R P Du ◽  
M Naik ◽  
D Evernden-Porelle ◽  
N Kartner ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Dna Sequences ◽  
Multidrug Resistant ◽  
Cross Resistance ◽  
Recipient Mouse ◽  
Strongly Correlated ◽  
Wild Type ◽  
Glycoprotein P ◽  
Single Drug ◽  
P Glycoprotein

The overexpression of a plasma membrane glycoprotein, P-glycoprotein, is strongly correlated with the expression of multidrug resistance. This phenotype (frequently observed in cell lines selected for resistance to a single drug) is characterized by cross resistance to many drugs, some of which are used in cancer chemotherapy. In the present study we showed that DNA-mediated transformants of mouse LTA cells with DNA from multidrug-resistant hamster cells acquired the multidrug resistance phenotype, that the transformants contained hamster P-glycoprotein DNA sequences, that these sequences were amplified whereas the recipient mouse P-glycoprotein sequences remained at wild-type levels, and that the overexpressed P-glycoprotein in these cells was of hamster origin. Furthermore, we showed that the hamster P-glycoprotein sequences were transfected independently of a group of genes that were originally coamplified and linked within a 1-megabase-pair region in the donor hamster genome. These data indicate that the high expression of P-glycoprotein is the only alteration required to mediate multidrug resistance.

scholarly journals Expression of P-glycoprotein in adult T-cell leukemia cells

Blood ◽  
1990 ◽  
Vol 76 (10) ◽  
pp. 2065-2071 ◽  
Author(s):  
Y Kuwazuru ◽  
S Hanada ◽  
T Furukawa ◽  
A Yoshimura ◽  
T Sumizawa ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cell ◽  
Multidrug Resistant ◽  
Leukemia Cells ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Glycoprotein P ◽  
Adult T Cell Leukemia ◽  
P Glycoprotein ◽  
Mdr1 Mrna

We have examined the expression of P-glycoprotein (P-gp) in adult T- cell leukemia (ATL) samples from 25 patients. Based on immunoblotting with a monoclonal antibody against P-gp, C219, 8 of 20 ATL patients were P-gp positive at the initial presentation. All 6 patients at the relapsed stage were P-gp positive, and refractory to chemotherapy. The expression of MDR1 mRNA in P-gp-positive ATL cells was increased at the relapsed stage of one patient. P-gp of this patient was photolabeled with [3H]azidopine and the labeling was inhibited with nimodipine, vinblastine and progesterone. These results suggest that P-gp expressed in ATL cells from patients at relapsed stage has the same binding site(s) for the drugs as that in multidrug resistant cells, and is correlated with the refractory nature of the cells to chemotherapy.

scholarly journals Expression of P-glycoprotein in adult T-cell leukemia cells

Blood ◽  
1990 ◽  
Vol 76 (10) ◽  
pp. 2065-2071 ◽  
Author(s):  
Y Kuwazuru ◽  
S Hanada ◽  
T Furukawa ◽  
A Yoshimura ◽  
T Sumizawa ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cell ◽  
Multidrug Resistant ◽  
Leukemia Cells ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Glycoprotein P ◽  
Adult T Cell Leukemia ◽  
P Glycoprotein ◽  
Mdr1 Mrna

Abstract We have examined the expression of P-glycoprotein (P-gp) in adult T- cell leukemia (ATL) samples from 25 patients. Based on immunoblotting with a monoclonal antibody against P-gp, C219, 8 of 20 ATL patients were P-gp positive at the initial presentation. All 6 patients at the relapsed stage were P-gp positive, and refractory to chemotherapy. The expression of MDR1 mRNA in P-gp-positive ATL cells was increased at the relapsed stage of one patient. P-gp of this patient was photolabeled with [3H]azidopine and the labeling was inhibited with nimodipine, vinblastine and progesterone. These results suggest that P-gp expressed in ATL cells from patients at relapsed stage has the same binding site(s) for the drugs as that in multidrug resistant cells, and is correlated with the refractory nature of the cells to chemotherapy.

Inhibition of P-glycoprotein by cyclosporin A analogues and metabolites

1999 ◽  
Vol 77 (1) ◽  
pp. 47-58 ◽  
Author(s):  
Michel Demeule ◽  
Alain Laplante ◽  
Arash Sepehr-Araé ◽  
Édith Beaulieu ◽  
Diana Averill-Bates ◽  
...  
Keyword(s):  
Atpase Activity ◽  
Cyclosporin A ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Multidrug Resistant ◽  
Hydroxyl Group ◽  
Glycoprotein P ◽  
Ovary Cells ◽  
Psc 833 ◽  
P Glycoprotein

The interaction between P-glycoprotein (P-gp) from membranes isolated from multidrug-resistant Chinese hamster ovary cells and cyclosporin A (CsA) analogues and its metabolites was characterized. Screening of these latter as chemosensitizers was performed using three different assays: (i) vinblastine uptake, (ii) photoaffinity labeling by [125I]iodoaryl azidoprazosin, and (iii) P-gp ATPase activity. Oxidation of the hydroxyl group at position 1 of CsA (200-096), CsG (215-834), or CsD (PSC-833) increased their inhibition of P-gp. CsA analogues (208-032, 208-183) modified at position 11 retained their ability to inhibit P-gp while analogues modified at position 2 (CsC and CsD) lost their efficiency. The inhibitions induced by metabolites of CsA were also compared to those obtained with CsG metabolites. From all the molecules tested, PSC-833 and 280-446 peptolide were the strongest inhibitors. Our results indicate that modifications of CsA analogues at position 1 and 2 are critical for their interaction with P-gp and that CsA metabolites retain a portion of the inhibitory activity of the parent drug.Key words: P-glycoprotein, cyclosporin A, vinblastine uptake, photolabeling, ATPase activity.

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