scholarly journals Reversion of P-Glycoprotein-Mediated Multidrug Resistance in Human Leukemic Cell Line by Diallyl Trisulfide

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Qing Xia ◽  
Zhi-Yong Wang ◽  
Hui-Qing Li ◽  
Yu-Tao Diao ◽  
Xiao-Li Li ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Resistance Mechanism ◽  
Leukemic Cell ◽  
Diallyl Trisulfide ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Resistance Reversal ◽  
Human Leukemic Cell Line ◽  
Multiple Signaling

Multidrug resistance (MDR) is the major obstacle in chemotherapy, which involves multiple signaling pathways. Diallyl trisulfide (DATS) is the main sulfuric compound in garlic. In the present study, we aimed to explore whether DATS could overcome P-glycoprotein-(P-gp-)mediated MDR in K562/A02 cells, and to investigate whether NF-κB suppression is involved in DATS-induced reversal of MDR. MTT assay revealed that cotreatment with DATS increased the response of K562/A02 cells to adriamycin (the resistance reversal fold was 3.79) without toxic side effects. DATS could enhance the intracellular concentration of adriamycin by inhibiting the function and expression of P-gp, as shown by flow cytometry, RT-PCR, and western blot. In addition, DATS resulted in more K562/A02 cell apoptosis, accompanied by increased expression of caspase-3. The expression of NF-κB/p65 (downregulation) was significantly linked to the drug-resistance mechanism of DATS, whereas the expression of IκBαwas not affected by DATS. Our findings demonstrated that DATS can serve as a novel, nontoxic modulator of MDR, and can reverse the MDR of K562/A02 cells in vitro by increasing intracellular adriamycin concentration and inducing apoptosis. More importantly, we proved for the first time that the suppression of NF-κB possibly involves the molecular mechanism in the course of reversion by DATS.

Design, Synthesis and Biological Evaluation of Dimethyl Cardamonin (DMC) Derivatives as P-glycoprotein-mediated Multidrug Resistance Reversal Agents

2020 ◽  
Vol 17 (10) ◽  
pp. 1270-1282
Author(s):  
Ximeng Shi ◽  
Yuyu Zhao ◽  
Licheng Zhou ◽  
Huanhuan Yin ◽  
Jianwen Liu ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Biological Evaluation ◽  
Glycoprotein P ◽  
Design Synthesis ◽  
Reversal Agents ◽  
Protein Levels ◽  
P Glycoprotein ◽  
Resistance Reversal ◽  
Mcf 7

Background: P-glycoprotein (P-gp) has been regarded as an important factor in the multidrug resistance (MDR) of tumor cells within the last decade, which can be solved by inhibiting Pgp to reverse MDR. Thus, it is an effective strategy to develop inhibitor of P-gp. Objective: In this study, the synthesis of a series of derivatives had been carried out by bioisosterism design on the basis of Dimethyl Cardamonin (DMC). Subsequently, we evaluated their reversal activities as potential P-glycoprotein (P-gp)-mediated Multidrug Resistance (MDR) agents. Methods: Dimethyl cardamonin derivatives were synthesized from acetophenones and the corresponding benzaldehydes in the presence of 40% KOH by Claisen-Schmidt reaction. Their cytotoxicity and reversal activities in vitro were assessed with MTT. Moreover, the compound B4 was evaluated by Doxorubicin (DOX) accumulation, Western blot and wound-healing assays deeply. Results and Conclusion: The results showed that compounds B2, B4 and B6 had the potency of MDR reversers with little intrinsic cytotoxicity. Meanwhile, these compounds also demonstrated the capability to inhibit MCF-7 and MCF-7/DOX cells migration. Besides, the most compound B4 was selected for further study, which promoted the accumulation of DOX in MCF-7/DOX cells and inhibited the expressionof P-gp at protein levels. Conclusion: The above findings may provide new insights for the research and development of Pgp- mediated MDR reversal agents.

scholarly journals Immuno-oncology agent IPI-549 is a modulator of P-glycoprotein (P-gp, MDR1, ABCB1)-mediated multidrug resistance (MDR) in cancer: In vitro and in vivo

2019 ◽  
Vol 442 ◽  
pp. 91-103 ◽  
Author(s):  
Albert A. De Vera ◽  
Pranav Gupta ◽  
Zining Lei ◽  
Dan Liao ◽  
Silpa Narayanan ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Glycoprotein P ◽  
P Glycoprotein

scholarly journals Pharmacokinetic Alteration of Paclitaxel by Ferulic Acid Derivative

Pharmaceutics ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 593 ◽  
Author(s):  
Jaeok Lee ◽  
Song Wha Chae ◽  
LianJi Ma ◽  
So Yeon Lim ◽  
Sarah Alnajjar ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Ferulic Acid ◽  
Acid Derivative ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Substrate Drug

P-glycoprotein (P-gp) is known to be involved in multidrug resistance (MDR) and modulation of pharmacokinetic (PK) profiles of substrate drugs. Here, we studied the effects of synthesized ferulic acid (FA) derivatives on P-gp function in vitro and examined PK alteration of paclitaxel (PTX), a well-known P-gp substrate drug by the derivative. Compound 5c, the FA derivative chosen as a significant P-gp inhibitor among eight FA candidates by in vitro results, increased PTX AUCinf as much as twofold versus the control by reducing PTX elimination in rats. These results suggest that FA derivative can increase PTX bioavailability by inhibiting P-gp existing in eliminating organs.

Detection of P-glycoprotein in ovarian cancer: a molecular marker associated with multidrug resistance.

1985 ◽  
Vol 3 (3) ◽  
pp. 311-315 ◽  
Author(s):  
D R Bell ◽  
J H Gerlach ◽  
N Kartner ◽  
R N Buick ◽  
V Ling
Keyword(s):  
Ovarian Cancer ◽  
Multidrug Resistance ◽  
Resistance Mutation ◽  
Advanced Ovarian Cancer ◽  
Surface Glycoprotein ◽  
Glycoprotein P ◽  
Cell Surface Glycoprotein ◽  
P Glycoprotein ◽  
Mutant Lines

A multidrug resistance phenotype is frequently observed in animal and human cell lines selected for in vitro resistance to a single chemotherapeutic agent. Overexpression of a highly conserved cell-surface glycoprotein (P-glycoprotein) is consistently associated with this phenotype in these mutant lines. A monoclonal antibody against P-glycoprotein was used to examine tumor samples from five patients with advanced ovarian cancer for evidence of P-glycoprotein overexpression. High levels of P-glycoprotein were detected in samples from two patients suggesting that a multidrug resistance mutation may also occur in ovarian cancer. This finding has broad implications for the understanding of nonresponse to chemotherapy in a variety of human neoplasms, and may provide a rational explanation for failure of chemotherapy in treatment of advanced ovarian cancer.

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 Antioxidant, Anti-Inflammatory, and Multidrug Resistance Modulation Activity of Silychristin Derivatives

Antioxidants ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 303 ◽  
Author(s):  
Jitka Viktorová ◽  
Simona Dobiasová ◽  
Kateřina Řehořová ◽  
David Biedermann ◽  
Kristýna Káňová ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
No Production ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Resistance Modulation

Silychristin A is the second most abundant compound of silymarin. Silymarin complex was previously described as an antioxidant with multidrug resistance modulation activity. Here, the results of a classical biochemical antioxidant assay (ORAC) were compared with a cellular assay evaluating the antioxidant capacity of pure silychristin A and its derivatives (anhydrosilychristin, isosilychristin and 2,3-dehydrosilychristin A). All the tested compounds acted as antioxidants within the cells, but 2,3-dehydro- and anhydro derivatives were almost twice as potent as the other tested compounds. Similar results were obtained in LPS-stimulated macrophages, where 2,3-dehydro- and anhydrosilychristin inhibited NO production nearly twice as efficiently as silychristin A. The inhibition of P-glycoprotein (P-gp) was determined in vitro, and the respective sensitization of doxorubicin-resistant ovarian carcinoma overproducing P-gp was detected. Despite the fact that the inhibition of P-gp was demonstrated in a concentration-dependent manner for each tested compound, the sensitization of the resistant cell line was observed predominantly for silychristin A and 2,3-dehydrosilychristin A. However, anhydrosilychristin and isosilychristin affected the expression of both the P-gp (ABCB1) and ABCG2 genes. This is the first report showing that silychristin A and its 2,3-dehydro-derivative modulate multidrug resistance by the direct inhibition of P-gp, in contrast to anhydrosilychristin and isosilychristin modulating multidrug resistance by downregulating the expression of the dominant transmembrane efflux pumps.

Feasibility of using quinine, a potential multidrug resistance-reversing agent, in combination with mitoxantrone and cytarabine for the treatment of acute leukemia.

1992 ◽  
Vol 10 (11) ◽  
pp. 1730-1736 ◽  
Author(s):  
E Solary ◽  
D Caillot ◽  
B Chauffert ◽  
R O Casasnovas ◽  
M Dumas ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Acute Leukemia ◽  
Leukemic Cell ◽  
Serum Levels ◽  
Acute Leukemias ◽  
P Glycoprotein ◽  
Blast Cells ◽  
Human Leukemic Cell Line ◽  
State Concentration ◽  
Severe Mucositis

PURPOSE We demonstrated previously that sera from quinine-treated patients reversed the multidrug resistance (MDR) of a human leukemic cell line. We now report a phase I and II clinical study that examined the toxicity of the combination of quinine with mitoxantrone and cytarabine (Ara-C). PATIENTS AND METHODS Fifteen adult patients with relapsed or refractory acute leukemia were treated with quinine formiate (30 mg/kg/d in continuous intravenous (IV) infusion from day 1 through day 5 or 6) associated with Ara-C (1 g/m2 in 3-hour IV infusion twice a day for 5 days) and five increasing doses of mitoxantrone (from 8 mg/m2/d for 4 days to 12 mg/m2/d for 5 days). RESULTS The main toxicity was severe myelosuppression: the mean times to leukocyte recovery (> 500/microL), granulocytes recovery (> 500/microL), and platelet count recovery (> 50,000/microL) were 23 days (range, 17 to 29 days), 30.6 days (range, 17 to 48 days), and 35.4 days (range, 14 to 75 days), respectively. The nonhematopoietic toxicity of this regimen was acceptable. Nausea and vomiting were common, but severe mucositis was observed in only two patients. Cardiotoxicity was limited to transient episodes of moderate supraventricular tachycardia and a clinically well-tolerated bradycardia. Tinnitus and vertigo were observed in 10 cases (67%), and mild hearing loss and transient increase of serum bilirubin were observed in six patients (40%). Total quinine serum levels reached a steady-state concentration between 6.4 and 18 mg/L in 24 hours. Complete remission (CR) was achieved in eight of 14 (57%) assessable patients, and partial response (PR) was achieved in two additional patients (14%). P-glycoprotein expression was detected on blast cells from five of 13 studied patients before treatment. A response was observed in all P-glycoprotein-positive cases. CONCLUSION Quinine can be used safely as a potential reversing agent of MDR for the treatment of clinically resistant acute leukemias.

3-benzazecine-based cyclic allene derivatives as highly potent P-glycoprotein inhibitors overcoming doxorubicin multidrug resistance

2019 ◽  
Vol 11 (16) ◽  
pp. 2095-2106 ◽  
Author(s):  
Alexander A Titov ◽  
Mauro Niso ◽  
Modesto de Candia ◽  
Maxim S Kobzev ◽  
Alexey V Varlamov ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Multidrug Resistant ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Uptake Assay ◽  
Calcein Am ◽  
Inhibition Potency ◽  
Glycoprotein Inhibitors ◽  
Allene System

Aim: Enamino 3-benzazecine compounds, incorporating the C6-C8 allene system, were synthesized and evaluated in vitro as inhibitors of P-glycoprotein (P-gp) and/or multidrug resistance-associated protein 1 (MRP1), two efflux pumps mainly connected with multidrug resistance (MDR) in cancer cells. Results & methodology: Most of the synthesized compounds were selective P-gp inhibitors in Calcein-AM uptake assay. Structure–activity relationships (SARs) pointed out that CO2Me derivatives are more potent than acetyl derivatives, and 10,11-dimethoxy compounds are five to tenfold more potent inhibitors than the respective unsubstituted compounds, and that the P-gp inhibition potency is mainly related to volume parameters. Conclusion: Nanomolar P-gp inhibitors, such as 23 (IC50 = 4.2 nM), restored the antiproliferative activity of doxorubicin in multidrug-resistant cells. The observed activities showed that 3-benzazecine-based compounds may be promising MDR reversers.

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