Effects of P-Glycoprotein and Its Inhibitors on Apoptosis in K562 Cells

Zu, Ya-qiong; Yang, Zhiyong; Tang, Song-Shan; Han, Ying; Ma, Jun

doi:10.3390/molecules190913061

Cited by 30 publications

(28 citation statements)

References 35 publications

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“…When expressed in neoplastic cells, P-gp could induce strong resistance (amounting several hundred times) against a large group of structurally unrelated chemicals belonging to a cluster of P-gp substrates [ 12 ]. However, several lines of evidence indicated that P-gp may depress the initiation and progression of apoptosis, independently of its drug-efflux activity, through different regulatory pathways [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

L1210 Cells Overexpressing ABCB1 Drug Transporters Are Resistant to Inhibitors of the N- and O-glycosylation of Proteins

et al. 2017

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Overexpression of P-glycoprotein (P-gp, drug transporter) in neoplastic cells is the most frequently observed molecular cause of multidrug resistance. Here, we show that the overexpression of P-gp in L1210 cells leads to resistance to tunicamycin and benzyl 2-acetamido-2-deoxy-α-d-galactopyranoside (GalNAc-α-O-benzyl). Tunicamycin induces both glycosylation depression and ubiquitination improvement of P-gp. However, the latter is not associated with large increases in molecular mass as evidence for polyubiquitination. Therefore, P-gp continues in maturation to an active membrane efflux pump rather than proteasomal degradation. P-gp-positive L1210 cells contain a higher quantity of ubiquitin associated with cell surface proteins than their P-gp-negative counterparts. Thus, P-gp-positive cells use ubiquitin signaling for correct protein folding to a higher extent than P-gp-negative cells. Elevation of protein ubiquitination after tunicamycin treatment in these cells leads to protein folding rather than protein degradation, resulting at least in the partial lack of cell sensitivity to tunicamycin in L1210 cells after P-gp expression. In contrast to tunicamycin, to understand why P-gp-positive cells are resistant to GalNAc-α-O-benzyl, further research is needed.

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Section: Introductionmentioning

confidence: 99%

L1210 Cells Overexpressing ABCB1 Drug Transporters Are Resistant to Inhibitors of the N- and O-glycosylation of Proteins

et al. 2017

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“…also have found that TcdA activates caspase-3, −6, −8, and −9 activity, caspase-3 activity increased more quickly than the other caspases, and demonstrated the involvement of caspase-activating cascades in toxin A-induced apoptosis. In addition, Zu et al (23) also found that P-gp related apoptosis was caspase-mediated.…”

Section: Discussionmentioning

confidence: 98%

“…The P-gp expression level of K562/A02 cells decreased significantly compared with the control group after treatment with TcdA (P<0.05), suggesting that TcdA could inhibit cell growth and reverse MDR of cells by reducing P-gp expression. Zu et al (23) found that expression of P-gp inhibits apoptosis in tumor cells, P-gp inhibitor leads to cell death and directly induces apoptosis. In addition, they pointed that inhibition of P-gp function is an effective way to induce apoptosis and overcome MDR.…”

Section: Discussionmentioning

confidence: 99%

Effects of Clostridiumï¿½difficile toxin A on K562/A02 cell proliferation, apoptosis and multi-drug resistance

Zhang

et al. 2018

Oncol Lett

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The aim of the present study was to investigate the cytotoxic effect and multi-drug resistance (MDR) of Clostridium difficile toxin A (TcdA) on K562/A02 cells, and understand its underlying molecular pathways. K562/A02 cells were treated with TcdA at different concentrations for 24, 48 and 72 h, and the inhibition effect and drug resistance of TcdA on K562/A02 cell proliferation was assessed by methyl thiazolyl tetrazolium colorimetric assay. Furthermore, cell cycle-apoptosis was analyzed by flow cytometry, P-glycoprotein (P-gp) expression was determined by western blot analysis and caspase-3 activity was measured using a caspase-3 activity kit. TcdA inhibited K562/A02 cell proliferation in a time- and dose-dependent manner. The inhibition rate of K562/A02 cells reached 8.76±0.76, 28.55±0.43, 47.89±0.27, 58.08±0.06 and 57.70±0.79% following treatment with 50, 100, 200, 400 and 800 ng/ml TcdA, respectively, for 24 h. K562/A02 cells in the G0/G1 phase increased and cells in the S phase decreased following treatment with TcdA (P<0.05), and the apoptotic rates in the 200 and 400 ng/ml concentration groups were 14.05 and 22.89%, respectively. In addition, TcdA (50 ng/ml) significantly inhibited the proliferation of K562/A02 cells and reduced the half maximal inhibitory concentration of these drugs in combination with chemotherapy drugs. The reversal folds were 3.09, 2.89 and 2.79, respectively. Furthermore, TcdA treatment was associated with the upregulation of P-gp in K562/A02 cells, and caspase-3 activity was observed to increase in K562/A02 cells following TcdA treatment, when compared with untreated controls (P<0.05). These findings suggested that TcdA may be able to inhibit K562/A02 cell growth, induce cell apoptosis by decreasing P-gp levels and caspase-3 activation, and partially reverse MDR. Further studies are required to evaluate the potential of TcdA as a candidate for the chemotherapy of hematologic malignancies.

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“…P-gp transports neutral or cationic hydrophobic and unmodified compounds, and it is involved in the resistance of several important chemotherapy agents including anthracyclines (e.g., doxorubicin), taxanes (e.g., paclitaxel), vinca alkaloids (e.g., vinblastine), antibiotics (e.g., actinomycin D), tyrosine kinase inhibitors (TKIs) (e.g., imatinib), epidermal growth factor receptor TKIs (e.g., erlotinib) which shows why this transporter can modulate the efficiency of treatment regimens used in many cancer types [28]. Lastly, glycoprotein-P can participate in the apoptosis-related resistance either by its efflux activity or by regulating cell proliferation, differentiation and death [29]. For instance, the downregulation of P-gp expression can affect the downregulation of survivin expression-an anti-apoptotic protein-demonstrating that they might share same regulators and therefore, modulate apoptosis [29][30][31].…”

Section: Multidrug Resistance In Cancermentioning

confidence: 99%

“…Lastly, glycoprotein-P can participate in the apoptosis-related resistance either by its efflux activity or by regulating cell proliferation, differentiation and death [29]. For instance, the downregulation of P-gp expression can affect the downregulation of survivin expression-an anti-apoptotic protein-demonstrating that they might share same regulators and therefore, modulate apoptosis [29][30][31].…”

Section: Multidrug Resistance In Cancermentioning

confidence: 99%

The Effect of Nanosystems on ATP-Binding Cassette Transporters: Understanding the Influence of Nanosystems on Multidrug Resistance Protein-1 and P-glycoprotein

Mello

Moraes

Maia

et al. 2020

IJMS

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The cancer multidrug resistance is involved in the failure of several treatments during cancer treatment. It is a phenomenon that has been receiving great attention in the last years due to the sheer amount of mechanisms discovered and involved in the process of resistance which hinders the effectiveness of many anti-cancer drugs. Among the mechanisms involved in the multidrug resistance, the participation of ATP-binding cassette (ABC) transporters is the main one. The ABC transporters are a group of plasma membrane and intracellular organelle proteins involved in the process of externalization of substrates from cells, which are expressed in cancer. They are involved in the clearance of intracellular metabolites as ions, hormones, lipids and other small molecules from the cell, affecting directly and indirectly drug absorption, distribution, metabolism and excretion. Other mechanisms responsible for resistance are the signaling pathways and the anti- and pro-apoptotic proteins involved in cell death by apoptosis. In this study we evaluated the influence of three nanosystem (Graphene Quantum Dots (GQDs), mesoporous silica (MSN) and poly-lactic nanoparticles (PLA)) in the main mechanism related to the cancer multidrug resistance such as the Multidrug Resistance Protein-1 and P-glycoprotein. We also evaluated this influence in a group of proteins involved in the apoptosis-related resistance including cIAP-1, XIAP, Bcl-2, BAK and Survivin proteins. Last, colonogenic and MTT (3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide) assays have also been performed. The results showed, regardless of the concentration used, GQDs, MSN and PLA were not cytotoxic to MDA-MB-231 cells and showed no impairment in the colony formation capacity. In addition, it has been observed that P-gp membrane expression was not significantly altered by any of the three nanomaterials. The results suggest that GQDs nanoparticles would be suitable for the delivery of other multidrug resistance protein 1 (MRP1) substrate drugs that bind to the transporter at the same binding pocket, while MSN can strongly inhibit doxorubicin efflux by MRP1. On the other hand, PLA showed moderate inhibition of doxorubicin efflux by MRP1 suggesting that this nanomaterial can also be useful to treat MDR (Multidrug resistance) due to MRP1 overexpression.

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Effects of P-Glycoprotein and Its Inhibitors on Apoptosis in K562 Cells

Cited by 30 publications

References 35 publications

L1210 Cells Overexpressing ABCB1 Drug Transporters Are Resistant to Inhibitors of the N- and O-glycosylation of Proteins

L1210 Cells Overexpressing ABCB1 Drug Transporters Are Resistant to Inhibitors of the N- and O-glycosylation of Proteins

Effects of Clostridiumï¿½difficile toxin A on K562/A02 cell proliferation, apoptosis and multi-drug resistance

The Effect of Nanosystems on ATP-Binding Cassette Transporters: Understanding the Influence of Nanosystems on Multidrug Resistance Protein-1 and P-glycoprotein

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