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Biochemical and Biophysical Research... Jun 2022Multidrug resistant tumor cells show collaterally sensitive to a range of non-toxic drugs. In this report, we describe the isolation of several P-glycoprotein-knockout...
Multidrug resistant tumor cells show collaterally sensitive to a range of non-toxic drugs. In this report, we describe the isolation of several P-glycoprotein-knockout cell clones, using CRISPR/Cas9, from Chinese hamster multidrug resistant model cell line and its parental cells (e.g., CHOC5 and AuxB1, respectively). All three P-glycoprotein-knockout clones of CHOC5 cells show complete loss of resistance to anti-cancer drugs (e.g., colchicine and doxorubicin), while gaining resistance to well characterized collateral sensitivity drugs (e.g., verapamil, progesterone and NSC73306). A correlation between P-glycoprotein and Sorcin expression levels and a possible role for the latter in low grade resistance to colchicine and doxorubicin was observed. Furthermore, we show that P-glycoprotein expression is necessary for the ROS-mediated mechanism of collateral sensitivity. However, expectantly, P-glycoprotein-knockout clones of CHOC5 cells revealed a dramatic increase in the accumulation of Rhodamine 123, Mito tracker red and doxorubicin, but not Hoechst 33342. The latter findings and their significance to P-glycoprotein collateral sensitivity remain to be determined.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; CHO Cells; Colchicine; Cricetinae; Doxorubicin; Drug Collateral Sensitivity; Drug Resistance; Verapamil
PubMed: 35381425
DOI: 10.1016/j.bbrc.2022.03.148 -
Doklady. Biochemistry and Biophysics Dec 2022In the study on cells of the Caco-2 line, the affiliation of malondialdehyde (MDA) to modulators and substrates of P-glycoprotein (Pgp) was assessed, and the biological...
In the study on cells of the Caco-2 line, the affiliation of malondialdehyde (MDA) to modulators and substrates of P-glycoprotein (Pgp) was assessed, and the biological role of Pgp in conditions of oxidative stress (OS) was studied. MDA was used at concentrations of 10, 50, 100, and 150 μM; OS was simulated by incubation with hydrogen peroxide (HO) at concentrations of 0.1-100 μM for 24 h. The relative amount of Pgp was evaluated by the Western blot hybridization, and the activity was estimated by the transport of its substrate fexofenadine (HPLC with UV detection, HPLC MS/MS). In this study, it was shown that MDA at concentrations of 10 and 50 μM and exposure duration of 24 h increases the relative amount and activity of Pgp by acting through CAR and PXR, and MDA can be transported by Pgp. The induction of Pgp under the action of MDA during the development of OS can have a protective significance, ensuring the removal of the peroxidation product from cells into the extracellular space and thereby increasing the viability of cells.
Topics: Humans; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Caco-2 Cells; Hydrogen Peroxide; Tandem Mass Spectrometry; Malondialdehyde
PubMed: 36786982
DOI: 10.1134/S1607672922060096 -
Advances in Experimental Medicine and... 2019The anticancer potential of Ganoderma (Lingzhi) and its extracts has been widely demonstrated, including antiproliferative and apoptosis inductive, antimetastatic,... (Review)
Review
The anticancer potential of Ganoderma (Lingzhi) and its extracts has been widely demonstrated, including antiproliferative and apoptosis inductive, antimetastatic, antiangiogenic, and multidrug resistance reversional activities, involving a variety of cellular and molecular mechanisms besides antitumor immunology. Intrinsic- and extrinsic-initiated apoptotic pathway in association with cell cycle arresting, telomerase inhibiting, autophagy, and oxidative stress is involved in the antiproliferative and apoptosis inductive activities of Ganoderma and its extracts. The inhibition of tumor cell adhesion, invasion, and migration by Ganoderma and its extracts involves molecular mechanisms such as AP-1, NF-κB, MMP, cadherin, β-integrin, c-Met, FAK, EMT, and so on. Targeting the major pro-angiogenic stimulus, VEGF, and its receptor contributes to the inhibition of tumor angiogenesis by Ganoderma and its extracts. Inhibition against the ATP-dependent transmembrane drug transporter such as P-glycoprotein (P-gp) on the surface of resistant tumor cells to prevent reduction of the intracellular accumulation of anticancer drugs by pumping out the drugs plays an important role in the activities of Ganoderma and its extracts to reverse tumor cell multidrug resistance.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Antineoplastic Agents; Apoptosis; Biological Products; Cell Line, Tumor; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Neoplasms; Reishi
PubMed: 31777015
DOI: 10.1007/978-981-32-9421-9_3 -
Current Pharmaceutical Design 2018Medicinal value of natural products comes from symbiotic and competitive evolution in Earth's complex biosphere. Billions of years of co-evolutionary interactions among... (Review)
Review
Medicinal value of natural products comes from symbiotic and competitive evolution in Earth's complex biosphere. Billions of years of co-evolutionary interactions among millions of species have produced a large repertoire of defense molecules effective in fighting bacteria, viral, and fungal pathogens. Each species contains millions of different and useful molecules and new research technologies enabled the screening of molecules and complex mixtures from diverse biological sources. Traditional use of plants and other species led to the discovery of many bioactive compounds with various properties. In the last four decades, a large number of them were evaluated for their potential to treat cancer. Penetration of drugs into the cancer cell is necessary for their lethal pharmacological effect through interaction with intracellular target molecules. Increased activity of membrane efflux pumps reduces the intracellular drug accumulation, thereby preventing drug-target interactions. The discovery of the efflux transporter P-glycoprotein (P-gp) in multidrug resistant (MDR) cancer cells prompted the efforts in overcoming drug resistance by P-gp inhibition. The search for nontoxic anticancer agents from natural sources able to overcome MDR has been imperative in the field of drug design and discovery. Herein, we review various natural compounds from diverse sources emphasizing their potential to inhibit P-gp activity and/or expression.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antineoplastic Agents; Biological Products; Drug Design; Drug Discovery; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Neoplasms
PubMed: 30648503
DOI: 10.2174/1381612825666190112164211 -
Current Drug Metabolism 2016P-glycoprotein (P-gp), a well known ATP dependent efflux membrane transporter, has been attracting considerable interests of medical researchers due to its efflux pump... (Review)
Review
BACKGROUND
P-glycoprotein (P-gp), a well known ATP dependent efflux membrane transporter, has been attracting considerable interests of medical researchers due to its efflux pump effect being a primary cause of multidrug resistance (MDR) and poor bioavailability (BA) of anticancer agents. How to resolve the aforesaid problems has become the research hot-points in the medical and pharmaceutical fields. The past three decades have witnessed rapid development of the P-gp inhibition-based strategies used for modulating pharmacokinetics (PK) and thus overcoming MDR and improving BA of anticancer drugs.
METHODS
An electronic search of PubMed database from inception to April, 2016 was conducted. Additionally, we searched the reference lists of included studies and carried out a citation search for the included studies via Web of Science to find other potentially relevant studies.
RESULTS AND CONCLUSION
Lots of the studies of the P-gp inhibition-based strategies are under preclinical phase and the obtained results are exciting and may represent great promise in the clinical application potential. In order to provide useful information for the development of novel strategies for improving BA of anticancer drugs, this article aims to review the research progress in the P-gp inhibition-based strategies that has been acquired over the last three decades, with focus on the P-gp inhibitors, herbal constituents and pharmaceutical excipients as well as novel P-gp-linked drug delivery systems (DDSs). Additionally, the fundamental knowledge on P-gp also is briefly discussed.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antineoplastic Agents; Humans
PubMed: 27364832
DOI: 10.2174/1389200217666160629112717 -
Drug Metabolism and Pharmacokinetics Apr 2020Effect of long-term treatment with cigarette smoke extract (CSE) on the function and expression of P-glycoprotein (P-gp) in lung alveolar epithelial cells was examined...
Effect of long-term treatment with cigarette smoke extract (CSE) on the function and expression of P-glycoprotein (P-gp) in lung alveolar epithelial cells was examined using A549/P-gp cell line expressing P-gp. CSE treatment suppressed P-gp activity in a concentration- and treatment time-dependent manner. The suppression of P-gp activity by CSE was irreversible for at least 96 h after removal of CSE. In addition, CSE treatment suppressed the expression of P-gp mRNA and protein. In order to understand the mechanisms underlying P-gp suppression by CSE, the role of reactive oxygen species (ROS) was examined. CSE treatment increased intracellular ROS level, and suppressed catalase activity. α-Tocopherol suppressed ROS production by CSE, and ameliorated the suppression of P-gp activity by CSE, suggesting that ROS is involved in CSE-induced suppression of P-gp. The role of intracellular signaling pathways such as the nuclear factor κB and mitogen-activated protein kinase pathways was also examined. Among these pathways, the involvement of extracellular signal-regulated kinase (ERK) pathway was suggested. Taken together, long-term CSE treatment may suppress P-gp via modulation of ROS level and ERK pathway in alveolar epithelial cells.
Topics: A549 Cells; ATP Binding Cassette Transporter, Subfamily B, Member 1; Epithelial Cells; Humans; Lung Neoplasms; Mitogen-Activated Protein Kinases; Plant Extracts; Reactive Oxygen Species; Signal Transduction; Smoke
PubMed: 32037157
DOI: 10.1016/j.dmpk.2019.12.001 -
Medicinal Research Reviews Jan 2021Multidrug resistance (MDR) remains one of the major impediments for efficacious cancer chemotherapy. Increased efflux of multiple chemotherapeutic drugs by transmembrane... (Review)
Review
Multidrug resistance (MDR) remains one of the major impediments for efficacious cancer chemotherapy. Increased efflux of multiple chemotherapeutic drugs by transmembrane ATP-binding cassette (ABC) transporter superfamily is considered one of the primary causes for cancer MDR, in which the role of P-glycoprotein (P-gp/ABCB1) has been most well-established. The clinical co-administration of P-gp drug efflux inhibitors, in combination with anticancer drugs which are P-gp transport substrates, was considered to be a treatment modality to surmount MDR in anticancer therapy by blocking P-gp-mediated multidrug efflux. Extensive attempts have been carried out to screen for sets of nontoxic, selective, and efficacious P-gp efflux inhibitors. In this review, we highlight the recent achievements in drug design, characterization, structure-activity relationship (SAR) studies, and mechanisms of action of the newly synthetic, potent small molecules P-gp inhibitors in the past 5 years. The development of P-gp inhibitors will increase our knowledge of the mechanisms and functions of P-gp-mediated drug efflux which will benefit drug discovery and clinical cancer therapeutics where P-gp transporter overexpression has been implicated in MDR.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Antineoplastic Agents; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Neoplasms
PubMed: 33047304
DOI: 10.1002/med.21739 -
Biochemical and Biophysical Research... Jan 2019Gambogenic acid (GNA), an active ingredient isolated from Gamboge, which possesses diverse antitumor effects in vivo and vitro. Here we were mainly designed to...
Gambogenic acid (GNA), an active ingredient isolated from Gamboge, which possesses diverse antitumor effects in vivo and vitro. Here we were mainly designed to understand the role of GNA in drug resistance in HepG2/Adr cells. The alteration of cytotoxic drugs IC was examined using the MTT method. Cell apoptosis and uptake of P-glycoprotein (P-gp) substrates were measured under a flow cytometry and fluorescence microscope, respectively. Moreover, the ATPase activity, the expression of P-gp and P-gp-related proteins were also investigated. Results of the MTT method indicated that GNA increased the chemosensitivity of doxorubicin (DOX) and paclitaxel (PTX) in the HepG2/Adr cells and promoted the cell apoptosis in the presence of DOX. Meanwhile, it was also increased the retention of P-gp substrates DOX and Rhodamine 123 (Rho-123) while did not affect the ATPase activity. Furthermore, the down-regulation of P-gp expression could be contributed to multidrug resistance (MDR) upon a reversal concentration of 0.8 μg/mL GNA. Mechanistically, the expression of P-gp was reduced by GNA may result from the inhibition of the NF-kB and MAPK pathway. Collectively, GNA could be a potential inhibitor to reverse P-gp-mediated MDR in liver cancer therapy.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Adenosine Triphosphatases; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Hep G2 Cells; Humans; Liver Neoplasms; Mitogen-Activated Protein Kinases; NF-kappa B; Rhodamine 123; Xanthenes
PubMed: 30538042
DOI: 10.1016/j.bbrc.2018.12.028 -
The AAPS Journal Mar 2017P-glycoprotein (Pgp) is an ATP-binding cassette (ABC) transporter that plays a major role in cardiovascular drug disposition by effluxing a chemically and structurally... (Review)
Review
P-glycoprotein (Pgp) is an ATP-binding cassette (ABC) transporter that plays a major role in cardiovascular drug disposition by effluxing a chemically and structurally diverse range of cardiovascular therapeutics. Unfortunately, drug-drug interactions (DDIs) with the transporter have become a major roadblock to effective cardiovascular drug administration because they can cause adverse drug reactions (ADRs) or reduce the efficacy of drugs. Cardiovascular ion channel inhibitors are particularly susceptible to DDIs and ADRs with Pgp because they often have low therapeutic indexes and are commonly coadministered with other drugs that are also Pgp substrates. DDIs from cardiovascular ion channel inhibitors with the transporter occur because of inhibition or induction of the transporter and the transporter's tissue and cellular localization. Inhibiting Pgp can increase absorption and reduce excretion of drugs, leading to elevated drug plasma concentrations and drug toxicity. In contrast, inducing Pgp can have the opposite effect by reducing the drug plasma concentration and its efficacy. A number of in vitro and in vivo studies have already demonstrated DDIs from several cardiovascular ion channel inhibitors with human Pgp and its animal analogs, including verapamil, digoxin, and amiodarone. In this review, Pgp-mediated DDIs and their effects on pharmacokinetics for different categories of cardiovascular ion channel inhibitors are discussed. This information is essential for improving pharmacokinetic predictions of cardiovascular therapeutics, for safer cardiovascular drug administration and for mitigating ADRs emanating from Pgp.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Biological Transport; Cardiovascular Agents; Drug Interactions; Humans; Ion Channels
PubMed: 28028729
DOI: 10.1208/s12248-016-0023-y -
Food Chemistry May 2021ABCB1 (P-glycoprotein/MDR1) is a multidrug efflux transporter that has previously been involved in cholesterol and vitamin D metabolism. Our aim was to explore whether...
ABCB1 (P-glycoprotein/MDR1) is a multidrug efflux transporter that has previously been involved in cholesterol and vitamin D metabolism. Our aim was to explore whether ABCB1 is also involved in vitamin K efflux. Vitamin K apical efflux was significantly decreased in presence of ABCB1 inhibitor in Caco-2 cells (-20.4%; p < 0.05) and increased in Griptite cells overexpressing ABCB1 (+40.7%; p < 0.05). In vivo, the vitamin K postprandial response was higher in male Abcb1 mice after gavage compared to control animals (+115%; p < 0.05), but was unchanged in female mice. Finally, a vitamin K transintestinal efflux and a biliary vitamin K efflux were observed, but the specific involvement of ABCB1 could not be confirmed in these pathways. Overall, we showed for the first time that ABCB1 is involved in enterocyte vitamin K efflux in both cell and mouse models and regulates vitamin K absorption in mice.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Caco-2 Cells; Enterocytes; Female; Humans; Male; Mice, Mutant Strains; Postprandial Period; Recombinant Proteins; Vitamin K; Mice
PubMed: 33172753
DOI: 10.1016/j.foodchem.2020.128510