New uracil analogs as downregulators of ABC transporters in 5-fluorouracil-resistant human leukemia HL-60 cell line.

New uracil analogs as downregulators of ABC transporters in 5-fluorouracil-resistant human leukemia HL-60 cell line. Mol Biol Rep. 2019 Nov 18;: Authors: Długosz-Pokorska A, Pięta M, Janecki T, Janecka A Abstract Overexpression of ATP-binding cassette (ABC) transporters causing multidrug resistance (MDR) in cancer cells is one of the major obstacles in cancer chemotherapy. The 5-FU resistant subclone (HL-60/5FU) of the human HL-60 promyelocytic leukemia cell line was selected by the conventional method of continuous exposure of the cells to the drug up to 0.08 mmol/L concentration. HL-60/5FU cells exhibited six-fold enhanced resistance to 5-FU than HL-60 cells. RT-PCR and ELISA assay showed significant overexpression of MDR-related ABC transporters, ABCB1, ABCG2 but especially ABCC1 in the HL-60/5FU as compared with the parental cell line. Three novel synthetic 5-methylidenedihydrouracil analogs, U-236, U-332 and U-359, selected as highly cytotoxic for HL-60 cells in MTT test, showed similar cytotoxicity in the resistant cell line. When co-incubated with 5-FU, these analogs were found to down-regulate the expression of all three transporters. However, the most pronounced effect was caused by U-332 which almost completely abolished ABCC1 expression in the resistant HL-60/5FU cells. Additionally, U-332 inhibited the activity of ATPase, an enzyme which catalyzes hydrolysis of ATP, providing energy to efflux drugs from the cells through the cellular m...
Source: Molecular Biology Reports - Category: Molecular Biology Authors: Tags: Mol Biol Rep Source Type: research

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Multidrug resistance (MDR) in cancer arises from cross-resistance to structurally- and functionally-divergent chemotherapeutic drugs. In particular, MDR is characterized by increased expression and activity of ATP-binding cassette (ABC) superfamily transporters. Sphingolipids are substrates of ABC proteins in cell signaling, membrane biosynthesis, and inflammation, for example, and their products can favor cancer progression. Glucosylceramide (GlcCer) is a ubiquitous glycosphingolipid (GSL) generated by glucosylceramide synthase, a key regulatory enzyme encoded by the UDP-glucose ceramide glucosyltransferase (UGCG) gene. S...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Glycobiology and Extracellular Matrices Source Type: research
CONCLUSIONS: This finding indicates that c-Rel, RelA and NF-κB1 subunits are responsible for the resistance of HL-60/5FU cells to 5-FU and that U-332 is able to reverse this resistance. U-332 can be viewed as an important lead compound in the search for novel drug candidates that would not cause multidrug resistance in cancer cells. PMID: 32122395 [PubMed - in process]
Source: BMC Pharmacology and Toxicology - Category: Drugs & Pharmacology Tags: BMC Pharmacol Toxicol Source Type: research
Authors: Feng Z, Chen Q Abstract Acute myeloid leukemia is a common hematological malignancy that often exhibits strong drug resistance when treated using conventional chemotherapy. Although numerous studies have been carried out to develop methods of overcoming drug resistance, the results have generally been unsatisfactory. CD40 ligand (CD40L) has been shown to improve the sensitivity of cancer cells to drug treatment. In the present study, Adriamycin (ADM)-resistant human monocytic THP-1 cells (THP-1/A cells) were developed by incubating THP-1 cells with increasing concentrations of ADM. Cells were transfected w...
Source: Experimental and Therapeutic Medicine - Category: General Medicine Tags: Exp Ther Med Source Type: research
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 potentiat...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
Publication date: May 2020Source: Biomedicine &Pharmacotherapy, Volume 125Author(s): Ka-Na Lin, Yue-Lian Jiang, Shun-Guo Zhang, Shi-Ying Huang, Hao LiAbstractBackground and purposeMultidrug resistance (MDR) is a great challenge and obstacle in cancer treatment. It is a common problem in the treatment of acute myeloid leukemia (AML). Whether grape seed proanthocyanidin extract (GSPE) could reverse MDR in patients with AML is still unknown. The aim of this study was to investigate the MDR reverse ability of GSPE and its possible mechanism in vitro.Materials and methodsHuman leukemia cell line HL-60 cells and HL-ADR cells...
Source: Biomedicine and Pharmacotherapy - Category: Drugs & Pharmacology Source Type: research
Abstract The majority of cancers detected every year are treated with anti-cancer compounds. Unfortunately, many tumors become resistant to antineoplastic drugs. One option is to use cocktails of compounds acting on different targets to try to overcome the resistant cells. This type of approach can produce good results, but is often accompanied by a sharp increase of associated side effects. The strategy presented herein focuses on the use of a single compound acting on two different biological targets enhancing potency and lowering the toxicity of the chemotherapy. In this light, the approach presented in the cur...
Source: Bioorganic Chemistry - Category: Chemistry Authors: Tags: Bioorg Chem Source Type: research
In this study, the cytotoxicity of the crude extract (DCB) and compounds isolated from the bark of Dichrostachys cinerea, namely, betulinic acid (1), glyceryl-1-hexacosanoate (2), 7-hydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one (3), and 6-hydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one (4), was investigated. The study was extended to the assessment of the mode of induction of apoptosis by DCB and compound 1. The resazurin reduction assay was used for cytotoxicity studies. Assessments of cell cycle distribution, apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) were performed by flow cytometry...
Source: Evidence-based Complementary and Alternative Medicine - Category: Complementary Medicine Tags: Evid Based Complement Alternat Med Source Type: research
In this study, we found midostaurin, a Food and Drug Administration (FDA)-approved anti-leukemia drug, can antagonize ATP-binding cassette subfamily B member 1 (ABCB1)-mediated MDR. Our results showed that midostaurin significantly antagonized ABCB1-mediated MDR, but not the MDR mediated by ATP-binding cassette subfamily G member 2 (ABCG2). Mechanism studies showed that midostaurin reversed MDR by inhibiting the function of the ABCB1 without downregulating or change of subcellular localization of ABCB1 transporter. In addition, midostaurin inhibited the ATPase activity of ABCB1 in a concentration-dependent manner, and the ...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
ns LF Abstract PIM-1 is a kinase which has been related to the oncogenic processes like cell survival, proliferation and multidrug resistance (MDR). This kinase is known for its ability to phosphorylate the main extrusion pump (ABCB1) related to the MDR phenotype. In the present work, we testes a new mechanistic insight on the AZD1208 (PIM-1 specific inhibitor) under interaction with chemotherapy agents such as Daunorubicin (DNR) and Vincristine (VCR). In order to verify a potential cytotoxic effect based on pharmacological synergism, two MDR cell lines were used: Lucena resistant to VCR) and FEPS (resistant to DN...
Source: Current Topics in Medicinal Chemistry - Category: Chemistry Authors: Tags: Curr Top Med Chem Source Type: research
In this study we tested the clinoptilolite, chabazite, and natrolite ability to be loaded by antitumor ribonuclease binase and the cytotoxicity of the obtained complexes. We found the optimal conditions for binase loading into zeolites and established the dynamic of its release. Cytotoxic effects of zeolite-binase complexes toward colorectal cancer Caco2 cells were characterized after 24 and 48 h of incubation with cells using MTT-test. Zeolites were toxic by itselfs and reduced cells viability by 30% (clinoptilolite), 40% (chabazite), and 70% (natrolite) after 48 h of incubation. Binase complexes with clinoptilolite as we...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
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