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

Długosz-Pokorska, Angelika; Pięta, Marlena; Janecki, Tomasz; Janecka, Anna

doi:10.1007/s11033-019-05017-w

Cited by 8 publications

(6 citation statements)

References 45 publications

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“…Based on the resistance mechanisms discussed, certain SMIs recently studied may also be considered as potential agents to potentiate 5-FU cytotoxicity effects. Patients evaluated with higher expression of ABC transporters such as ABCC1, ABCB1, and ABCG2 for instance, may benefit significantly from 5-FU therapy when co-administered with uracil analogue U-332 that may abrogate the expression of all three transporters [ 283 ]. Alternatively, patients assessed with DPD overexpression commonly associated with incidence DYPD*2A polymorphisms may consider the use of 5-FU together with JTE-013 to effectively inhibit S1PR2 as the upstream regulator of DPD expression [ 236 ].…”

Section: Reversal Strategiesmentioning

confidence: 99%

Recent Updates on Mechanisms of Resistance to 5-Fluorouracil and Reversal Strategies in Colon Cancer Treatment

Azwar

Seow

Abdullah

et al. 2021

Biology

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5-Fluorouracil (5-FU) plus leucovorin (LV) remain as the mainstay standard adjuvant chemotherapy treatment for early stage colon cancer, and the preferred first-line option for metastatic colon cancer patients in combination with oxaliplatin in FOLFOX, or irinotecan in FOLFIRI regimens. Despite treatment success to a certain extent, the incidence of chemotherapy failure attributed to chemotherapy resistance is still reported in many patients. This resistance, which can be defined by tumor tolerance against chemotherapy, either intrinsic or acquired, is primarily driven by the dysregulation of various components in distinct pathways. In recent years, it has been established that the incidence of 5-FU resistance, akin to multidrug resistance, can be attributed to the alterations in drug transport, evasion of apoptosis, changes in the cell cycle and DNA-damage repair machinery, regulation of autophagy, epithelial-to-mesenchymal transition, cancer stem cell involvement, tumor microenvironment interactions, miRNA dysregulations, epigenetic alterations, as well as redox imbalances. Certain resistance mechanisms that are 5-FU-specific have also been ascertained to include the upregulation of thymidylate synthase, dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase, and the downregulation of thymidine phosphorylase. Indeed, the successful modulation of these mechanisms have been the game plan of numerous studies that had employed small molecule inhibitors, plant-based small molecules, and non-coding RNA regulators to effectively reverse 5-FU resistance in colon cancer cells. It is hoped that these studies would provide fundamental knowledge to further our understanding prior developing novel drugs in the near future that would synergistically work with 5-FU to potentiate its antitumor effects and improve the patient’s overall survival.

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Section: Reversal Strategiesmentioning

confidence: 99%

Recent Updates on Mechanisms of Resistance to 5-Fluorouracil and Reversal Strategies in Colon Cancer Treatment

Azwar

Seow

Abdullah

et al. 2021

Biology

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“…The important finding of the research presented here and in our previous papers [31,33] was the identification of the novel uracil analog as a potent inhibitor of NF-κB and ABCC1 transporter expression. The inactivation of NF-κB subunits was shown to correlate with the inhibition of ABC transporter activity which may lead to the increased accumulation of a drug in cancer cells.…”

Section: Discussionmentioning

confidence: 58%

“…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. U-332 almost completely abolished ABCC1 expression in the resistant HL-60/5FU cells disturbing therefore drug efflux [31].…”

Section: Introductionmentioning

confidence: 92%

“…The process was repeated until the cells were able to tolerate up to 10 mg/L of 5-FU. The detailed description of this procedure was given elsewhere [31].…”

Section: Cell Culturementioning

confidence: 99%

“…1), caused in HL-60 cells excessive DNA damage which led to the cell cycle arrest in G2/M phase and apoptosis. To determine the activity of U-332 in the resistant cells, we recently selected a 5-FU resistant subclone (HL-60/5FU) of HL-60 cell line by the conventional method of the continuous exposure of the cells to 5-FU up to 0.08 mmol/L concentration [31]. HL-60/5FU cells exhibited a 6-fold enhanced resistance to 5-FU as compared with HL-60 cells.…”

Section: Introductionmentioning

confidence: 99%

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New uracil analog U-332 is an inhibitor of NF-κB in 5-fluorouracil-resistant human leukemia HL-60 cell line

Długosz-Pokorska

Pięta

Kędzia

et al. 2020

BMC Pharmacol Toxicol

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Background: 5-Fluorouracil (5-FU) is an antimetabolite that interferes with DNA synthesis and has been widely used as a chemotherapeutic drug in various types of cancers. However, the development of drug resistance greatly limits its application. Overexpression of ATP-binding cassette (ABC) transporters in many types of cancer is responsible for the reduction of the cellular uptake of various anticancer drugs causing multidrug resistance (MDR), the major obstacle in cancer chemotherapy. Recently, we have obtained a novel synthetic 5-FU analog, U-332 [(R)-3-(4-bromophenyl)-1-ethyl-5-methylidene-6-phenyldihydrouracil], combining a uracil skeleton with an exo-cyclic methylidene group. U-332 was highly cytotoxic for HL-60 cells and showed similar cytotoxicity in the 5-FU resistant subclone (HL-60/5FU), in which this analog almost completely abolished expression of the ATP-binding cassette (ABC) transporter, multidrug resistance associate protein 1 (ABCC1). The expression of ABC transporters is usually correlated with NF-κB activation. The aim of this study was to determine the level of NF-κB subunits in the resistant HL-60/5-FU cells and to evaluate the potential of U-332 to inhibit activation of NF-κB family members in this cell line. Methods: Anti-proliferative activity of compound U-332 was assessed by the MTT assay. In order to disclose the mechanism of U-332 cytotoxicity, quantitative real-time PCR analysis of the NF-κB family genes, c-Rel, RelA, RelB, NF-κB1, and NF-κB2, was investigated. The ability of U-332 to reduce the activity of NF-κB members was studied by ELISA test. Results: In this report it was demonstrated, using RT-PCR and ELISA assay, that members of the NF-κB family c-Rel, RelA, RelB, NF-κB1, and NF-κB2 were all overexpressed in the 5-FU-resistant HL-60/5FU cells and that U-332 potently reduced the activity of c-Rel, RelA and NF-κB1 subunits in this cell line. 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.

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ATP-binding cassette efflux transporters and MDR in cancer

Pote

Gacche

2023

Drug Discovery Today

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

Cited by 8 publications

References 45 publications

Recent Updates on Mechanisms of Resistance to 5-Fluorouracil and Reversal Strategies in Colon Cancer Treatment

Recent Updates on Mechanisms of Resistance to 5-Fluorouracil and Reversal Strategies in Colon Cancer Treatment

New uracil analog U-332 is an inhibitor of NF-κB in 5-fluorouracil-resistant human leukemia HL-60 cell line

ATP-binding cassette efflux transporters and MDR in cancer

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