Expression of some ATP-binding cassette transporters in acute myeloid leukemia

Salvia, Antonella Maria; Cuviello, Flavia; Coluzzi, Sabrina; Nuccorini, Roberta; Attolico, Immacolata; Pascale, Sara Pasquina; Bisaccia, Faustino; Pizzuti, Michele; Ostuni, Angela

doi:10.4081/hr.2017.7406

Cited by 21 publications

(16 citation statements)

References 22 publications

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“…Activation of NF-κB or/and overexpression of ABC transmembrane proteins play a major role in the resistance of tumor cells to chemotherapy [2][3][4]. Many chemotherapeutic agents, including 5-FU, doxorubicin, etoposide or cisplatin have been reported to activate NF-κB and to upregulate expression of ABC transporters [37][38][39][40]. In several cancer cell lines the inhibition of either NF-κB or ABC transporter activity increased intracellular accumulation of chemotherapeutic drugs [41][42][43].…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…Despite advances in cancer research, chemotherapy remains the first-line treatment for AML, the efficacy of which is limited by the development of MDR. The overexpression of drug-efflux pumps has been implicated in the failure of AML chemotherapy, causing disease refraction or relapse (27). Therefore, substances that are capable of restoring chemosensitivity are continuously being investigated to maintain cytotoxicity and the clinical response of chemotherapeutics.…”

Section: Discussionmentioning

confidence: 99%

WYE-354 restores Adriamycin sensitivity in multidrug-resistant acute myeloid leukemia cell lines

et al. 2019

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Multidrug resistance (MDR) is a major reason for the failure of acute myeloid leukemia (AML) therapy. Agents that reverse MDR and sensitize AML cells to chemotherapy are of great clinical significance. The present study developed Adriamycin (Adr)-resistant cell lines, namely K562/Adr200 and K562/Adr500, which exhibited MDR. The upregulation of ATP-binding cassette subfamily B member 1 (ABCB1) was confirmed as the mechanism of resistance by reverse transcription-quantitative polymerase chain reaction and western blot analyses. Subsequently, the role of the mammalian target of rapamycin (mTOR) kinase inhibitor, WYE-354, in sensitizing the K562/Adr200 and K562/Adr500 cell lines to Adr was evaluated. At sub-cytotoxic concentrations, WYE-354 increased Adr cytotoxicity in the K562/Adr200 and K562/Adr500 cells. WYE-354 restored Adr sensitivity in the resistant cells by inhibiting ABCB1-mediated substrate efflux, thereby leading to an accumulation of Adr, an increase in Adr-mediated G2/M cell cycle arrest and the induction of apoptosis. Furthermore, WYE-354 stimulated the ATPase activity of ABCB1, which was consistent with in silico predictions using a human ABCB1 mouse homology model, indicating that WYE-354 is a potent substrate of ABCB1. WYE-354 did not regulate the expression of ABCB1 at the concentrations used in the present study. These findings indicate that WYE-354 may be a competitive inhibitor of ABCB1-mediated efflux and a potential candidate in combination with standard chemotherapy for overcoming MDR. Further clinical investigations are warranted to validate this combination in vivo .

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“…It is well known that P-glycoprotein (P-gp) overexpression in tumor tissues is the major mechanism of MDR, yet it is not the solely mechanism. Rising researches revealed that MDR-associated proteins (MRPs), members of ABC transporter superfamily, play important parts in cellular multidrug resistance [24, 25]. MRPs chiefly exist in the plasma membrane and seem to act as a drug pump which can reduce cellular drug levels, resulting in cellular multidrug resistance [24].…”

Section: Discussionmentioning

confidence: 99%

IL-13 Contributes to Drug Resistance of NK/T-Cell Lymphoma Cells by Regulating ABCC4

Qin

Xie

et al. 2018

BioMed Research International

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Background Extranodal natural killer/T (NK/T) cell lymphoma, nasal type (ENKTL), represents a rare subtype of T-cell lymphomas with aggressive clinical behavior and is relatively resistant to chemotherapy. However, there is relatively poor understanding of molecular pathogenesis of multidrug resistance in ENKTL. Here, we aimed to explore the biological roles and potential mechanism of IL-13 and ABCC4 in multidrug resistance of NK/T-cell lymphoma. Methods ELISA analysis was used to determine the level of serum IL-13 and immunohistochemical analysis was applied to detect the ABCC4 expression level in patients with human NK/T-cell lymphoma. Western blot assay was employed to measure the expression of ABCC4 in cells. Lenti-sh-ABCC4 viruses were constructed to knock down ABCC4 in YTS cells. CCK-8 assay and flow cytometric analysis were performed to detect the effects of IL-13 and ABCC4 on cell proliferation and apoptosis. CCK-8 assay was conducted to detect the effect of IL-13 and ABCC4 on cell sensitivity to adriamycin (ADM) in YTS cells. Results Levels of serum IL-13 and ABCC4 expression were observed to be upregulated in patients with human NK/T-cell lymphoma. Moreover, ABCC4 protein expression was also increased in NK/T-cell lymphoma YTS cells compared to the normal NK cells. Interestingly, IL-13 promoted ABCC4 expression in YTS cells. IL-13 promoted proliferation and suppressed apoptosis of YTS cells and reversed the effects of ABCC4 knockdown on promotive proliferation and inhibitory apoptosis. In addition, IL-13 enhanced YTS cell chemotherapy resistance to ADM by promoting ABCC4 expression. Conclusion Our findings concluded that IL-13 inhibited chemotherapy sensitivity of NK/T-cell lymphoma cells by regulating ABCC4, disrupting which may effectively improve the therapy protocols against resistant NK/T-cell lymphoma.

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Expression of some ATP-binding cassette transporters in acute myeloid leukemia

Cited by 21 publications

References 22 publications

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

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

WYE-354 restores Adriamycin sensitivity in multidrug-resistant acute myeloid leukemia cell lines

IL-13 Contributes to Drug Resistance of NK/T-Cell Lymphoma Cells by Regulating ABCC4

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