ABCG2 inhibition as a therapeutic approach for overcoming multidrug resistance in cancer

Hasanabady, Maryam Hosseini; Kalalinia, Fatemeh

doi:10.1007/s12038-016-9601-5

Cited by 45 publications

(42 citation statements)

References 93 publications

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“…For example, McDonald et al previously demonstrated that docetaxel-resistant MDA-MB and MCF-7 breast cancer cells developed a cross-resistance to paclitaxel and vincristine (20), concordant to the findings of the present study. Multiple reports have indicated that resistant sublines commonly express MDR-1 and MRP proteins (9,21,22). Clinical studies also report the development of cross-resistance to multiple anticancer agents following the initial success of chemotherapy (23,24), which may also be due to the overexpression of MDR-1 and MRPs.…”

Section: Discussionmentioning

confidence: 99%

“…Although certain patients initially respond to these classical cytotoxic drugs, patients exhibit high rates of systemic relapse during early stages and decreased overall survival times following metastasis (6,7). This may be due to drug resistance development arising from the overexpression of drug-efflux pumps, including the multidrug resistance (MDR)-associated transporter P-glycoprotein (MDR-1) or proteins from the MDR-associated protein (MRP) family, collectively members of the ATP-binding cassette (ABC) transporter superfamily (8,9).…”

Section: Introductionmentioning

confidence: 99%

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Establishment and characterization of a triple negative basal-like breast cancer cell line with multi-drug resistance

et al. 2017

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Abstract. Triple-negative breast carcinoma (TNBC) is one of the most aggressive subtypes of breast cancer and is associated with an unfavorable prognosis. The management of TNBC is currently based on the use of classical cytotoxic drugs, i.e., anthracyclines and/or microtubule-binding agents (TBAs). However, conventional chemotherapy is not always effective in these tumors and a systemic relapse is often observed, potentially due to the development of multi-drug resistance (MDR). Therefore, an improved understanding of MDR mechanisms may improve the therapeutic strategies for TNBC. In the present study, a paclitaxel-resistant (TxR) breast cancer cell subline of HCC1806 TNBC cells was established and characterized. The resistance index of this subline was calculated according to the IC 50 of HCC1806-TxR relative to the parental HCC1806 cells (16.86-fold). TxR-cells also exhibited cross-resistance to vinblastin, doxorubicin and etoposide (~14-, ~4-and ~3-fold, respectively). As assessed with reverse transcription-quantitative polymerase chain reaction, TxR-resistant cells exhibited the upregulated expression of a number of multidrug resistance-associated genes, including MDR-1, MRP-1, -5, -6 and YB-1. The TxR cells also exhibited an increased expression of MDR-related proteins including MDR1 and MRP-1, which led to a substantial increase (5.4-fold) of the paclitaxel efflux from TxR-cells. In addition, the pro-apoptotic protein Fas was downregulated, whereas the anti-apoptotic Bcl-2 was upregulated, in TxR-cells. This may explain why a reduced extent of apoptosis was observed when TxR cells were exposed to TBAs and topoisomerase type II inhibitors, relative to the parental HCC1806 cells. Thus, the HCC1806-TxR cell line may serve as an appropriate model for the analysis of chemoresistance mechanisms in TNBCs, and for the investigation of novel anticancer agents for overcoming MDR-mediated mechanisms in TNBC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Establishment and characterization of a triple negative basal-like breast cancer cell line with multi-drug resistance

et al. 2017

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“…Finally, ABCG2/breast cancer resistant protein (BCRP) is a well‐defined efflux transporter first identified in a breast cancer cell line selected for resistance to mitoxantrone. Similar to the other MDR transporters, BCRP serves as an efflux pump for many diverse scaffolds of xenobiotics, including 7‐ethyl‐10‐hydroxycamptothecin (SN‐38), tyrosine kinase inhibitors, methotrexate, and is involved in drug resistance in colon, breast cancer, and gastric carcinomas …”

Section: Mechanisms Of Multidrug Resistancementioning

confidence: 99%

Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy

Arnst

Banerjee

Chen

et al. 2019

Medicinal Research Reviews

115

107

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Microtubule (MT)‐targeting agents are highly successful drugs as chemotherapeutic agents, and this is attributed to their ability to target MT dynamics and interfere with critical cellular functions, including, mitosis, cell signaling, intracellular trafficking, and angiogenesis. Because MT dynamics vary in the different stages of the cell cycle, these drugs tend to be the most effective against mitotic cells. While this class of drug has proven to be effective against many cancer types, significant hurdles still exist and include overcoming aspects such as dose limited toxicities and the development of resistance. Newer generations of developed drugs attack these problems and alternative approaches such as the development of dual tubulin and kinase inhibitors are being investigated. This approach offers the potential to show increased efficacy and lower toxicities. This review covers different categories of MT‐targeting agents, recent advances in dual inhibitors, and current challenges for this drug target.

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“…However, some types of cancer cells overexpress BCRP/ABCG2 and acquire resistance to anticancer drugs, and thus BCRP/ABCG2 holds promise as a potent molecular target in chemotherapy aimed at these cancers. Reports of interaction between several tyrosine kinase inhibitors and BCRP/ABCG2 prompted investigation of many kinds of modulators for their ability to reverse multidrug resistance mediated by BCRP/ABCG2 . Intensive structure–activity relationship studies have identified natural and chemically synthesized flavonoids as promising candidates exhibiting such reversal effects .…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 5‐Hydroxy‐3′,4′,7‐trimethoxyflavone and Related Compounds and Elucidation of Their Reversal Effects on BCRP/ABCG2‐Mediated Anticancer Drug Resistance

et al. 2018

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3',4',7-Trimethoxyflavone (TMF) has been reported to show a potent reversal effect on drug resistance mediated by breast cancer resistance protein (BCRP)/ATP-binding cassette subfamily G member 2 (ABCG2). In this study, we designed and synthesized five derivatives with either a hydroxy group or a fluorine atom at C-5 and several kinds of capping moiety at the C-7 hydroxy group, on the same 3',4'-dimethoxy-substituted flavone skeleton. We subsequently evaluated the efficacies of these compounds against BCRP-expressing human leukaemia K562/BCRP cells. Reversal of drug resistance was expressed as the concentration of compound causing a twofold reduction in drug sensitivity (RI ). Of the synthesized compounds, the reversal effect of 5-hydroxy-3',4',7-trimethoxyflavone (HTMF, RI 7.2 nm) towards 7-ethyl-10-hydroxycamptothecin (SN-38) was stronger than that of TMF (RI 18 nm). Fluoro-substituted 5-fluoro-3',4',7-trimethoxyflavone (FTMF, RI 25 nm) and monoglycosylated 7-(β-glucosyloxy)-5-hydroxy-3',4'-dimethoxyflavone (GOHDMF, 91 nm) also exhibited reversal effects, whereas the di- and triglycoside derivatives did not. TMF, HTMF and FTMF at 0.01-10 μm upregulated the K562/BCRP cellular accumulation of Hoechst 33342 nuclear staining dye. In addition, western blotting revealed that treatment of K562/BCRP cells with 0.1 μm TMF, HTMF or FTMT suppressed the expression of BCRP. HTMF showed the strongest inhibition of BCRP-mediated efflux and suppression of BCRP expression of the three effective synthesized flavones.

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ABCG2 inhibition as a therapeutic approach for overcoming multidrug resistance in cancer

Cited by 45 publications

References 93 publications

Establishment and characterization of a triple negative basal-like breast cancer cell line with multi-drug resistance

Establishment and characterization of a triple negative basal-like breast cancer cell line with multi-drug resistance

Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy

Synthesis of 5‐Hydroxy‐3′,4′,7‐trimethoxyflavone and Related Compounds and Elucidation of Their Reversal Effects on BCRP/ABCG2‐Mediated Anticancer Drug Resistance

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