Targeting breast cancer resistance protein (BCRP/ABCG2): Functional inhibitors and expression modulators

Zattoni, Ingrid Fatima; Delabio, Letícia Carani; Dutra, Julia de Paula; Kita, Diogo Henrique; Scheiffer, Gustavo; Hembecker, Marina; Pereira, Giovana da Silva; Moure, Vivian Rotuno; Valdameri, Gláucio

doi:10.1016/j.ejmech.2022.114346

Cited by 36 publications

(24 citation statements)

References 273 publications

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“…So far, a variety of potential inhibitors for ABCG2 have been reported, constantly improving the efficacy, the selectivity, or the ability to act as pan-inhibitors for the three MDR-associated transporters [ 18 , 19 , 20 ]. However, creating an ideal inhibitor of BCRP is a challenging task.…”

Section: Introductionmentioning

confidence: 99%

The More the Better—Investigation of Polymethoxylated N-Carboranyl Quinazolines as Novel Hybrid Breast Cancer Resistance Protein Inhibitors

et al. 2023

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The ineffectiveness and failing of chemotherapeutic treatments are often associated with multidrug resistance (MDR). MDR is primarily linked to the overexpression of ATP-binding cassette (ABC) transporter proteins in cancer cells. ABCG2 (ATP-binding cassette subfamily G member 2, also known as the breast cancer resistance protein (BCRP)) mediates MDR by an increased drug efflux from the cancer cells. Therefore, the inhibition of ABCG2 activity during chemotherapy ought to improve the efficacy of the administered anti-cancer agents by reversing MDR or by enhancing the agents’ pharmacokinetic properties. Significant efforts have been made to develop novel, powerful, selective, and non-toxic inhibitors of BCRP. However, thus far the clinical relevance of BCRP-selective MDR-reversal has been unsuccessful, due to either adverse drug reactions or significant toxicities in vivo. We here report a facile access towards carboranyl quinazoline-based inhibitors of ABCG2. We determined the influence of different methoxy-substitution patterns on the 2-phenylquinazoline scaffold in combination with the beneficial properties of an incorporated inorganic carborane moiety. A series of eight compounds was synthesized and their inhibitory effect on the ABCG2-mediated Hoechst transport was evaluated. Molecular docking studies were performed to better understand the structure-protein interactions of the novel inhibitors, exhibiting putative binding modes within the inner binding site. Further, the most potent, non-toxic compounds were investigated for their potential to reverse ABCG2-mediated mitoxantrone (MXN) resistance. Of these five evaluated compounds, N-(closo-1,7-dicarbadodecaboran(12)-9-yl)-6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-quinazolin-4-amine (DMQCd) exhibited the strongest inhibitory effect towards ABCG2 in the lower nanomolar ranges. Additionally, DMQCd was able to reverse BCRP-mediated MDR, making it a promising candidate for further research on hybrid inorganic-organic compounds.

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Section: Introductionmentioning

confidence: 99%

The More the Better—Investigation of Polymethoxylated N-Carboranyl Quinazolines as Novel Hybrid Breast Cancer Resistance Protein Inhibitors

et al. 2023

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“…The most widely studied ABC proteins are ABCB1 and ABCG2 (6,7,28-30). ABCG2 is associated with multidrug resistance in a variety of tumor cells (31)(32)(33)(34)(35)(36)(37)(38), and is involved in forming side population cells and tumor stem cells (10,39,40). However, studies on the relationship between ABCG2 and multidrug resistance of hepatoma cells are rare (41).…”

Section: Discussionmentioning

confidence: 99%

Drug resistance of hepatoma cells induced by ATP‑binding cassette transporter G2 by reducing intracellular drug concentration

Ding

Liu

et al. 2023

Exp Ther Med

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The side effects and drug resistance during chemotherapy seriously affect the outcome of and may lead to the failure of chemotherapy for patients with hepatoma. The aim of the present study was to investigate the association between the expression of ATP-binding cassette transporter G2 (ABCG2) in hepatoma cells and the drug resistance of hepatoma. An MTT assay was used to determine the half-maximal inhibitory concentration (IC 50 ) of Adriamycin (ADM) in hepatoma HepG2 cells after treatment with ADM for 24 h. An ADM-resistant hepatoma cell subline, HepG2/ADM, was generated from the HepG2 hepatoma cell line through a stepwise selection with ADM doses from 0.01 to 0.1 µg/ml. The HepG2/ABCG2 cell line, an ABCG2-overexpressing hepatoma cell line, was established by transfecting the ABCG2 gene into HepG2 cells. The MTT assay was then used to detect the IC 50 of ADM in HepG2/ADM and HepG2/ABCG2 cells after treatment with ADM for 24 h and the resistance index was calculated. The apoptosis, cell cycle and ABCG2 protein expression levels in HepG2/ADM, HepG2/ABCG2 cells, HepG2/PCDNA3.1 and their parental HepG2 cells were detected by flow cytometry. In addition, flow cytometry was used to detect the efflux effect of HepG2/ADM and HepG2/ABCG2 cells after ADM treatment. ABCG2 mRNA expression in cells was detected by reverse transcription-quantitative PCR. After 3 months of ADM treatment, HepG2/ADM cells grew stably in the cell culture medium containing 0.1 µg/ml ADM and the cells were named HepG2/ADM cells. ABCG2 was overexpressed in HepG2/ABCG2 cells. The IC 50 of ADM in HepG2, HepG2/PCDNA3.1, HepG2/ADM and HepG2/ABCG2 cells was 0.72±0.03, 0.74±0.01, 11.17±0.59 and 12.75±0.47 µg/ml, respectively. The cell apoptotic rate of HepG2/ADM and HepG2/ABCG2 cells was not significantly different compared with that of HepG2 and HepG2/PCDNA3.1 cells (P>0.05), but the G 0 /G 1 phase population of the cell cycle decreased and the proliferation index increased significantly (P<0.05). The expression levels of ABCG2 gene and protein in HepG2/ADM and HepG2/ABCG2 cells were significantly higher than those in HepG2 and HepG2/PCDNA3.1 cells (P<0.01), but there was no significant difference between HepG2 and HepG2/PCDNA3.1 cells (P>0.05). The ADM efflux effect of HepG2/ADM and HepG2/ABCG2 cells was significantly higher than that of parental HepG2 and HepG2/PCDNA3.1 cells (P<0.05). Therefore, the present study demonstrated that ABCG2 expression is highly increased in drug-resistant hepatoma cells and that high expression of ABCG2 is involved in the drug resistance of hepatoma by reducing the intracellular drug concentration.

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“…ABCG2 substrate chemotherapeutic substances in tumor cells can be transferred to the outside of tumor cells, which reduces the sensitivity of tumor cells to chemotherapy drugs. This leads to the emergence of multidrug resistance [ 32 , 33 ]. For instance, the expression of the ABC transporters was similarly increased after TGF-β or Twist in breast cancer cells, and zeb1 exhibited the reverse-transition EMT and its resistance to the virobistar [ 34 , 35 ].…”

Section: Therapeutic Resistance Of Tumorsmentioning

confidence: 99%

Epithelial–Mesenchymal Transition-Mediated Tumor Therapeutic Resistance

Zhang²,

Dai³

et al. 2022

Molecules

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Cancer is one of the world’s most burdensome diseases, with increasing prevalence and a high mortality rate threat. Tumor recurrence and metastasis due to treatment resistance are two of the primary reasons that cancers have been so difficult to treat. The epithelial–mesenchymal transition (EMT) is essential for tumor drug resistance. EMT causes tumor cells to produce mesenchymal stem cells and quickly adapt to various injuries, showing a treatment-resistant phenotype. In addition, multiple signaling pathways and regulatory mechanisms are involved in the EMT, resulting in resistance to treatment and hard eradication of the tumors. The purpose of this study is to review the link between EMT, therapeutic resistance, and the molecular process, and to offer a theoretical framework for EMT-based tumor-sensitization therapy.

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Targeting breast cancer resistance protein (BCRP/ABCG2): Functional inhibitors and expression modulators

Cited by 36 publications

References 273 publications

The More the Better—Investigation of Polymethoxylated N-Carboranyl Quinazolines as Novel Hybrid Breast Cancer Resistance Protein Inhibitors

The More the Better—Investigation of Polymethoxylated N-Carboranyl Quinazolines as Novel Hybrid Breast Cancer Resistance Protein Inhibitors

Drug resistance of hepatoma cells induced by ATP‑binding cassette transporter G2 by reducing intracellular drug concentration

Epithelial–Mesenchymal Transition-Mediated Tumor Therapeutic Resistance

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