Journal articles: 'ABCG2 inhibitors'

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Henrich, Curtis J., Heidi R. Bokesch, Michael Dean, Susan E. Bates, Robert W. Robey, Ekaterina I. Goncharova, Jennifer A. Wilson, and James B. McMahon. "A High-Throughput Cell-Based Assay for Inhibitors of ABCG2 Activity." Journal of Biomolecular Screening 11, no. 2 (December 16, 2005): 176–83. http://dx.doi.org/10.1177/1087057105284576.

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ABCG2 is a member of the adenosine triphosphate (ATP)-binding cassette family of multidrug transporters associated with resistance of tumor cells to many cytotoxic agents. Evaluation of modulators of ABCG2 activity has relied on methods such as drug sensitization, biochemical characterization, and transport studies. To search for novel inhibitors of ABCG2, a fluorescent cell-based assay was developed for application in high-throughput screening. Accumulation of pheophorbide a (PhA), an ABCG2-specific substrate, forms the basis for the assay in NCI-H460/MX20 cells overexpressing wild-type ABCG2. Treatment of these cells with 10 μM fumitremorgin C (FTC), a specific ABCG2 inhibitor, increased cell accumulation of PhA to 5.6 times control (Z′ 0.5). Validation included confirmation with known ABCG2 inhibitors: FTC, novobiocin, tariquidar, and quercetin. Verapamil, reported to inhibit P-glycoprotein but not ABCG2, had insignificant activity. Screening of a library of 3523 natural products identified 11 compounds with high activity (≥ 50% of FTC, confirmed by reassay), including 3 flavonoids, members of a family of compounds that include ABCG2 inhibitors. One of the inhibitors detected, eupatin, was moderately potent (IC50 of 2.2 μM) and, like FTC, restored sensitivity of resistant cells to mitoxantrone. Application of this assay to other libraries of synthetic compounds and natural products is expected to identify novel inhibitors of ABCG2 activity.

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Kokubo, Shoji, Shinobu Ohnuma, Megumi Murakami, Haruhisa Kikuchi, Shota Funayama, Hideyuki Suzuki, Taiki Kajiwara, et al. "A Phenylfurocoumarin Derivative Reverses ABCG2-Mediated Multidrug Resistance In Vitro and In Vivo." International Journal of Molecular Sciences 22, no. 22 (November 19, 2021): 12502. http://dx.doi.org/10.3390/ijms222212502.

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The ATP-binding cassette subfamily G member 2 (ABCG2) transporter is involved in the development of multidrug resistance in cancer patients. Many inhibitors of ABCG2 have been reported to enhance the chemosensitivity of cancer cells. However, none of these inhibitors are being used clinically. The aim of this study was to identify novel ABCG2 inhibitors by high-throughput screening of a chemical library. Among the 5812 compounds in the library, 23 compounds were selected in the first screening, using a fluorescent plate reader-based pheophorbide a (PhA) efflux assay. Thereafter, to validate these compounds, a flow cytometry-based PhA efflux assay was performed and 16 compounds were identified as potential inhibitors. A cytotoxic assay was then performed to assess the effect these 16 compounds had on ABCG2-mediated chemosensitivity. We found that the phenylfurocoumarin derivative (R)-9-(3,4-dimethoxyphenyl)-4-((3,3-dimethyloxiran-2-yl)methoxy)-7H-furo [3,2-g]chromen-7-one (PFC) significantly decreased the IC50 of SN-38 in HCT-116/BCRP colon cancer cells. In addition, PFC stimulated ABCG2-mediated ATP hydrolysis, suggesting that this compound interacts with the substrate-binding site of ABCG2. Furthermore, PFC reversed the resistance to irinotecan without causing toxicity in the ABCG2-overexpressing HCT-116/BCRP cell xenograft mouse model. In conclusion, PFC is a novel inhibitor of ABCG2 and has promise as a therapeutic to overcome ABCG2-mediated MDR, to improve the efficiency of cancer chemotherapy.

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Natarajan, Karthika, Jasjeet Bhullar, Suneet Shukla, Mehmet Burcu, Suresh V. Ambudkar, and Maria R. Baer. "The Pim Kinase Inhibitor SGI-1776 Chemosensitizes Multidrug Resistant Cells by Both Inhibiting Drug Transport by ABCB1 and ABCG2 and Decreasing ABCB1 and ABCG2 Surface Expression On Cells That Overexpress Pim-1." Blood 120, no. 21 (November 16, 2012): 2462. http://dx.doi.org/10.1182/blood.v120.21.2462.2462.

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Abstract Abstract 2462 Overexpression of the ATP-binding cassette (ABC) cellular drug efflux proteins ABCB1 and ABCG2 on acute myeloid leukemia (AML) cells is associated with inferior chemotherapy outcomes. Nevertheless, inhibitors of drug transport have not improved treatment outcomes in clinical trials. The serine/threonine kinase Pim-1, encoded by a proto-oncogene originally identified as the proviral integration site in Moloney murine leukemia virus lymphomagenesis, is expressed in AML and is implicated in regulation of multiple key cellular processes, as well as drug resistance. Our group has shown that Pim-1 phosphorylates ABCB1 and ABCG2 and promotes their translocation to the cell surface, where they mediate drug efflux. The imidazo[1,2-b]pyridazine small molecule SGI-1776 (Tolero Pharmaceuticals, Inc. Salt Lake City, UT) is the first Pim kinase inhibitor to have entered clinical testing. SGI-1776 has been shown to sensitize ABCB1-overexpressing drug-resistant cells to ABCB1 substrate cancer chemotherapy drugs, but chemosensitization was found to be associated with direct inhibition of drug transport mediated by ABCB1. Moreover, while silencing of Pim-1 expression with siRNA was found to sensitize ABCG2-overexpressing cells to ABCG2 substrate chemotherapy drugs, the effects of SGI-1776 on resistance mediated by ABCG2 have not been studied. Therefore we studied the Pim-1-dependent and -independent effects of SGI-1776 on chemosensitivity of cells overexpressing ABCB1 and ABCG2. SGI-1776 at the Pim-1-inhibitory and non-cytotoxic concentration of 1 μM decreased the IC50s of ABCB1 and ABCG2 substrate drugs including daunorubicin and mitoxantrone 2- to 4-fold in leukemia and myeloma cell lines overexpressing ABCB1 and ABCG2, but had no effect on the IC50 of the non-substrate drug cytarabine, and no effect in parental cells. SGI-1776 also increased apoptosis of ABCB1- and ABCG2-overexpressing leukemia and myeloma cells exposed to ABCB1 and ABCG2 substrate chemotherapy drugs, respectively, and decreased their colony formation in the presence of substrate, but not non-substrate, chemotherapy drugs, with no effect on parental cells. We found that SGI-1776 decreased ABCB1 and ABCG2 surface expression, measured by flow cytometry, on K562/ABCB1 (p=0.013) and K562/ABCG2 (p=0.0038) leukemia cells, respectively, both of which express Pim-1 at high levels, without decrease in total cellular ABCB1 and ABCG2 expression, measured by Western blot analysis. In contrast, SGI-1776 had no effect on ABCB1 and ABCG2 surface expression on HL60/VCR leukemia and 8226/MR20 myeloma cells, which express ABCB1 and ABCG2, respectively, but express Pim-1 at lower levels. Thus SGI-1776 decreased ABCB1 and ABCG2 surface expression on cells that overexpress Pim-1, consistent with decreased cell surface translocation of ABCB1 and ABCG2 as a result of inhibition of Pim-1, but also chemosensitized cells expressing ABCB1 and ABCG2 in the absence of effects on ABCB1 and ABCG2 cell surface expression. We found that SGI-1776 indeed inhibited uptake of fluorescent substrates of both ABCB1 and ABCG2, measured by flow cytometry, in a concentration-dependent manner. We further determined that SGI-1776 inhibited ABCB1 and ABCG2 photoaffinity labeling with the transport substrate [125I]-IAAP and stimulated ABCB1 and ABCG2 ATPase activity, consistent with binding to drug-binding sites of ABCB1 and ABCG2 and inhibition of substrate transport by both proteins. Thus SGI-1776 both inhibits drug transport by ABCB1 and ABCG2 and decreases ABCB1 and ABCG2 surface expression on cells that overexpress Pim-1. Pim-1 is thought to be a clinically promising therapeutic target in AML and other malignancies, and other Pim kinase inhibitors are in preclinical and clinical development. Subsequent clinically applicable Pim kinase inhibitors should be characterized with regard to interactions with ABCB1 and ABCG2. In particular, while therapeutic strategies based on inhibition of drug transport mediated by ABCB1 with competitive inhibitors including PSC-833, zosuquidar and cyclosporin A have largely been clinically unsuccessful, inhibition of ABCB1 and ABCG2 cell surface translocation by Pim kinase inhibitors may have therapeutic implications. Disclosures: No relevant conflicts of interest to declare.

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Curran, Sean, Toni-Marie Achilli, Elizabeth Leary, Benjamin T. Wilks, Marguerite M. Vantangoli, Kim Boekelheide, and Jeffrey R. Morgan. "A 3D spheroid system to evaluate inhibitors of the ABCG2 transporter in drug uptake and penetration." TECHNOLOGY 03, no. 01 (March 2015): 54–63. http://dx.doi.org/10.1142/s2339547815500028.

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None of the ABCG2 inhibitors are effective clinically against multidrug resistant tumors overexpressing ABCG2. New in vitro models are needed to characterize inhibitors and discover new ones. We report a 3D spheroid model and image-based method to quantify ABCG2 action. Nonadhesive micro-molds were used to self-assemble spheroids overexpressing ABCG2; these spheroids were then incubated with the transporter substrate Hoechst 33342. Time-lapse fluorescent microscopy was used to determine the transporter-dependent efflux of Hoechst 33342 and dose response of three inhibitors (Ko143, Iressa, Elacridar). This 3D microtissue model was also used to determine the time to maximal effect as well as duration of effect after inhibitor removal. All acted within one hour and Elacridar had a surprisingly long duration of effect, active 5 hours after removal. This model can be used with multiple cell types, provides new insight into the pharmacokinetics of inhibitors, and can be adapted to high throughput analyses.

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Barrera, Borja, Jon A. Otero, Estefanía Egido, Julio G. Prieto, Anna Seelig, Ana I. Álvarez, and Gracia Merino. "The Anthelmintic Triclabendazole and Its Metabolites Inhibit the Membrane Transporter ABCG2/BCRP." Antimicrobial Agents and Chemotherapy 56, no. 7 (April 16, 2012): 3535–43. http://dx.doi.org/10.1128/aac.06345-11.

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ABSTRACTABCG2/BCRP is an ATP-binding cassette transporter that extrudes compounds from cells in the intestine, liver, kidney, and other organs, such as the mammary gland, affecting pharmacokinetics and milk secretion of antibiotics, anticancer drugs, and other compounds and mediating drug-drug interactions. In addition, ABCG2 expression in cancer cells may directly cause resistance by active efflux of anticancer drugs. The development of ABCG2 modulators is critical in order to improve drug pharmacokinetic properties, reduce milk secretion of xenotoxins, and/or increase the effective intracellular concentrations of substrates. Our purpose was to determine whether the anthelmintic triclabendazole (TCBZ) and its main plasma metabolites triclabendazole sulfoxide (TCBZSO) and triclabendazole sulfone (TCBZSO2) inhibit ABCG2 activity. ATPase assays using human ABCG2-enriched membranes demonstrated a clear ABCG2 inhibition exerted by these compounds. Mitoxantrone accumulation assays using murine Abcg2- and human ABCG2-transduced MDCK-II cells confirmed that TCBZSO and TCBZSO2are ABCG2 inhibitors, reaching inhibitory potencies between 40 and 55% for a concentration range from 5 to 25 μM. Transepithelial transport assays of ABCG2 substrates in the presence of both TCBZ metabolites at 15 μM showed very efficient inhibition of the Abcg2/ABCG2-mediated transport of the antibacterial agents nitrofurantoin and danofloxacin. TCBZSO administration also inhibited nitrofurantoin Abcg2-mediated secretion into milk by more than 2-fold and increased plasma levels of the sulfonamide sulfasalazine by more than 1.5-fold in mice. These results support the potential role of TCBZSO and TCBZSO2as ABCG2 inhibitors to participate in drug interactions and modulate ABCG2-mediated pharmacokinetic processes.

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Wang, Jing-Quan, Jonathan Y. Li, Qiu-Xu Teng, Zi-Ning Lei, Ning Ji, Qingbin Cui, Leli Zeng, Yihang Pan, Dong-Hua Yang, and Zhe-Sheng Chen. "Venetoclax, a BCL-2 Inhibitor, Enhances the Efficacy of Chemotherapeutic Agents in Wild-Type ABCG2-Overexpression-Mediated MDR Cancer Cells." Cancers 12, no. 2 (February 18, 2020): 466. http://dx.doi.org/10.3390/cancers12020466.

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Previous studies have shown that small-molecule BCL-2 inhibitors can have a synergistic interaction with ABCG2 substrates in chemotherapy. Venetoclax is a potent and selective BCL-2 inhibitor, approved by the FDA in 2016 for the treatment of patients with chronic lymphocytic leukemia (CLL). 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 potentiates the efficacy of wild-type ABCG2 substrate drugs. These findings may provide useful guidance in combination therapy against wild-type ABCG2-mediated MDR cancer in clinical practice.

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Stockmann, Philipp, Lydia Kuhnert, Wencke Leinung, Cathleen Lakoma, Birte Scholz, Svetlana Paskas, Sanja Mijatović, Danijela Maksimović-Ivanić, Walther Honscha, and Evamarie Hey-Hawkins. "The More the Better—Investigation of Polymethoxylated N-Carboranyl Quinazolines as Novel Hybrid Breast Cancer Resistance Protein Inhibitors." Pharmaceutics 15, no. 1 (January 10, 2023): 241. http://dx.doi.org/10.3390/pharmaceutics15010241.

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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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Inoue, Yutaka, Takashi Morita, Mari Onozuka, Ken-ichi Saito, Kazumi Sano, Kazuhiko Hanada, Masami Kondo, et al. "Impact of Q141K on the Transport of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors by ABCG2." Cells 8, no. 7 (July 23, 2019): 763. http://dx.doi.org/10.3390/cells8070763.

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The ATP-binding cassette transporter ABCG2 is expressed in various organs, such as the small intestine, liver, and kidney, and influences the pharmacokinetics of drugs that are its substrates. ABCG2 is also expressed by cancer cells and mediates resistance to anticancer agents by promoting the efflux of these drugs. In the present study, we investigated the interactions between epidermal growth factor receptor tyrosine kinase inhibitors and ABCG2 by MTT assay, intracellular drug accumulation assay, and FACS. This study showed that four epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) (gefitinib, erlotinib, lapatinib, and afatinib) were transported from tumor cells as substrates of ABCG2. Q141K is a common single-nucleotide polymorphism of ABCG2 in Asians. We demonstrated that the extracellular efflux of gefitinib, erlotinib, and lapatinib was reduced by Q141K, whereas afatinib transport was not affected. In addition, all four EGFR TKIs inhibited the transport of other substrates by both wild-type and variant ABCG2 at 0.1 μM concentrations. Accordingly, epidermal growth factor receptor tyrosine kinase inhibitors may induce interactions with other drugs that are substrates of ABCG2, and single-nucleotide polymorphisms of ABCG2 may influence both the pharmacokinetics and efficacy of these anticancer agents.

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Di Micco, Simone, Veronica Di Sarno, Martina Rossi, Vincenzo Vestuto, Takumi Konno, Sara Novi, Mario Felice Tecce, et al. "In Silico Identification and In Vitro Evaluation of New ABCG2 Transporter Inhibitors as Potential Anticancer Agents." International Journal of Molecular Sciences 24, no. 1 (December 31, 2022): 725. http://dx.doi.org/10.3390/ijms24010725.

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Different molecular mechanisms contribute to the development of multidrug resistance in cancer, including increased drug efflux, enhanced cellular repair mechanisms and alterations of drug metabolism or drug targets. ABCG2 is a member of the ATP-binding cassette superfamily transporters that promotes drug efflux, inducing chemotherapeutic resistance in malignant cells. In this context, the development of selective ABCG2 inhibitors might be a suitable strategy to improve chemotherapy efficacy. Thus, through a multidisciplinary approach, we identified a new ABCG2 selective inhibitor (8), highlighting its ability to increase mitoxantrone cytotoxicity in both hepatocellular carcinoma (EC50from 8.67 ± 2.65 to 1.25 ± 0.80 μM) and transfected breast cancer cell lines (EC50from 9.92 ± 2.32 to 2.45 ± 1.40 μM). Moreover, mitoxantrone co-administration in both transfected and non-transfected HEK293 revealed that compound 8 notably lowered the mitoxantrone EC50, demonstrating its efficacy along with the importance of the ABCG2 extrusion pump overexpression in MDR reversion. These results were corroborated by evaluating the effect of inhibitor 8 on mitoxantrone cell uptake in multicellular tumor spheroids and via proteomic experiments.

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Wu, Zhuo-Xun, Yuqi Yang, Qiu-Xu Teng, Jing-Quan Wang, Zi-Ning Lei, Jing-Qiu Wang, Sabrina Lusvarghi, Suresh V. Ambudkar, Dong-Hua Yang, and Zhe-Sheng Chen. "Tivantinib, A c-Met Inhibitor in Clinical Trials, Is Susceptible to ABCG2-Mediated Drug Resistance." Cancers 12, no. 1 (January 12, 2020): 186. http://dx.doi.org/10.3390/cancers12010186.

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Tivantinib, also known as ARQ-197, is a potent non-ATP competitive selective c-Met inhibitor currently under phase 3 clinical trial evaluation for liver and lung cancers. In this study, we explored factors that may lead to tivantinib resistance, especially in regards to its interaction with ATP-binding cassette super-family G member 2 (ABCG2). ABCG2 is one of the most important members of the ATP-binding cassette (ABC) transporter family, a group of membrane proteins that play a critical role in mediating multidrug resistance (MDR) in a variety of cancers, including those of the liver and lung. Tivantinib received a high score in docking analysis, indicating a strong interaction between tivantinib and ABCG2, and an ATPase assay indicated that tivantinib stimulated ABCG2 ATPase activity in a concentration-dependent manner. An MTT assay showed that ABCG2 overexpression significantly desensitized both the cancer cells and ABCG2 transfected-HEK293 cells to tivantinib and that this drug resistance can be reversed by ABCG2 inhibitors. Furthermore, tivantinib upregulated the protein expression of ABCG2 without altering the cell surface localization of ABCG2, leading to increased resistance to substrate drugs, such as mitoxantrone. Altogether, these data demonstrate that tivantinib is a substrate of ABCG2, and, therefore, ABCG2 overexpression may decrease its therapeutic effect. Our study provides evidence that the overexpression of ABCG2 should be monitored in clinical settings as an important risk factor for tivantinib drug resistance.

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Le, Minh-Tri, Viet-Nham Hoang, Dac-Nhan Nguyen, Thi-Hoang-Linh Bui, Thien-Vy Phan, Phuong Nguyen-Hoai Huynh, Thanh-Dao Tran, and Khac-Minh Thai. "Structure-Based Discovery of ABCG2 Inhibitors: A Homology Protein-Based Pharmacophore Modeling and Molecular Docking Approach." Molecules 26, no. 11 (May 23, 2021): 3115. http://dx.doi.org/10.3390/molecules26113115.

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ABCG2 is an ABC membrane protein reverse transport pump, which removes toxic substances such as medicines out of cells. As a result, drug bioavailability is an unexpected change and negatively influences the ADMET (absorption, distribution, metabolism, excretion, and toxicity), leading to multi-drug resistance (MDR). Currently, in spite of promising studies, screening for ABCG2 inhibitors showed modest results. The aim of this study was to search for small molecules that could inhibit the ABCG2 pump. We first used the WISS MODEL automatic server to build up ABCG2 homology protein from 655 amino acids. Pharmacophore models, which were con-structed based on strong ABCG2 inhibitors (IC50 < 1 μM), consist of two hydrophobic (Hyd) groups, two hydrogen bonding acceptors (Acc2), and an aromatic or conjugated ring (Aro|PiR). Using molecular docking method, 714 substances from the DrugBank and 837 substances from the TCM with potential to inhibit the ABCG2 were obtained. These chemicals maybe favor synthesized or extracted and bioactivity testing.

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Strouse, J. Jacob, Irena Ivnitski-Steele, Hadya M. Khawaja, Dominique Perez, Jerec Ricci, Tuanli Yao, Warren S. Weiner, et al. "A Selective ATP-Binding Cassette Subfamily G Member 2 Efflux Inhibitor Revealed via High-Throughput Flow Cytometry." Journal of Biomolecular Screening 18, no. 1 (August 24, 2012): 26–38. http://dx.doi.org/10.1177/1087057112456875.

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Chemotherapeutics tumor resistance is a principal reason for treatment failure, and clinical and experimental data indicate that multidrug transporters such as ATP-binding cassette (ABC) B1 and ABCG2 play a leading role by preventing cytotoxic intracellular drug concentrations. Functional efflux inhibition of existing chemotherapeutics by these pumps continues to present a promising approach for treatment. A contributing factor to the failure of existing inhibitors in clinical applications is limited understanding of specific substrate/inhibitor/pump interactions. We have identified selective efflux inhibitors by profiling multiple ABC transporters against a library of small molecules to find molecular probes to further explore such interactions. In our primary screening protocol using JC-1 as a dual-pump fluorescent reporter substrate, we identified a piperazine-substituted pyrazolo[1,5-a]pyrimidine substructure with promise for selective efflux inhibition. As a result of a focused structure-activity relationship (SAR)–driven chemistry effort, we describe compound 1 (CID44640177), an efflux inhibitor with selectivity toward ABCG2 over ABCB1. Compound 1 is also shown to potentiate the activity of mitoxantrone in vitro as well as preliminarily in vivo in an ABCG2-overexpressing tumor model. At least two analogues significantly reduce tumor size in combination with the chemotherapeutic topotecan. To our knowledge, low nanomolar chemoreversal activity coupled with direct evidence of efflux inhibition for ABCG2 is unprecedented.

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Juvale, Kapil, and Michael Wiese. "Design of inhibitors of BCRP/ABCG2." Future Medicinal Chemistry 7, no. 12 (August 2015): 1521–27. http://dx.doi.org/10.4155/fmc.15.83.

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Henrich, Curtis J., Robert W. Robey, Kentaro Takada, Heidi R. Bokesch, Susan E. Bates, Suneet Shukla, Suresh V. Ambudkar, James B. McMahon, and Kirk R. Gustafson. "Botryllamides: Natural Product Inhibitors of ABCG2." ACS Chemical Biology 4, no. 8 (July 10, 2009): 637–47. http://dx.doi.org/10.1021/cb900134c.

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Huang, Fang-Fang, Li Zhang, Yan-Hui Yu, Fang-ping Chen, Hui Zeng, Ting Niu, and Deng-shu Wu. "PTEN Regulated BCRP/ABCG2 and Side Population Through PI3K/Akt Pathway In Chronic Myeloid Leukemia." Blood 122, no. 21 (November 15, 2013): 5408. http://dx.doi.org/10.1182/blood.v122.21.5408.5408.

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Abstract A small population of cancer stem cells named as “side population (SP)” has been demonstrated to be responsible for many solid tumor maintenance. However, the role of SP in leukemic pathogenesis is still controversial. The resistance of leukemic stem cells in response to targeted therapies such as tyrosine kinase inhibitors (TKIs) results in therapeutic failure or refractory/relapsed disease in chronic myeloid leukemia (CML). The drug pump, ABCG2, is well-known as a specific marker of SP and could be controlled by several pathways including PI3K/Akt. Our data demonstrated that compared to wild type K562 cells, the higher percentage of ABCG2+ cells corresponded to the higher SP fraction in K562/ABCG2 (ABCG2 overexpressing) and K562/IMR (resistance to imatinib) cells, which exhibited enhanced drug resistance along with downregulated PTEN and activated p-Akt. It could be abrogated by both PI3K inhibitor LY294002 and mTOR inhibitor rapamycin. Moreover, in CML patients at accelerated phase/blastic phase (AP/BP), increased SP phenotype rather than ABCG2 expression accompanied with loss of PTEN protein and up-regulation of p-Akt expression was observed. These results suggested that expression of ABCG2 and fraction of SP may be regulated by PTEN through PI3K/Akt pathway, which will be the potentially effective strategy for targeting CML stem cells. Disclosures: No relevant conflicts of interest to declare.

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van Tellingen, Olaf, Mark C. de Gooijer, Stefanie Zuidema, Amber Meurs, Ceren H. Çitirikkaya, Nikkie Venekamp, and Jos H. Beijnen. "EXTH-72. CONTINUOUS INFUSION STUDIES REVEAL THE POTENCY OF ELACRIDAR TO ACT AS A PHARMACO-ENHANCER FOR TREATMENT OF INTRACRANIAL DISEASES BY INHIBITING ABCB1 AND ABCG2 AT THE BLOOD-BRAIN BARRIER." Neuro-Oncology 22, Supplement_2 (November 2020): ii103. http://dx.doi.org/10.1093/neuonc/noaa215.426.

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Abstract The blood-brain barrier (BBB) is a formidable hurdle to successful pharmacotherapy of intracranial diseases. ABCB1 and ABCG2 are efflux transporters that play an important role in the BBB, keeping substances out of the brain. Elacridar and tariquidar are third-generation ABCB1-inhibitors developed for treatment of multidrug-resistant tumors. Later, they were shown to also inhibit ABCG2. We aim to improve pharmacotherapy of brain cancer by concomitant use of potentially effective drugs with elacridar. This study was undertaken to determine the relationship between the plasma concentration of the inhibitor and the brain-to-plasma (B/P) ratio of (model) substrate drugs in order to assess which type of drug may best qualify taking into account clinically achievable plasma levels of the inhibitor. We used Abcg2;Abcb1a/b double knockout (DKO), Abcb1a/b KO, Abcg2 KO and wild-type mice receiving a cocktail of 9 drugs at a fixed low dose plus a range of doses of inhibitor by 3-h intraperitoneal infusion to achieve steady-state conditions. DKO mice are the reference for complete inhibition, while single KO mice allow interrogation of the other transporter when using dual substrate drugs. Complete inhibition of Abcb1 by elacridar requires plasma levels of about 1000 nM. Inhibition of Abcg2 is more difficult. For erlotinib and palbociclib about 1000 nM of elacridar is sufficient, but other more profound substrate drugs (e.g. vemurafenib and afatinib) do not reach the B/P ratios achieved in DKO mice, even at 4000 nM. The improvement in B/P ratio that can be reached differs per substrate. Compounds like palbociclib benefit markedly from elacridar with B/P ratios rising from 0.25 to 7, whereas others (e.g. erlotinib and dasatinib) increase from about 0.10 to only 0.40. Thus, elacridar is an efficient pharmaco-enhancer of ABCB1 substrates and weaker ABCG2 substrates, but is not able to improve brain delivery of drugs that are profound ABCG2 substrates.

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To, Kenneth K. W., Zhirong Zhan, Thomas Litman, and Susan E. Bates. "Regulation of ABCG2 Expression at the 3′ Untranslated Region of Its mRNA through Modulation of Transcript Stability and Protein Translation by a Putative MicroRNA in the S1 Colon Cancer Cell Line." Molecular and Cellular Biology 28, no. 17 (June 23, 2008): 5147–61. http://dx.doi.org/10.1128/mcb.00331-08.

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ABSTRACT ABCG2 is recognized as an important efflux transporter in clinical pharmacology and is potentially important in resistance to chemotherapeutic drugs. To identify epigenetic mechanisms regulating ABCG2 mRNA expression at its 3′ untranslated region (3′UTR), we performed 3′ rapid amplification of cDNA ends with the S1 parental colon cancer cell line and its drug-resistant ABCG2-overexpressing counterpart. We found that the 3′UTR is >1,500 bp longer in parental cells and, using the miRBase TARGETs database, identified a putative microRNA (miRNA) binding site, distinct from the recently reported hsa-miR520h site, in the portion of the 3′UTR missing from ABCG2 mRNA in the resistant cells. We hypothesized that the binding of a putative miRNA at the 3′UTR of ABCG2 suppresses the expression of ABCG2. In resistant S1MI80 cells, the miRNA cannot bind to ABCG2 mRNA because of the shorter 3′UTR, and thus, mRNA degradation and/or repression on protein translation is relieved, contributing to overexpression of ABCG2. This hypothesis was rigorously tested by reporter gene assays, mutational analysis at the miRNA binding sites, and forced expression of miRNA inhibitors or mimics. The removal of this epigenetic regulation by miRNA could be involved in the overexpression of ABCG2 in drug-resistant cancer cells.

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Kathawala, Rishil J., Claudia M. Espitia, Trace M. Jones, Shariful Islam, Pranav Gupta, Yun-Kai Zhang, Zhe-Sheng Chen, Jennifer S. Carew, and Steffan T. Nawrocki. "ABCG2 Overexpression Contributes to Pevonedistat Resistance." Cancers 12, no. 2 (February 12, 2020): 429. http://dx.doi.org/10.3390/cancers12020429.

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MLN4924 (pevonedistat) is a first-in-class NEDD8-activating enzyme (NAE) inhibitor in clinical trials for the treatment of solid tumors and hematologic malignancies. Despite the promising activity of MLN4924 observed in early trials, drug resistance has been noted in some patients. Identifying the underlying cause of treatment failure may help to better stratify patients that are most likely to benefit from this novel agent. Early preclinical studies revealed that the development of NAEβ mutations promotes resistance to MLN4924. However, these mutations have not been detected in patients that are relapsed/refractory to MLN4924, suggesting that other mechanisms are driving clinical resistance. To better understand the potential mechanisms of MLN4924 resistance, we generated MLN4924-resistant ovarian cancer cells. Interestingly, these cells did not develop mutations in NAEβ. Transcriptome analyses revealed that one of the most upregulated genes in resistant cells was ABCG2. This result was validated by quantitative real-time PCR and immunoblotting. Importantly, the sensitivity of MLN4924-resistant cells was restored by lentiviral short hairpin RNA (shRNA) targeting ABCG2. Further investigation using ABCG2-overexpressing NCI-H460/MX20 cells determined that these cells are resistant to the anticancer effects of MLN4924 and can be sensitized by co-treatment with the ABCG2 inhibitors YHO-13351 and fumitremorgin C. Finally, HEK293 models with overexpression of wild-type ABCG2 (R482) and variants (R482G and R482T) all demonstrated significant resistance to MLN4924 compared to wild-type cells. Overall, these findings define an important molecular resistance mechanism to MLN4924 and demonstrate that ABCG2 may be a useful clinical biomarker that predicts resistance to MLN4924 treatment.

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Eadie, Laura N., Verity A. Saunders, Tamara M. Leclercq, Susan Branford, Deborah L. White, and Timothy P. Hughes. "The Allosteric Inhibitor ABL001 Is Susceptible to Resistance in Vitro Mediated By Overexpression of the Drug Efflux Transporters ABCB1 and ABCG2." Blood 126, no. 23 (December 3, 2015): 4841. http://dx.doi.org/10.1182/blood.v126.23.4841.4841.

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Abstract Tyrosine Kinase Inhibitors (TKIs) result in excellent responses in Chronic Myeloid Leukaemia (CML) patients. However, secondary resistance is observed in ~35% of patients, mostly due to Bcr-Abl kinase domain (KD) mutations. Overexpression of the efflux transporter ABCB1 is a known mediator of primary resistance to imatinib (IM) and nilotinib (NIL). ABL001, a potent allosteric inhibitor, binds to the myristate pocket of the Bcr-Abl KD. In this study, we modelled ABL001 resistance in vitro with particular focus on ABCB1 and ABCG2. ABL001 sensitivity was evaluated in BCR -ABL1 + cell lines K562, K562-Dox (ABCB1 overexpressing) and K562-ABCG2 (transfected with ABCG2 overexpression vector). Also, K562, K562-Dox and KU812 cells were made resistant to ABL001 by culturing long term in increasing concentrations of ABL001 (increased once >80% survival in culture for >10 days). Parental ABL001 naive cells were maintained in parallel culture. Initial onset of resistance was characterised by significantly increased IC50ABL001 based on AnnexinV/7-AAD cytotoxicity assays performed at each ABL001 dose escalation. Resistance mechanisms were interrogated during escalation and once 10 μM was reached (based on clinically achievable doses). Protein expression levels of efflux transporters ABCB1/ABCG2 were examined by flow cytometry; KD mutation sequencing and Bcr-Abl protein quantitation were performed. K562-Dox and K562-ABCG2 cells demonstrated significantly increased IC50ABL001 compared with parental K562 control cells: 256 and 299 nM respectively vs 23 nM, p<0.001 suggesting both ABCB1 and ABCG2 are important in ABL001 transport. Furthermore, resistance was reversible through use of specific inhibitors cyclosporin (ABCB1) and Ko143 (ABCG2). IC50ABL001 +inhibitors was comparable to that of control K562 cells: K562-Dox +cyclosporin=11 nM; K562-ABCG2 +Ko143=15 nM. A prior study identified ABCB1 overexpression as an initiator of resistance to IM and NIL (expression increased up to 7- and 5-fold in IM and NIL resistant cells compared with respective control cells p<0.002). In this study, expression levels of ABCB1 and ABCG2 were interrogated in 3 ABL001 resistant cell lines; results indicated overexpression of both transporters was integral in development of resistance. Up to 17- and 60-fold greater levels of ABCB1 and ABCG2 respectively was observed in resistant vs control cells (Table 1). No KD mutations were detected in early resistance intermediates; however, a myristate pocket mutation was detected in later stage KU812 ABL001 resistant cells (percentage mutation correlated with IC50ABL001). Table 1. ABL001 resistance characteristics in selected resistant intermediates IC50ABL001 (nM) Fold change (MFI) Bcr-Abl over expression KD mutation ABCB1 ABCG2 K562 Control 23 N N K562 500 nM ABL001 >2500 p <0.001 -1.4 p =0.003 48.3 p =0.007 Y N K562 10 μM ABL001 27, 800p <0.001 -2.3 p =0.535 60.3 p <0.001 Y N K562 10 μM ABL001 +Ko143 89 p <0.001 K562-Dox Control 256 N N K562-Dox 500 nM ABL001 2393 p <0.001 2.3 p <0.001 -2.9 p <0.001 N N K562-Dox 500 nM ABL001 +cyclosporin 17 p <0.001 K562-Dox 10 μM ABL001 >50, 000 p <0.001 -1.6 p <0.001 -0.1 p <0.001 N N KU812 Control 2.7 N N KU812 5 nM ABL001 6.4 p <0.001 2.2 p =0.008 4.0 p =0.002 Y N KU812 10 μM ABL001 33, 300 p <0.001 8.1 p =0.003 11.0 p =0.010 Y Y (90%) p-value: resistant vs respective control; n>3; N=No; Y=Yes While further in vitro and in vivo studies will determine the clinical relevance of efflux-mediated resistance to ABL001 mono- and combination therapy, our preclinical data provide evidence that kinase domain mutations may not be the predominant cause of ABL001 resistance; drug transporters likely play an important role as well. Susceptibility to ABCB1 overexpression is well recognised for IM and NIL resistance and we now show it is also relevant for ABL001. ABCG2-mediated resistance has not been observed with NIL or IM but is clearly important for ABL001. ABL001 treatment induced ABCG2 overexpression in two cell lines; both have negligible basal expression. ABCG2 overexpression preceded Bcr-Abl overexpression and mutation emergence. Importantly, ABL001 resistance was completely reversible in the presence of the ABCG2 inhibitor Ko143 (K562 10 μM ABL001 cells). Given the lack of strong evidence for ABCG2-mediated transport of NIL or IM at clinically relevant concentrations, our data provide a strong rationale for the use of ABL001 in combination with either of these TKIs. Disclosures Branford: Ariad: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Qiagen: Membership on an entity's Board of Directors or advisory committees. White:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Hughes:ARIAD: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

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Silbermann, Katja, Jiyang Li, Vigneshwaran Namasivayam, Fabian Baltes, Gerd Bendas, Sven Marcel Stefan, and Michael Wiese. "Superior Pyrimidine Derivatives as Selective ABCG2 Inhibitors and Broad-Spectrum ABCB1, ABCC1, and ABCG2 Antagonists." Journal of Medicinal Chemistry 63, no. 18 (July 31, 2020): 10412–32. http://dx.doi.org/10.1021/acs.jmedchem.0c00961.

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Sava, Georgina P., Hailing Fan, Rosemary A. Fisher, Sabrina Lusvarghi, Sunil Pancholi, Suresh V. Ambudkar, Lesley-Ann Martin, R. Charles Coombes, Lakjaya Buluwela, and Simak Ali. "ABC-transporter upregulation mediates resistance to the CDK7 inhibitors THZ1 and ICEC0942." Oncogene 39, no. 3 (September 17, 2019): 651–63. http://dx.doi.org/10.1038/s41388-019-1008-y.

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Abstract The CDK7 inhibitors (CDK7i) ICEC0942 and THZ1, are promising new cancer therapeutics. Resistance to targeted drugs frequently compromises cancer treatment. We sought to identify mechanisms by which cancer cells may become resistant to CDK7i. Resistant lines were established through continuous drug selection. ABC-transporter copy number, expression and activity were examined using real-time PCR, immunoblotting and flow cytometry. Drug responses were measured using growth assays. ABCB1 was upregulated in ICEC0942-resistant cells and there was cross-resistance to THZ1. THZ1-resistant cells upregulated ABCG2 but remained sensitive to ICEC0942. Drug resistance in both cell lines was reversible upon inhibition of ABC-transporters. CDK7i response was altered in adriamycin- and mitoxantrone-resistant cell lines demonstrating ABC-transporter upregulation. ABCB1 expression correlated with ICEC0942 and THZ1 response, and ABCG2 expression with THZ2 response, in a panel of cancer cell lines. We have identified ABCB1 upregulation as a common mechanism of resistance to ICEC0942 and THZ1, and confirmed that ABCG2 upregulation is a mechanism of resistance to THZ1. The identification of potential mechanisms of CDK7i resistance and differences in susceptibility of ICEC0942 and THZ1 to ABC-transporters, may help guide their future clinical use.

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Sorf, Ales, Simona Sucha, Anselm Morell, Eva Novotna, Frantisek Staud, Alzbeta Zavrelova, Benjamin Visek, Vladimir Wsol, and Martina Ceckova. "Targeting Pharmacokinetic Drug Resistance in Acute Myeloid Leukemia Cells with CDK4/6 Inhibitors." Cancers 12, no. 6 (June 16, 2020): 1596. http://dx.doi.org/10.3390/cancers12061596.

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Pharmacotherapy of acute myeloid leukemia (AML) remains challenging, and the disease has one of the lowest curability rates among hematological malignancies. The therapy outcomes are often compromised by the existence of a resistant AML phenotype associated with overexpression of ABCB1 and ABCG2 transporters. Because AML induction therapy frequently consists of anthracycline-like drugs, their efficiency may also be diminished by drug biotransformation via carbonyl reducing enzymes (CRE). In this study, we investigated the modulatory potential of the CDK4/6 inhibitors abemaciclib, palbociclib, and ribociclib on AML resistance using peripheral blood mononuclear cells (PBMC) isolated from patients with de novo diagnosed AML. We first confirmed inhibitory effect of the tested drugs on ABCB1 and ABCG2 in ABC transporter-expressing resistant HL-60 cells while also showing the ability to sensitize the cells to cytotoxic drugs even as no effect on AML-relevant CRE isoforms was observed. All tested CDK4/6 inhibitors elevated mitoxantrone accumulations in CD34+ PBMC and enhanced accumulation of mitoxantrone was found with abemaciclib and ribociclib in PBMC of FLT3-ITD- patients. Importantly, the accumulation rate in the presence of CDK4/6 inhibitors positively correlated with ABCB1 expression in CD34+ patients and led to enhanced apoptosis of PBMC in contrast to CD34− samples. In summary, combination therapy involving CDK4/6 inhibitors could favorably target multidrug resistance, especially when personalized based on CD34− and ABCB1-related markers.

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White, Deborah L., Liu Lu, Timothy P. Clackson, Verity A. Saunders, and Timothy P. Hughes. "ATP Dependent Efflux Transporters ABCB1 and ABCG2 Are Unlikely to Impact the Efficacy, or Mediate Resistance to the Tyrosine Kinase Inhibitor, Ponatinib." Blood 118, no. 21 (November 18, 2011): 2745. http://dx.doi.org/10.1182/blood.v118.21.2745.2745.

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Abstract Abstract 2745 Ponatinib is a potent pan-BCR-ABL tyrosine kinase inhibitor (TKI) currently in a pivotal phase 2 clinical trial. Ponatinib (PON) was specifically designed to target both native and all mutant forms of BCR-ABL, including T315I. The phase I study of oral ponatinib in patients with refractory CML/ALL or other hematologic malignancies recently reported that 66% and 53% of patients with CP-CML achieved MCyR and CCyR respectively (Cortes et al., ASH 2011 abstract #210). While extensive modelling experiments in BaF3 cells have been performed characterising in vitro response to ponatinib, little is known about the interactions of this drug and drug transporters that impact the response of other tyrosine kinase inhibitors (TKIs). To explore this we have examined both the degree of in vitro kinase inhibition mediated by ponatinib in BCR-ABL+ cell lines, and the intracellular uptake and retention (IUR) of ponatinib achieved. The IC50 was determined by assessing the reduction in %p-Crkl in response to increasing concentrations of ponatinib in vitro. The IUR assay was performed as previously using [14-C]-ponatinib. To determine the role of ABCB1 and ABCG2, both previously implicated in the transport of other TKIs, IC50 analysis was performed on K562 cells, and variants; ABCB1 overexpressing K562-DOX and ABCG2 overexpressing K562-ABCG2. As shown in Table 1, in contrast to the results previously observed with imatinib (IM), nilotinib (NIL) and dasatinib (DAS) there was no significant difference in the IC50ponatinib between these three cell lines, suggesting neither ABCB1 nor ABCG2 play a major role in ponatinib transport. Furthermore, the addition of either the ABCB1 and ABCG2 inhibitor pantoprazole, or the multidrug resistance (MDR) inhibitor cyclosporin did not result in a significant change in the IC50ponatinib in any of the cell lines tested. In contrast the addition of either pantoprazole or cyclosporin resulted in a significant reduction in IC50IM, IC50NIL. and IC50DAS of K562-DOX cells, supporting the notion that these TKIs interact with ABCB1.Table 1:The IC50 of ponatinib (compared to IM, NIL and DAS) in K562 cells and the over-expressing variants DOX and ABCG2 in the presence of the ABC inhibitors pantoprazole and cyclosporin. n=5. *p<0.05IC50% reduction in IC50+ pantoprazole+ cyclosporinPON (nM)IM (μM)NIL (nM)DAS (nM)PONIMNILDASPONIMNILDASK5627.793751111544*NA−107NA2DOX7.919*598*100*1018*63*1655*88*ABCG26.4730025*6NA To further examine the effect of ABC transporters on ponatinib efflux we have determined the IUR of [14-C]-ponatinib in K562, DOX and ABCG2 cell lines. We demonstrate no significant difference in the IUR between these cell lines at 37°C (n=6) (K562 vs DOX p=0.6; K562 vs ABCG2 p=0.37 and DOX vs ABCG2 p=0.667 at 2uM respectively). Temperature dependent IUR experiments reveal a significant reduction in the ponatinib IUR at 4°C compared to 37°C in K562 cells (n=6) (p=0.008), DOX cells (p=0.004) and ABCG2 cells (p=0.002) supporting the likely involvement of an ATP/temperature dependent, and yet to be determined, component of ponatinib influx. There was no significant difference in the IUR between these cell lines at 4°C (p=0.824, p=0.7 and p=0.803 respectively). Importantly, these data are consistent with the IC50ponatinib findings. If ATP dependent efflux pumps (ABCB1 and ABCG2) were actively transporting ponatinib, a significant decrease in IUR in DOX and ABCG2 at 37°C compared to K562 cells would be expected, but is not observed here. Analysis of ponatinib IUR in the prototypic ABCB1 over-expressing CEM-VBL100 cells, and their parental, ABCB1 null counterparts (CCRF-CEM) further confirmed these findings. The IUR in VBL100 cells was significantly higher than that observed in CEM's (p<0.001; n=5), providing further evidence that ponatinib was not being exported from the cell actively via ABCB1. These data suggest that the transport of ponatinib is, at least in part, temperature-dependent indicating a yet to be determined ATP transporter may be involved in the transport of ponatinib into leukaemic cells. Importantly, this data suggests that ponatinib is unlikely to be susceptible to resistance via the major ATP efflux transporters (ABCB1 or ABCG2) that have been previously demonstrated to significantly impact the transport of, and mediate resistance to other clinically available TKIs. Disclosures: White: BMS: Honoraria, Research Funding; Novartis Pharmaceuticals: Honoraria, Research Funding. Clackson:ARIAD: Employment. Hughes:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ARIAD: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Lecerf-Schmidt, Florine, Basile Peres, Glaucio Valdameri, Charlotte Gauthier, Evelyn Winter, Léa Payen, Attilio Di Pietro, and Ahcène Boumendjel. "ABCG2: recent discovery of potent and highly selective inhibitors." Future Medicinal Chemistry 5, no. 9 (June 2013): 1037–45. http://dx.doi.org/10.4155/fmc.13.71.

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Henrich, C. J., R. W. Robey, H. R. Bokesch, S. E. Bates, S. Shukla, S. V. Ambudkar, M. Dean, and J. B. McMahon. "New inhibitors of ABCG2 identified by high-throughput screening." Molecular Cancer Therapeutics 6, no. 12 (December 7, 2007): 3271–78. http://dx.doi.org/10.1158/1535-7163.mct-07-0352.

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Sim, Hong-May, Chong-Yew Lee, Pui Lai Rachel Ee, and Mei-Lin Go. "Dimethoxyaurones: Potent inhibitors of ABCG2 (breast cancer resistance protein)." European Journal of Pharmaceutical Sciences 35, no. 4 (November 2008): 293–306. http://dx.doi.org/10.1016/j.ejps.2008.07.008.

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Nicolle, E., A. Boumendjel, S. Macalou, E. Genoux, A. Ahmed-Belkacem, P. A. Carrupt, and A. Di Pietro. "QSAR analysis and molecular modeling of ABCG2-specific inhibitors." Advanced Drug Delivery Reviews 61, no. 1 (January 2009): 34–46. http://dx.doi.org/10.1016/j.addr.2008.10.004.

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28

Michaelis, Martin, Florian Rothweiler, Thomas Nerreter, Mohsen Sharifi, Taravat Ghafourian, and Jindrich Cinatl. "Karanjin interferes with ABCB1, ABCC1, and ABCG2." Journal of Pharmacy & Pharmaceutical Sciences 17, no. 1 (March 10, 2014): 92. http://dx.doi.org/10.18433/j3bw2s.

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PURPOSE: The prominent ATP-binding cassette (ABC) transporters ABCB1, ABCC1, and ABCG2 are involved in substance transport across physiological barriers and therefore in drug absorption, distribution, and elimination. They also mediate multi-drug resistance in cancer cells. Different flavonoids are known to interfere with different ABC transporters. Here, the effect of the furanoflavonol karanjin, a potential drug with antiglycaemic, gastroprotective, antifungal, and antibacterial effects, was investigated on ABCB1, ABCC1, and ABCG2-mediated drug transport in comparison to the flavonoids apigenin, genistein, and naringenin. METHODS: Cells expressing the relevant transporters (ABCB1: UKF-NB-3ABCB1, UKF-NB-3rVCR10; ABCC1: G62, PC-3rVCR20; ABCG2: UKF-NB-3ABCG2) were used in combination with specific fluorescent and cytotoxic ABC transporter substrates and ABC transporter inhibitors to study ABC transporter function. Moreover, the effects of the investigated flavonoids were determined on the ABC transporter ATPase activities. RESULTS: Karanjin interfered with drug efflux mediated by ABCB1, ABCC1, and ABCG2 and enhanced the ATPase activity of all three transporters. Moreover, karanjin exerted more pronounced effects than the control flavonoids apigenin, genistein, and naringenin on all three transporters. Most notably, karanjin interfered with ABCB1 at low concentrations being about 1µM. CONCLUSIONS: Taken together, these findings should be taken into account during further consideration of karanjin as a potential drug for different therapeutic indications. The effects on ABCB1, ABCC1, and ABCG2 may affect the pharmacokinetics of co-administered drugs. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.METHODS: Cells expressing the relevant transporters (ABCB1: UKF-NB-3ABCB1, UKF-NB-3rVCR10; ABCC1: G62, PC-3rVCR20; ABCG2: UKF-NB-3ABCG2) were used in combination with specific fluorescent and cytotoxic ABC transporter substrates and ABC transporter inhibitors to study ABC transporter function. Moreover, the effects of the investigated flavonoids were determined on the ABC transporter ATPase activities.RESULTS: Karanjin interfered with drug efflux mediated by ABCB1, ABCC1, and ABCG2 and enhanced the ATPase activity of all three transporters. Moreover, karanjin exerted more pronounced effects than the control flavonoids apigenin, genistein, and naringenin on all three transporters. Most notably, karanjin interfered with ABCB1 at low concentrations being about 1µM.CONCLUSIONS: Taken together, these findings should be taken into account during further consideration of karanjin as a potential drug for different therapeutic indications. The effects on ABCB1, ABCC1, and ABCG2 may affect the pharmacokinetics of co-administered drugs.

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Mountford, Joanne, Andrea Davies, Niove E. Jordanides, Athina Giannoudis, Claire M. Lucas, Sophia Hatziieremia, Robert J. Harris, et al. "Nilotinib concentration in Cell Lines and CML CD34+ Cells Is Not Mediated by Active Uptake or Efflux by Major Drug Transporters." Blood 112, no. 11 (November 16, 2008): 3205. http://dx.doi.org/10.1182/blood.v112.11.3205.3205.

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Abstract Tyrosine kinase inhibitors (TKIs) that preferentially inhibit the oncogenic Bcr-Abl fusion protein have radically changed the treatment of chronic myeloid leukaemia (CML). Imatinib mesylate ((IM) Gleevec®, Glivec®, STI571; Novartis) has been shown to induce almost complete hematological responses in patients after 12 months and major cytogenetic responses in 69%. However, the proportion of patients achieving molecular responses or having undetectable Bcr-Abl transcripts remains low. In addition to this failure to induce molecular response, resistance occurs in 10–15% of patients. Nilotinib ((NIL) AMN107; Novartis) has approximately 20-fold greater potency in in vitro assays but despite this improved potency in vitro and on bulk primary CML cells we have found that NIL is no better than IM in inducing apoptosis of the primitive CD34+ CML cell population. We previously showed that as with IM, CD34+ CML cells persist after NIL treatment and that NIL also has an anti-proliferative rather than pro-apoptotic effect, resulting in the accumulation of quiescent CD34+ cells. It has been proposed that this population of TKI-insensitive primitive cells may form a pool of disease in patients under treatment and contribute to the Bcr-Abl molecular signal detected in the majority of patients. This population must therefore, be specifically targeted in order to eradicate the disease in patients and to result in cure rather than control of the disease. One possible reason for the failure of NIL to kill CD34+ CML cells is that the cells do not accumulate sufficient intracellular levels of the drug due to either inadequate active uptake via the SLC transporter family, or to efflux via multidrug resistance proteins of the ATP-binding cassette (ABC) family. In order to determine the interaction of NIL with major clinically implicated drug transporters we have investigated interactions with ABCB1, MRP1 (ABCC1), ABCG2 and hOCT1 in CML cell lines and primitive (CD34+) primary CML cells. Determination of the distribution coefficient (logD) showed that NIL is more lipophilic than IM (logD of 2.4 vs 0.8 respectively) and assays using 14C-NIL in OCT1 over expressing KCL22 CML cells showed that accumulation of NIL is neither temperature dependent nor reduced by the inhibitors prazosin or amatadine. These data demonstrate that NIL uptake is not dependent on active import by hOCT1, however NIL did inhibit the uptake of a known OCT1 substrate tetraethylammonium bromide (TEA). Efflux assay in cell lines over-expressing MDR1, MRP1 or ABCG2 showed that NIL is not effluxed by any of these proteins. Over expression &/or the addition of specific inhibitors (PSC833, MK571, fumitremorgin C respectively) did not alter the cellular accumulation of NIL as assayed by radiolabelled drug accumulation assays, transepithelial transport, HPLC analysis or when p-CrkL was measured as a surrogate assay for Bcr-Abl inhibition. Using efflux assays with known substrates we found that NIL inhibited rhodamine efflux via MDR1, or BODIPY-prazosin efflux via ABCG2, but had no effect on Fluo-3 efflux via MRP1. Thus, rather than being a substrate NIL acts as an inhibitor of MDR1 and ABCG2 in these assays. To conclusively assess the effect of transporter activity in primary cells we first measured the expression of the transporters in primitive CD34+ CML cells. Unlike OCT1, the efflux transporters MDR1, MRP1 and ABCG2 are all expressed on CML CD34+ cells. When compared to normal CD34+ cells ABCG2 was over expressed (291%), MRP1 was expressed at very similar levels (108%) and surprisingly MDR1 was expressed at a much lower level in CML (13.5%). We treated CD34+ CML cells with NIL for 72hrs in the presence or absence of the transporter inhibitors. NIL reduced the total cell number and p-CrkL activity as expected however, these effects were not potentiated by any of the transporter inhibitors. Furthermore, NIL increased the number of quiescent CD34+ cells remaining after treatment but again transporter inhibitors did not modulate this effect. Therefore, we have found no evidence for either active uptake of NIL via hOCT1 or efflux via MDR1, MRP1 or ABCG2. It is unlikely that these transporters will have any effect on the clinical response to this drug in either MNCs or the more resistant CD34+ stem cell population.

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Wu, Yao, Xin-Ying Gao, Xin-Hui Chen, Shao-Long Zhang, Wen-Juan Wang, Xie-Huang Sheng, and De-Zhan Chen. "Fragment-centric topographic mapping method guides the understanding of ABCG2-inhibitor interactions." RSC Advances 9, no. 14 (2019): 7757–66. http://dx.doi.org/10.1039/c8ra09789e.

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Our study gains insight into the development of novel specific ABCG2 inhibitors, and develops a comprehensive computational strategy to understand protein ligand interaction with the help of AlphaSpace, a fragment-centric topographic mapping tool.

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Safar, Zsolt, Emese Kis, Franciska Erdo, Joseph K. Zolnerciks, and Peter Krajcsi. "ABCG2/BCRP: variants, transporter interaction profile of substrates and inhibitors." Expert Opinion on Drug Metabolism & Toxicology 15, no. 4 (March 16, 2019): 313–28. http://dx.doi.org/10.1080/17425255.2019.1591373.

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Mealey, Katrina L., Sandamali Dassanayake, and Neal S. Burke. "Tyrosine Kinase Inhibitors Enhance Ciprofloxacin-Induced Phototoxicity by Inhibiting ABCG2." Oncology 87, no. 6 (2014): 364–70. http://dx.doi.org/10.1159/000366132.

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Ishikawa, Toshihisa, Hiroshi Nakagawa, Yuichiro Hagiya, Naosuke Nonoguchi, Shin-ichi Miyatake, and Toshihiko Kuroiwa. "Key Role of Human ABC Transporter ABCG2 in Photodynamic Therapy and Photodynamic Diagnosis." Advances in Pharmacological Sciences 2010 (2010): 1–13. http://dx.doi.org/10.1155/2010/587306.

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Accumulating evidence indicates that ATP-binding cassette (ABC) transporter ABCG2 plays a key role in regulating the cellular accumulation of porphyrin derivatives in cancer cells and thereby affects the efficacy of photodynamic therapy and photodynamic diagnosis. The activity of porphyrin efflux can be affected by genetic polymorphisms in theABCG2gene. On the other hand, Nrf2, an NF-E2-related transcription factor, has been shown to be involved in oxidative stress-mediated induction of theABCG2gene. Since patients have demonstrated individual differences in their response to photodynamic therapy, transcriptional activation and/or genetic polymorphisms of theABCG2gene in cancer cells may affect patients' responses to photodynamic therapy. Protein kinase inhibitors, including imatinib mesylate and gefitinib, are suggested to potentially enhance the efficacy of photodynamic therapy by blocking ABCG2-mediated porphyrin efflux from cancer cells. This review article provides an overview on the role of human ABC transporter ABCG2 in photodynamic therapy and photodynamic diagnosis.

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Kochanek, Stanton J., David A. Close, Allen Xinwei Wang, Tongying Shun, Philip E. Empey, Julie L. Eiseman, and Paul A. Johnston. "Confirmation of Selected Synergistic Cancer Drug Combinations Identified in an HTS Campaign and Exploration of Drug Efflux Transporter Contributions to the Mode of Synergy." SLAS DISCOVERY: Advancing the Science of Drug Discovery 24, no. 6 (April 30, 2019): 653–68. http://dx.doi.org/10.1177/2472555219844566.

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Systematic unbiased high-throughput screening (HTS) of drug combinations (DCs) in well-characterized tumor cell lines is a data-driven strategy to identify novel DCs with potential to be developed into effective therapies. Four DCs from a DC HTS campaign were selected for confirmation; only one appears in clinicaltrials.gov and limited preclinical in vitro data indicates that the drug pairs interact synergistically. Nineteen DC-tumor cell line sets were confirmed to interact synergistically in three pharmacological interaction models. We developed an imaging assay to quantify accumulation of the ABCG2 efflux transporter substrate Hoechst. Gefitinib and raloxifene enhanced Hoechst accumulation in ABCG2 (BCRP)-expressing cells, consistent with inhibition of ABCG2 efflux. Both drugs also inhibit ABCB1 efflux. Mitoxantrone, daunorubicin, and vinorelbine are substrates of one or more of the ABCG2, ABCB1, or ABCC1 efflux transporters expressed to varying extents in the selected cell lines. Interactions between ABC drug efflux transporter inhibitors and substrates may have contributed to the observed synergy; however, other mechanisms may be involved. Novel synergistic DCs identified by HTS were confirmed in vitro, and plausible mechanisms of action studied. Similar approaches may justify the testing of novel HTS-derived DCs in mouse xenograft human cancer models and support the clinical evaluation of effective in vivo DCs in patients.

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Wu, Chung-Pu, Cheng-Yu Hung, Megumi Murakami, Yu-Shan Wu, Chun-Ling Lin, Yang-Hui Huang, Tai-Ho Hung, Jau-Song Yu, and Suresh V. Ambudkar. "P-glycoprotein Mediates Resistance to the Anaplastic Lymphoma Kinase Inhiitor Ensartinib in Cancer Cells." Cancers 14, no. 9 (May 9, 2022): 2341. http://dx.doi.org/10.3390/cancers14092341.

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Ensartinib (X-396) is a promising second-generation small-molecule inhibitor of anaplastic lymphoma kinase (ALK) that was developed for the treatment of ALK-positive non-small-cell lung cancer. Preclinical and clinical trial results for ensartinib showed superior efficacy and a favorable safety profile compared to the first-generation ALK inhibitors that have been approved by the U.S. Food and Drug Administration. Although the potential mechanisms of acquired resistance to ensartinib have not been reported, the inevitable emergence of resistance to ensartinib may limit its therapeutic application in cancer. In this work, we investigated the interaction of ensartinib with P-glycoprotein (P-gp) and ABCG2, two ATP-binding cassette (ABC) multidrug efflux transporters that are commonly associated with the development of multidrug resistance in cancer cells. Our results revealed that P-gp overexpression, but not expression of ABCG2, was associated with reduced cancer cell susceptibility to ensartinib. P-gp directly decreased the intracellular accumulation of ensartinib, and consequently reduced apoptosis and cytotoxicity induced by this drug. The cytotoxicity of ensartinib could be significantly reversed by treatment with the P-gp inhibitor tariquidar. In conclusion, we report that ensartinib is a substrate of P-gp, and provide evidence that this transporter plays a role in the development of ensartinib resistance. Further investigation is needed.

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Peng, Hui, Jing Qi, Zizheng Dong, and Jian-Ting Zhang. "Dynamic vs Static ABCG2 Inhibitors to Sensitize Drug Resistant Cancer Cells." PLoS ONE 5, no. 12 (December 7, 2010): e15276. http://dx.doi.org/10.1371/journal.pone.0015276.

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Boumendjel, Ahcène, Edwige Nicolle, Thomas Moraux, Bastien Gerby, Madeleine Blanc, Xavier Ronot, and Jean Boutonnat. "Piperazinobenzopyranones and Phenalkylaminobenzopyranones: Potent Inhibitors of Breast Cancer Resistance Protein (ABCG2)." Journal of Medicinal Chemistry 48, no. 23 (November 2005): 7275–81. http://dx.doi.org/10.1021/jm050705h.

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Zhang, Shuzhong, Xinning Yang, and Marilyn E. Morris. "Flavonoids Are Inhibitors of Breast Cancer Resistance Protein (ABCG2)-Mediated Transport." Molecular Pharmacology 65, no. 5 (April 20, 2004): 1208–16. http://dx.doi.org/10.1124/mol.65.5.1208.

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Kraege, Stefanie, Katja Stefan, Sebastian C. Köhler, and Michael Wiese. "Optimization of Acryloylphenylcarboxamides as Inhibitors of ABCG2 and Comparison with Acryloylphenylcarboxylates." ChemMedChem 11, no. 22 (October 27, 2016): 2547–58. http://dx.doi.org/10.1002/cmdc.201600455.

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Juvale, Kapil, Jennifer Gallus, and Michael Wiese. "Investigation of quinazolines as inhibitors of breast cancer resistance protein (ABCG2)." Bioorganic & Medicinal Chemistry 21, no. 24 (December 2013): 7858–73. http://dx.doi.org/10.1016/j.bmc.2013.10.007.

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de Gooijer, Mark C., Ping Zhang, Levi C. M. Buil, Stephan Freriks, Gang Li, Jos H. Beijnen, and Olaf van Tellingen. "DDRE-01. ACQUIRED AND INTRINSIC RESISTANCE TO VEMURAFENIB IN BRAFV600E-DRIVEN MELANOMA BRAIN METASTASES." Neuro-Oncology 22, Supplement_2 (November 2020): ii61. http://dx.doi.org/10.1093/neuonc/noaa215.246.

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Abstract BRAF V600-mutated melanoma brain metastases (MBMs) are responsive to BRAF inhibitors, but clinical responses are less durable than those of extracranial metastases. We studied the impact of the drug efflux proteins P-glycoprotein (P-gp; ABCB1) and breast cancer resistance protein (BCRP; ABCG2) at the blood-brain barrier (BBB) on the efficacy of vemurafenib against BRAFV600E-mutated A375 MBMs. We intracranially implanted A375 tumor cells in wild-type and Abcb1a/b;Abcg2-/- mice. We characterized the tumor BBB, analyzed drug levels in plasma and brain lesions after oral vemurafenib and determined the efficacy against brain metastases and subcutaneous lesions. MRI shows that A375 MBMs disrupt BBB integrity, but vemurafenib accumulation in MBMs was still reduced by P-gp/BCRP. Vemurafenib is also less efficacious against MBMs in wild-type mice compared to Abcb1a/b;Abcg2-/- mice. Vemurafenib efficacy against subcutaneous A375 tumors was similar in both strains. Even in Abcb1a/b;Abcg2-/- mice, A375 MBMs rapidly developed resistance, which was unrelated to pharmacokinetic issues or insufficient inhibition of MAPK/PI3K pathways. Taken together, these studies demonstrate that although the BBB is disrupted in MBMs, P-gp/BCRP still limit the efficacy of vemurafenib. Moreover, the response to vemurafenib is less and of shorter duration also due to rapidly acquired resistance, most likely by resorting to non-canonical growth signaling.

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Loh, Yen Siew, John D. Allen, Ammira Al-shabeeb, Ross D. Brown, Jia Li, Joshua Douglas, and Daniel Sze. "The Investigation of Mechanisms Underlying Hoechst 33342 Efflux in Myeloma ‘Side Population' Cells." Blood 114, no. 22 (November 20, 2009): 2759. http://dx.doi.org/10.1182/blood.v114.22.2759.2759.

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Abstract Abstract 2759 Poster Board II-735 A subpopulation of cells with characteristics of cancer stem cells can be identified by the side population (SP) phenotype that is based on the efflux of the fluorescent dye Hoechst 33342 and detected by flow cytometric analysis. We previously reported the identification of SP cells in 4 human myeloma cell lines (HMCL) and 18 of 21 bone marrow samples from patients with myeloma in which the percentage of SP cells ranged from 0 to 4.9% (median=0.3; mean=0.8; SD=1.2). We now report the mechanism underlying the Hoechst 33342 efflux in SP cells, which may be a contributor to the drug resistance in myeloma cancer stem cells (MCSC). SP and main population (MP) subsets of HMCL (KMS-11 and RPMI-8226), based on Hoechst-33342 staining, were analyzed or sorted by BD FACSAria™ II using a blue and red dual-wavelength analysis after UV excitation. In this study, we examined the activities of three main drug transporter classes associated to SP phenotype – ABCB1 (MDR1), ABCG2 (BCRP1) and ABCC (MRP). Inhibition of the SP phenotype using PSC833, Ko143, and sulfinpyrazone (ABCB1, ABCG2, and ABCC inhibitors respectively) were first tested. Only the Ko143 and sulfinpyrazone were able to inhibit the entire SP phenotype in HMCL. Next, the activity of each transporter in unfractionated, sorted-SP and sorted-MP cells was examined. Relative cellular accumulation of fluorescent substrate for each transporter, namely rhodamine123 1 μg/mL, mitoxantrone 20 μM, and fluo-3 am 1 μg/mL, was determined. Experiments were conducted in the presence or absence of specific inhibitors. There were significant increases of mitoxantrone (P=0.0033** and P=0.0262*) and fluo-3 am (P=0.0006*** and P=0.0152*) in unfractionated RPMI-8226 and KMS-11 in the presence of Ko143 and sulfinpyrazone respectively. In the presence of sulfinpyrazone, benzbromarone, or dipyridamole (ABCC inhibitors), there was a significant increase of fluo-3 am in both SP and MP cells (P<0.05) sorted from KMS-11, however, only the sorted-SP cells showed significant increase of mitoxantrone in the presence of Ko143 (P=0.0462*) (Figure 1A). This suggests that while both ABCC and ABCG2 activity were significant in HMCL, the ABCC activity was similar in both SP and MP cells, whereas the ABCG2 activity was higher in the SP cells. The addition of PSC833 did not increase the accumulation of rhodamine 123 in the unfractionated, sorted-SP, or sorted-MP cells. This confirmed that there is negligible ABCB1 activity in HMCL. Consistent with the functional assay, western blot results revealed no ABCB1 expression in both SP and MP cells from KMS-11. There was a moderate ABCC1 expression in both fractions, and more ABCG2 in SP than MP cells (Figure 1B). This report suggests that while ABCG2 and ABCC activity are present in myeloma cells, ABCG2 is the main contributor to defining the SP by Hoechst efflux and perhaps the molecular determinant of MCSC. However, whether the stem cell related characteristic differences between SP and MP cells are solely because of these transporters is far from conclusive. Understanding these principles will allow investigators to develop therapeutic approaches that capitalize on the uniqueness of MCSC, thereby targeting the malignant cell and sparing normal cells. In conclusion, this report elucidates a distinct drug transporter expression in myeloma SP cells that could be a crucial target in cancer drug development and future clinical trials in patients with myeloma. Disclosures: No relevant conflicts of interest to declare.

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Rudin, Charles M., Wanqing Liu, Apurva Desai, Theodore Karrison, Xuemin Jiang, Linda Janisch, Soma Das, et al. "Pharmacogenomic and Pharmacokinetic Determinants of Erlotinib Toxicity." Journal of Clinical Oncology 26, no. 7 (March 1, 2008): 1119–27. http://dx.doi.org/10.1200/jco.2007.13.1128.

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Purpose To assess the pharmacogenomic and pharmacokinetic determinants of skin rash and diarrhea, the two primary dose-limiting toxicities of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib. Patients and Methods A prospective clinical study of 80 patients with non–small-cell lung cancer, head and neck cancer, and ovarian cancer was performed. Detailed pharmacokinetics and toxicity of erlotinib were assessed. Polymorphic loci in EGFR, ABCG2, CYP3A4, and CYP3A5 were genotyped, and their effects on pharmacokinetics and toxicities were evaluated. Results A novel diplotype of two polymorphic loci in the ABCG2 promoter involving −15622C/T and 1143C/T was identified, with alleles conferring lower ABCG2 levels associated with higher erlotinib pharmacokinetic parameters, including area under the curve (P = .019) and maximum concentration (P = .006). Variability in skin rash was best explained by a multivariate logistic regression model incorporating the trough erlotinib plasma concentration (P = .034) and the EGFR intron 1 polymorphism (P = .044). Variability in diarrhea was associated with the two linked polymorphisms in the EGFR promoter (P < .01), but not with erlotinib concentration. Conclusion Although exploratory in nature, this combined pharmacogenomic and pharmacokinetic model helps to define and differentiate the primary determinants of skin and gastrointestinal toxicity of erlotinib. The findings may be of use both in designing trials targeting a particular severity of rash and in considering dose and schedule modifications in patients experiencing dose-limiting toxicities of erlotinib or similarly targeted agents. Further studies of the relationship between germline polymorphisms in EGFR and the toxicity and efficacy of EGFR inhibitors are warranted.

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Petersen, Malene J., Xamuel L. Lund, Susan J. Semple, Bevan Buirchell, Henrik Franzyk, Michael Gajhede, Kenneth T. Kongstad, Jan Stenvang, and Dan Staerk. "Reversal of ABCG2/BCRP-Mediated Multidrug Resistance by 5,3′,5′-Trihydroxy-3,6,7,4′-Tetramethoxyflavone Isolated from the Australian Desert Plant Eremophila galeata Chinnock." Biomolecules 11, no. 10 (October 18, 2021): 1534. http://dx.doi.org/10.3390/biom11101534.

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Multidrug resistance (MDR) is a major challenge in cancer treatment, and the breast cancer resistance protein (BCRP) is an important target in the search for new MDR-reversing drugs. With the aim of discovering new potential BCRP inhibitors, the crude extract of leaves of Eremophila galeata, a plant endemic to Australia, was investigated for inhibitory activity of parental (HT29par) as well as BCRP-overexpressing HT29 colon cancer cells resistant to the chemotherapeutic SN-38 (i.e., HT29SN38 cells). This identified a fraction, eluted with 40% acetonitrile on a solid-phase extraction column, which showed weak growth-inhibitory activity on HT29SN38 cells when administered alone, but exhibited concentration-dependent growth inhibition when administered in combination with SN-38. The major constituent in this fraction was isolated and found to be 5,3′,5′-trihydroxy-3,6,7,4′-tetramethoxyflavone (2), which at a concentration of 25 μg/mL potentiated the growth-inhibitory activity of SN-38 to a degree comparable to that of the known BCRP inhibitor Ko143 at 1 μM. A dye accumulation experiment suggested that 2 inhibits BCRP, and docking studies showed that 2 binds to the same BCRP site as SN-38. These results indicate that 2 acts synergistically with SN-38, with 2 being a BCRP efflux pump inhibitor while SN-38 inhibits topoisomerase-1.

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Cerveny, Lukas, Zuzana Ptackova, Marketa Durisova, and Frantisek Staud. "Interactions of protease inhibitors atazanavir and ritonavir with ABCB1, ABCG2, and ABCC2 transporters: Effect on transplacental disposition in rats." Reproductive Toxicology 79 (August 2018): 57–65. http://dx.doi.org/10.1016/j.reprotox.2018.05.008.

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Brummendorf, Tim H., Artur Gontarewicz, Gunhild Keller, Jürgen Moll, Melanie Braig, Imke Rohe, Edgar Jost, et al. "Resistance to Danusertib (formerly PHA-739358) in BCR-ABL-Positive Cells Is Mediated by Upregulation of the Drug Transporter Abcg2 and Can Be Suppressed in Vitro by Combination Treatment with Imatinib." Blood 114, no. 22 (November 20, 2009): 1724. http://dx.doi.org/10.1182/blood.v114.22.1724.1724.

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Abstract Abstract 1724 Poster Board I-750 The success of imatinib (IM, formerly STI571, Gleevec®) in the treatment of chronic myeloid leukemia (CML) is compromised by the development of primary or acquired IM-resistance, particularly in advanced phase disease as well as by a limited IM-effect on immature hematopoietic stem cells, emphasizing the need for novel therapeutic strategies. The small molecule inhibitor Danusertib (formerly PHA-739358) potently inhibits Aurora and ABL kinases. Here, the individual contribution of each pathway to the effect of Danusertib was investigated. Starting at very low concentration, a dose-dependent reduction of BCR-ABL activity was observed, whereas inhibition of Aurora kinase activity, assessed by phosphorylation of histone H3-Ser10, required substantially higher concentrations. In primary CD34+ CML cells, including initially quiescent leukemic stem cells, combination therapy with IM and Danusertib revealed a synergistic anti-proliferative activity, which also affected immature CD34+38- cells. Neither mono- nor combination therapy led to substantial induction of apoptosis in quiescent stem cells. Interestingly, under treatment with Danusertib, the emergence of resistant clones in a well-established murine Ba/F3-p210 cell model was considerably less frequent than with IM. Surprisingly, Danusertib-resistant cells did not have mutations in BCR-ABL or Aurora kinase domains and remained IM-sensitive. Analysis of resistance mechanisms using DNA-microarray suggests an overexpression of Abcg2 efflux transporter to be causative for the resistance arising under Danusertib treatment. In support of this finding, stable retroviral overexpression of Abcg2 in parental Ba/F3-p210 cells induced a resistant phenotype against Danusertib. Furthermore, the Abcg2 inhibitor Fumitremorgin C (FTC) could restore the sensitivity of resistant cells to Danusertib. Finally, significant re-expression of Abcg2 in parental Ba/F3-p210 cells upon treatment with the demethylating agent 5-Azacytidine suggests that an epigenetic mechanism might play a role in the regulation of Abcg2 gene expression in resistant clones. Detailed analyses of the methylation patterns of the Abcg2 promoter region are currently being performed. In conclusion, simultaneous in vitro exposure of Ba/F3-p210 cells to Danusertib and IM significantly reduced the emergence of drug resistance, raising hope that both epigenetic modulation of drug transporters involved in development of resistance as well as hypothesis-driven combinations of kinase inhibitors may eventually achieve durable disease control even in 2nd and 3rd line treatment of CML. Disclosures Brummendorf: Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Moll:Nerviano MS: Employment. Jost:MSD: Research Funding. Bokemeyer:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Holyoake:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squib: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Balabanov:Novartis : Research Funding; Bristol Myers Squibb: Research Funding.

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Özvegy-Laczka, Csilla, Tamás Hegedűs, György Várady, Olga Ujhelly, John D. Schuetz, András Váradi, György Kéri, László Őrfi, Katalin Német, and Balázs Sarkadi. "High-Affinity Interaction of Tyrosine Kinase Inhibitors with the ABCG2 Multidrug Transporter." Molecular Pharmacology 65, no. 6 (May 20, 2004): 1485–95. http://dx.doi.org/10.1124/mol.65.6.1485.

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Pick, Anne, Henrik Müller, and Michael Wiese. "Structure–activity relationships of new inhibitors of breast cancer resistance protein (ABCG2)." Bioorganic & Medicinal Chemistry 16, no. 17 (September 2008): 8224–36. http://dx.doi.org/10.1016/j.bmc.2008.07.034.

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Antoni, Frauke, Manuel Bause, Matthias Scholler, Stefanie Bauer, Simone A. Stark, Scott M. Jackson, Ioannis Manolaridis, et al. "Tariquidar-related triazoles as potent, selective and stable inhibitors of ABCG2 (BCRP)." European Journal of Medicinal Chemistry 191 (April 2020): 112133. http://dx.doi.org/10.1016/j.ejmech.2020.112133.

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Antoni, Frauke, David Wifling, and Günther Bernhardt. "Water-soluble inhibitors of ABCG2 (BCRP) – A fragment-based and computational approach." European Journal of Medicinal Chemistry 210 (January 2021): 112958. http://dx.doi.org/10.1016/j.ejmech.2020.112958.

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Journal articles on the topic 'ABCG2 inhibitors'

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