Molecular Pharmacology of ABCG2 and Its Role in Chemoresistance

Stacy, Alexandra E.; Jansson, Patric J.; Richardson, Des R.

doi:10.1124/mol.113.088609

Cited by 181 publications

(178 citation statements)

References 157 publications

(181 reference statements)

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“…ABCG2 has been reported to mediate MDR by effluxing numerous agents, including mitoxantrone (MX), topotecan, irinotecan, DOX, nilotinib, and imatinib (16,(18)(19)(20). Indeed, upregulated expression of ABCG2 is observed in a variety of cancer stem cells, leading to the speculation that ABCG2 provides cellular protection against cytotoxic agents for cancer stem cells, which are inherently present in the cancer cell populations (21,22).…”

Section: Introductionmentioning

confidence: 99%

Osimertinib (AZD9291) Enhanced the Efficacy of Chemotherapeutic Agents in ABCB1- and ABCG2-Overexpressing Cells In Vitro, In Vivo, and Ex Vivo

Chen

et al. 2016

Molecular Cancer Therapeutics

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The overexpression of ATP-binding cassette (ABC) transporters has been proved to be a major trigger for multidrug resistance (MDR) in certain types of cancer. In our study, we investigated whether osimertinib (AZD9291), a third-generation irreversible tyrosine kinase inhibitor of both activating EGFR mutations and resistance-associated T790M point mutation, could reverse MDR induced by ABCB1 and ABCG2 in vitro, in vivo, and ex vivo. Our results showed that osimertinib significantly increased the sensitivity of ABCB1-and ABCG2-overexpressing cells to their substrate chemotherapeutic agents in vitro and in the model of ABCB1-overexpressing KBv200 cell xenograft in nude mice. Mechanistically, osimertinib increased the intracellular accumulations of doxorubicin (DOX) and Rhodamine 123 (Rho 123) by inhibiting the efflux function of the transporters in ABCB1-or ABCG2-overexpressing cells but not in their parental sensitive cells. Furthermore, osimertinib stimulated the ATPase activity of both ABCB1 and ABCG2 and competed with the [ 125 I] iodoarylazidoprazosin photolabeling bound to ABCB1 or ABCG2, but did not alter the localization and expression of ABCB1 or ABCG2 in mRNA and protein levels nor the phosphorylations of EGFR, AKT, and ERK. Importantly, osimertinib also enhanced the cytotoxicity of DOX and intracellular accumulation of Rho 123 in ABCB1-overexpressing primary leukemia cells. Overall, these findings suggest osimertinib reverses ABCB1-and ABCG2-mediated MDR via inhibiting ABCB1 and ABCG2 from pumping out chemotherapeutic agents and provide possibility for cancer combinational therapy with osimertinib in the clinic.

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Section: Introductionmentioning

confidence: 99%

Osimertinib (AZD9291) Enhanced the Efficacy of Chemotherapeutic Agents in ABCB1- and ABCG2-Overexpressing Cells In Vitro, In Vivo, and Ex Vivo

Chen

et al. 2016

Molecular Cancer Therapeutics

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“…Other classes of anticancer drugs including vinblastine, cisplatin, and paclitaxel are not BCRP substrates (13). BCRP substrates are not limited to chemotherapeutics.…”

Section: Bcrp Substratesmentioning

confidence: 99%

“…BCRP substrates are not limited to chemotherapeutics. Drugs that have been shown to be BCRP substrates include, among others, prazosin, glyburide, cimetidine, sulfasalazine, and rosuvastatin (1,13). Nucleoside and nucleotide analogs such as AZT and lamivudine are also BCRP substrates (1).…”

Section: Bcrp Substratesmentioning

confidence: 99%

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Role of the Breast Cancer Resistance Protein (BCRP/ABCG2) in Drug Transport—an Update

Mao

Unadkat

2014

AAPS J

519

387

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Abstract. The human breast cancer resistance protein (BCRP, gene symbol ABCG2) is an ATP-binding cassette (ABC) efflux transporter. It was so named because it was initially cloned from a multidrugresistant breast cancer cell line where it was found to confer resistance to chemotherapeutic agents such as mitoxantrone and topotecan. Since its discovery in 1998, the substrates of BCRP have been rapidly expanding to include not only therapeutic agents but also physiological substances such as estrone-3-sulfate, 17β-estradiol 17-(β-D-glucuronide) and uric acid. Likewise, at least hundreds of BCRP inhibitors have been identified. Among normal human tissues, BCRP is highly expressed on the apical membranes of the placental syncytiotrophoblasts, the intestinal epithelium, the liver hepatocytes, the endothelial cells of brain microvessels, and the renal proximal tubular cells, contributing to the absorption, distribution, and elimination of drugs and endogenous compounds as well as tissue protection against xenobiotic exposure. As a result, BCRP has now been recognized by the FDA to be one of the key drug transporters involved in clinically relevant drug disposition. We published a highly-accessed review article on BCRP in 2005, and much progress has been made since then. In this review, we provide an update of current knowledge on basic biochemistry and pharmacological functions of BCRP as well as its relevance to drug resistance and drug disposition.

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“…The ATP-binding cassette, subfamily G, isoform 2 protein (ABCG2) is a molecular determinant of the SP phenotype, and has been suggested to be involved in multidrug resistance in cancer. The ABCG2 acts as efflux proteins to transport a variety of molecules, including certain chemotherapeutic drugs [72] . Data suggested that ABCG2 is a promising molecular marker for identification of CSCs in tumors.…”

Section: Regulation Of Abcg2mentioning

confidence: 99%

Potential Therapeutic Effects of Natural Extracts in Multiple Myeloma

Guo

et al. 2016

Cancer Cell Microenviron

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Multiple myeloma (MM) is the second most common hematologic malignancy characterized by proliferation of monoclonal plasmas cells in bone marrow. Despite the advent of new agents targeting the neoplastic clone and its microenvironment, MM is still to be hard-to-treat cancer, with patients experiencing subsequent phases of remission and relapse, eventually leading to therapies resistance and patient death. In the past decades, natural products have attracted increasing attention in the field of anti-myeloma treatment by virtue of their multiple bioactivities and lower toxicity. The present review will discuss the latest research progress and mechanisms through which these natural extracts inhibit tumor cell proliferation and normalize microenvironment in multiple myeloma. These include the induction of apoptosis, inhibition of bone injury and angiogenesis, and reversion of multidrug resistance.

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Molecular Pharmacology of ABCG2 and Its Role in Chemoresistance

Abstract: The ATP-binding cassette, subfamily G, isoform 2 protein (

Cited by 181 publications

References 157 publications

Osimertinib (AZD9291) Enhanced the Efficacy of Chemotherapeutic Agents in ABCB1- and ABCG2-Overexpressing Cells In Vitro, In Vivo, and Ex Vivo

Osimertinib (AZD9291) Enhanced the Efficacy of Chemotherapeutic Agents in ABCB1- and ABCG2-Overexpressing Cells In Vitro, In Vivo, and Ex Vivo

Role of the Breast Cancer Resistance Protein (BCRP/ABCG2) in Drug Transport—an Update

Potential Therapeutic Effects of Natural Extracts in Multiple Myeloma

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