Breast Cancer Resistance Protein Directly Confers SN-38 Resistance of Lung Cancer Cells

Kawabata, Shigeru; Oka, M.; Shiozawa, Ken; Tsukamoto, Kazuhiro; Nakatomi, Katsumi; Soda, Hiroshi; Fukuda, Minoru; Ikegami, Yoji; Sugahara, Kazuyuki; Yamada, Yasuaki; Kamihira, Shimeru; Doyle, L. Austin; Ross, Douglas D.; Kohno, Shigeru

doi:10.1006/bbrc.2001.4267

Cited by 221 publications

(177 citation statements)

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“…PC-6/SN2-5H cells over express BCRP and have highly functional efflux-pump activity, indicating high resistance to SN-38. 15,28 NCI-H358, NCI-H441, and NCI-H460 cells have moderate expression and functional pump activity of BCRP and demonstrate moderate to low resistance to SN-38. 28 Conversely, PC-6 and NCI-H69 cells never express BCRP and have high sensitivity to SN-38.…”

Section: Methodsmentioning

confidence: 99%

“…9 In our previous study, BCRP was not expressed in human small cell lung cancer PC-6 cells but was overexpressed in the SN-38-resistant subline, PC-6/ SN2-5H, which was selected from PC-6 cells by continuous exposure to SN-38. 15 In addition, the antisense oligonucleotide significantly suppressed BCRP expression and enhanced the sensitivity to SN-38 in PC-6/SN2-5H cells, indicating that BCRP re-expression directly confers SN-38 resistance. 15 However, the precise mechanisms underlying BCRP re-expression during acquisition of drug resistance remain unclear.…”

mentioning

confidence: 88%

“…15 In addition, the antisense oligonucleotide significantly suppressed BCRP expression and enhanced the sensitivity to SN-38 in PC-6/SN2-5H cells, indicating that BCRP re-expression directly confers SN-38 resistance. 15 However, the precise mechanisms underlying BCRP re-expression during acquisition of drug resistance remain unclear.…”

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confidence: 88%

“…11,12 The anticancer drugs that are effluxed by BCRP are mitoxantrone, anthracyclines, and topotecan-derived and topoisomerase I inhibitors, including 7-ethyl-10-hydroxycamptothecin (SN-38) (an active metabolite of irinotecan) and methotrexate. 10,[13][14][15][16][17] Moreover, because it is expressed physiologically in the placenta, bile canaliculi, colon, small intestine, and brain microvessel endothelium, BCRP may play a role in protecting the organism from potentially harmful xenobiotics in normal and cancer cells. 9 In our previous study, BCRP was not expressed in human small cell lung cancer PC-6 cells but was overexpressed in the SN-38-resistant subline, PC-6/ SN2-5H, which was selected from PC-6 cells by continuous exposure to SN-38.…”

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confidence: 99%

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Methylation status of breast cancer resistance protein detected by methylation‐specific polymerase chain reaction analysis is correlated inversely with its expression in drug‐resistant lung cancer cells

Nakano

Nakamura

Soda

et al. 2008

Cancer

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It is increasingly difficult to choose the proper tests to investigate an abnormal laboratory result, delaying the time to reach the correct diagnosis and increasing the cost of care. A wrong choice may also lead to clinically significant errors, which can be life threatening. To show how errors in test selection occur in routine medical practice, the authors describe an algorithm to evaluate patients with a prolonged activated partial thromboplastin time (PTT) and a normal prothrombin time. This exercise challenges the commonly held belief that errors in laboratory utilization occur primarily with esoteric and/or genetic testing, rather than in patients with common abnormalities such as a prolonged PTT. Am. J. Hematol. 2013. © 2012 Wiley Periodicals, Inc.

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Section: Methodsmentioning

confidence: 99%

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confidence: 88%

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confidence: 88%

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confidence: 99%

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Methylation status of breast cancer resistance protein detected by methylation‐specific polymerase chain reaction analysis is correlated inversely with its expression in drug‐resistant lung cancer cells

Nakano

Nakamura

Soda

et al. 2008

Cancer

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“…ABCG2, also called BCRP/MXR/ABCP, is a member of the G subfamily of human ABC transporters, and has been demonstrated to confer resistance to multiple cancer chemotherapeutic agents, such as mitoxantrone, flavopiridol, methotrexate, and the camptothecin derivatives SN-38 and topotecan. (7)(8)(9)(10) In addition to a potential role in cancer chemotherapy resistance, ABCG2 is expressed in the placenta, liver, small intestine, colon, blood-brain barrier, and in stem cells, suggesting a physiologic role in protection against xenobiotics. (11) The canonical structure of a functional ABC transporter, exemplified by P-gp and CFTR, consists of two transmembrane domains (TMDs), typically with twelve transmembrane α-helices, and two nucleotide-binding domains (NBDs) (12).…”

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Mutational Studies of G553 in TM5 of ABCG2: A Residue Potentially Involved in Dimerization

et al. 2006

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ABCG2 is an ATP-binding cassette half-transporter conferring resistance to chemotherapeutic agents such as mitoxantrone, irinotecan, and flavopiridol. With its one transmembrane and one ATP-binding domain, ABCG2 is thought to homodimerize for function. One conserved region potentially involved in dimerization is a 3-amino acid sequence in transmembrane segment 5 (residues 552-554). Mutations in the corresponding residues in the Drosophila white protein (an orthologue of ABCG2) are thought to disrupt heterodimerization. We substituted glycine 553 with leucine (G553L) followed by stable transfection in HEK 293 cells. The mutant was not detectable on the cell surface and markedly reduced protein expression levels were observed by immunoblot. A deficiency in N-linked glycosylation was suggested by reduction in molecular weight compared to the 72-kDa wild type ABCG2. Similar results were observed with the G553E mutant. Confocal microscopy demonstrated mostly ER localization of the G553L mutant in HEK 293 cells, even when coexpressed with the wild type protein. Despite its altered localization, the G553L and G553E mutants were cross-linked using amine-reactive cross-linkers with multiple arm lengths, suggesting that the monomers are in close proximity but unable to complete normal trafficking. Interestingly, when expressed in Sf9 insect cells, G553L traffics to the cell membrane but is unable to hydrolyze ATP or transport the Hoechst dye. Still, when coexpressed, the mutant interferes with the Hoechst transport activity of the wild type protein. These data show that glycine 553 is important for protein trafficking and are consistent with, but do not yet prove, its involvement in ABCG2 homodimerization.The ATP-binding cassette 1 (ABC) transporter family, with 48 known human members classified in seven subgroups, constitutes one of the largest families of membrane transporters present in all species (1). These proteins are involved in the energy-dependent transport of a † This research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.*To whom correspondence should be addressed. Tel: (301) 402-1357, Fax: (301) wide variety of substrates and play an important role in numerous genetic disorders (2), a wellcharacterized example of which is cystic fibrosis, caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR/ABCC7) protein (3). ABC transporters are also thought be responsible for the so called multidrug resistance phenomenon in antimicrobial (4) and anticancer (5) therapy; the most extensively studied example of the latter is resistance attributed to P-glycoprotein (P-gp/ABCB1)(6). ABCG2, also called BCRP/MXR/ABCP, is a member of the G subfamily of human ABC transporters, and has been demonstrated to confer resistance to multiple cancer chemotherapeutic agents, such as mitoxantrone, flavopiridol, methotrexate, and the camptothecin derivatives SN-38 and topotecan.(7-10) In addition to a potential role in c...

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Gefitinib Inhibition of Drug Resistance to Doxorubicin by Inactivating ABCG2 in Thyroid Cancer Cell Lines

López¹,

Wang‐Rodriguez²,

Chang³

et al. 2007

Arch Otolaryngol Head Neck Surg

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To investigate the regulation of the breast cancer resistance protein ABCG2/BRCP1 drug transporter by epidermal growth factor receptor (EGFR) kinase activity, and to determine whether gefitinib, an EGFR small molecule inhibitor, will modulate the effects of doxorubicin hydrochloride by inhibiting its extrusion from thyroid cancer cells.Design: Extrusion assays using flow cytometry analysis were used to determine the ability of thyroid cancer cells to extrude the chemotherapy drug, doxorubicin, via the ABCG2 drug transporter in the presence or absence of gefitinib. Immunofluorescence was employed to determine the cellular expression of ABCG2. The ABCG2 expression in ARO and WRO cell lines was analyzed by Western blot analysis. Inactivation of EGFR kinase by gefitinib was analyzed by Western blot analysis and immunofluorescence. A terminal deoxynucleotidyl transferasemediated deoxyuridine triphosphate nick-end labeling assay was performed to demonstrate ABCG2-mediated apoptosis in the presence of doxorubicin. Colony formation assays were performed to determine the effect of gefitinib on thyroid cancer cell survival in response to gefitinib, doxorubicin, or the combination of both drugs.Results: Inhibition of EGFR kinase activity by gefitinib causes the translocation of the ABCG2 drug transporter away from the plasma membrane, resulting in a concomitant decrease in doxorubicin extrusion in thyroid cancer cell lines. Both ARO and WRO demonstrated differential ABCG2 expression, whereas both were sensitized to doxorubicin-induced apoptosis on ABCG2 knockdown with short interfering RNA. The addition of gefitinib increases doxorubicin-induced cell death in thyroid cancer cells as measured by colony formation assay.Conclusions: Epidermal growth factor receptor regulates the function of the drug transporter ABCG2/ BCRP1 and correlates with ABCG2 protein expression levels. Inactivation of the EGFR kinase by gefitinib potentiates the cytotoxic effect of doxorubicin in thyroid cancer, most likely by decreasing the ability of the cell to extrude doxorubicin. The expression of ABCG2 may explain in part the ineffectiveness of doxorubicin as a single modality treatment for anaplastic thyroid cancer or for treatment of metastatic follicular thyroid cancer. Use of this combination treatment of gefitinib and doxorubicin may be a promising therapy for anaplastic thyroid and metastatic follicular thyroid cancer and needs to be investigated further.

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Breast Cancer Resistance Protein Directly Confers SN-38 Resistance of Lung Cancer Cells

Cited by 221 publications

References 19 publications

Methylation status of breast cancer resistance protein detected by methylation‐specific polymerase chain reaction analysis is correlated inversely with its expression in drug‐resistant lung cancer cells

Methylation status of breast cancer resistance protein detected by methylation‐specific polymerase chain reaction analysis is correlated inversely with its expression in drug‐resistant lung cancer cells

Mutational Studies of G553 in TM5 of ABCG2: A Residue Potentially Involved in Dimerization

Gefitinib Inhibition of Drug Resistance to Doxorubicin by Inactivating ABCG2 in Thyroid Cancer Cell Lines

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