Breast cancer resistance protein (BCRP/MXR/ABCG2) in acute myeloid leukemia: discordance between expression and function

Suvannasankha, Attaya; Minderman, Hans; O’Loughlin, Kieran L.; Nakanishi, Takeo; Greco, William R.; Ross, Douglas D.; Baer, Maria R.

doi:10.1038/sj.leu.2403395

Cited by 56 publications

(64 citation statements)

References 18 publications

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“…A significant correlation was found between ABCG2 expression and clinical stage and lymph node metastasis. In accordance with research in acute myeloid leukemia (11,27,28), adult acute lymphoblastic leukemia (29), non-small cell lung cancer (15) and esophageal squamous cell carcinoma (14), positive expression of ABCG2 may accelerate progression and metastasis in HNSCC. However, no significant correlation, only an increasing trend between ABCG2 expression and histological grade, was observed in the tumor tissues of the laryngeal and nasopharyngeal cancers.…”

Section: Discussionmentioning

confidence: 99%

Expression and function of ABCG2 in head and neck squamous cell carcinoma and cell lines

Shen

Dong

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. Overexpression of breast cancer resistance protein, the ATP-binding cassette, subfamily G, member2 (BCRP/ABCG2), confers multidrug resistance to tumor cells and often limits the efficacy of chemotherapy. The aim of this study was to investigate the expression and functional activity of ABCG2 in head and neck squamous cell carcinoma (HNSCC) and corresponding cell lines. Immunohistochemistry was performed to investigate the presence of the ABCG2 transporter in HNSCC tissues. Expression of ABCG2 in the Hep-2, Hep-2T, CNE and FaDu cell lines was analyzed by real-time quantitative reverse transcription-polymerase chain reaction and Western blotting at the levels of messenger RNA (mRNA) and protein, respectively. The drug sensitivity of the above four cell lines to mitoxantrone was detected using MTT, and the drug accumulation of mitoxantrone was analyzed by flow cytometry. Positive expression of ABCG2 was detected in 52.04% of the laryngeal cancer samples from 98 patients, in 65% of the 40 hypopharyngeal cancer samples and in 58.82% of the 34 nasopharyngeal cancer samples. The level of expression was found to be correlated with tumor TNM stage (P<0.05) and lymph node metastasis (P<0.01). All four HNSCC cell lines expressed ABCG2 at the mRNA and protein levels. The levels of ABCG2 expression in the four cell lines were significantly correlated with the function and sensitivity to mitoxantrone. The addition of fumitremorgin C at a concentration of 5 µM to mitoxantrone treatment caused a varied increase in mitoxantrone accumulation of 1.09-fold, 1.33-fold (P<0.01), 1.4-fold (P<0.01) and 1-fold in the Hep-2, Hep-2T, CNE and FaDu cells, respectively. Expression of ABCG2 varied among the different types of carcinoma tissues and each HNSCC cell line, and it induced multidrug resistance and separation of cancer stem cells attributing to its efflux pump function. Thus, ABCG2 expression may be an unfavorable prognostic factor for HNSCC. Due to the negligible expression and function of ABCG2, we suggest that the FaDu cell line is suitable to be a negative control in studies involving HNSCC. Taken together, ABCG2 is a promising universal biomarker of cancer stem cells and a target gene for HNSCC chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Expression and function of ABCG2 in head and neck squamous cell carcinoma and cell lines

Shen

Dong

et al. 2011

Experimental and Therapeutic Medicine

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“…However, in AML samples, only the mitoxantrone F fumitremorgin C assay could be correlated with BCRP expression as in some other studies (22,39,40), except for one study (41), because GG918 is also a good modulator of Pgp (39,42). Therefore, we have selected the mitoxantrone F fumitremorgin C assay rather than the mitoxantrone F GG918 assay to assess BCRP function.…”

Section: Discussionmentioning

confidence: 99%

“…Some modulators could inhibit two ABC proteins. For example, GG918 could inhibit Pgp and BCRP activity in patients who coexpressed these two proteins (41,42). Apart from anthracycline, Ara-C is a drug administered in the treatment of AML.…”

Section: Discussionmentioning

confidence: 99%

MRP3, BCRP, and P-Glycoprotein Activities are Prognostic Factors in Adult Acute Myeloid Leukemia

Benderra

Faussat

Sayada

et al. 2005

Clinical Cancer Research

136

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Purpose: P-Glycoprotein (Pgp) is associated with poor outcome in acute myeloid leukemia (AML). We have investigated other ATP-binding cassette proteins such as BCRP, MRP1, MRP2, MRP3, and MRP5 for their potential implication in chemoresistance. Experimental Design and Results: Eighty five AML patient samples were analyzed in this study. First, MRP3 function was higher in patients which had a high level of leukocytes (P = 0.01), a M5 FAB subtype (P = 0.04), and an intermediate or poor cytogenesis (P = 0.05). BCRP activity was not correlated with clinical or biological variables, but high Pgp activity was correlated with the following variables: CD34 expression (P = 0.002), FAB subtype (P = 0.002), intermediate or poor cytogenesis (P = 0.02), and elderly patients (P = 0.03). Second, Pgp, MRP3, and BCRP activities were correlated with complete remission (P = 0.02, P = 0.04, and P = 0.04, respectively), disease-free survival (P = 0.02, P = 0.03, and P = 0.25, respectively), and overall survival (P = 0.04, P = 0.04, and P = 0.05, respectively) in multivariate analysis.The patient samples expressing one or none of these Pgp, MRP3, or BCRP functional proteins have a better prognosis than the patients expressing two or three of these functional proteins (complete remission, P = 0.02; disease-free survival, P = 0.01; overall survival, P < 0.001).Conclusions: BCRP and MRP3 may also be involved in chemoresistance in AML, especially MRP3 in patients with M5 FAB. Additional modulation of BCRP or MRP3 to Pgp modulation may be necessary in some patients in order to improve the treatment outcome.

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“…Cell lines expressing Pgp, MRP-1 and BCRP were not resistant to amonafide L-malate, based on resistance ratios (RRs; ratio of In cryopreserved pretreatment marrow blasts from 22 sAML patients characterized for MDR protein expression and function, 6 cyclosporin A, a modulator of Pgp, MRP-1 and BCRP, enhanced the uptake of amonafide significantly less than daunorubicin and idarubicin uptake ( Table 1).…”

Section: Letters To the Editormentioning

confidence: 99%

“…In term fetus, neonate, or normal adult differentiated tissues OFA-iLRP expression was not detected on the cell surface. 6,7 In contrast, OFA/iLR is re-expressed on a broad range of malignancies including some hematological tumor entities. [8][9][10] By utilizing a mouse anti-OFA/iLR monoclonal antibody (Dr J Coggin, Mobile, Al, USA) we show that OFA/iLR is frequently expressed on the surface of malignant plasma cells of patients with MGUS, MM and plasma cell leukemia (Figures 1a and b).…”

Section: Letters To the Editormentioning

confidence: 99%

Amonafide L-malate is not a substrate for multidrug resistance proteins in secondary acute myeloid leukemia

2008

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unresponsiveness could explain the absence of cell death effects after STAT6 siRNA transfection and could be due to the activation of other transcription factors, such as nuclear factorkB, known to control BCL-XL expression.To test whether the phosphorylation status of STAT6 and its nuclear translocation coincides with the expression of BCL-XL protein in vivo, we studied their expression in a series of 28 tumor samples, collected between 1988 and 1998 in the Institute of Pathology of Ulm. Twenty-six out of 28 PMBL cases exhibited nuclear staining for P-STAT6 in more than 40% of the neoplastic cells and 25 out of 28 PMBL cases exhibited cytoplasmic staining for BCL-XL in more than 50% of the neoplastic cells. There was a clear correlation between nuclear P-STAT6 accumulation and BCL-XL expression as 25 out of 28 cases (89%) showed staining for both ( Figure 3e, A and C), whereas 2 out of 28 cases (7%) were negative for both ( Figure 3e, B and D). Actually, there was just one single case with a high percentage of P-STAT6 positive lymphoma nuclei and a very low percentage of BCL-XL-positivity within the lymphoma cell compartment. This might be due to the absence of transcriptional activators required to activate BCL-XL transcription in association with STAT6, such as nuclear factor-kB or Ets transcription factors. According to the linear correlation analysis, we found a Pearson correlation coefficient of r ¼ 0.39 (Po0.05) between the percentage of the cells immunoreactive for BCL-XL and the percentage of the cells immunoreactive for P-STAT6. In summary, these data strongly suggest that STAT6 upregulates BCL-XL expression not only in MedB-1 cells but also in PMBL tumors.Altogether, our results provide evidence that SOCS-1 gene defects strongly contribute to constitutive STAT6 activation and promote cell survival in PMBL cell lines. STAT6 regulates cell proliferation and survival and BCL-XL expression in MedB-1 cells. Its association with BCL-XL expression in primary PMBL cases suggests that the deregulation of the SOCS1/STAT6 pathway plays a critical role in PMBL pathogenesis. AcknowledgementsWe thank Adeline Henry for help in flow cytometry. We are thankful to William Hempel for careful reading and editing the paper.O Ritz 1,7 , C Guiter 2,3,4,7 These authors contributed equally to this study.

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Breast cancer resistance protein (BCRP/MXR/ABCG2) in acute myeloid leukemia: discordance between expression and function

Cited by 56 publications

References 18 publications

Expression and function of ABCG2 in head and neck squamous cell carcinoma and cell lines

Expression and function of ABCG2 in head and neck squamous cell carcinoma and cell lines

MRP3, BCRP, and P-Glycoprotein Activities are Prognostic Factors in Adult Acute Myeloid Leukemia

Amonafide L-malate is not a substrate for multidrug resistance proteins in secondary acute myeloid leukemia

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