Breast Cancer Resistance Protein and P-Glycoprotein in 149 Adult Acute Myeloid Leukemias

Benderra, Zineb; Faussat, Anne-Marie; Sayada, Lydia; Perrot, Jean‐Yves; Chaoui, Driss; Marie, Jean‐Pierre; Legrand, Ollivier

doi:10.1158/1078-0432.ccr-04-0795

Cited by 163 publications

(102 citation statements)

References 38 publications

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“…The negligible effect of ABCG2 overexpression on CR, different from what has been reported by other groups, 5,7,14 can be explained by the inclusion of fludarabine in the induction we used. In 3 different ABCB1-overexpressing cell-line systems, we previously demonstrated that the use of fludarabine decreases the resistance index more in the resistant sublines than in their parental ones.…”

Section: Discussioncontrasting

confidence: 79%

“…Benderra et al have compared the relation between MDR phenotype and idarubicin sensitivity, concluding that ABCG2 is not a prognostic factor for patients treated with idarubicin, but the relatively low number of patients (N ¼ 30) included in their analysis could have masked the correlation. 5 Considering the biological characteristics of patients with ABCG2 overexpression, it is noteworthy that higher protein level was associated only with high WBC count (>30 Â10 9 /L), favorable/intermediate cytogenetics, and with the presence of FLT3-ITD mutation. In fact, ABCG2 overexpression was detected in 70% of FLT3-mutated patients compared with 41% of ABCG2 positivity in FLT3-unmutated patients.…”

Section: Discussionmentioning

confidence: 98%

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Concomitant ABCG2 overexpression and FLT3‐ITD mutation identify a subset of acute myeloid leukemia patients at high risk of relapse

Tiribelli¹,

Geromin²,

Michelutti³

et al. 2010

Cancer

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BACKGROUND: ABCG2 protein overexpression and FLT3 internal tandem duplication (ITD) correlate with higher relapse rate and shorter disease-free survival (DFS) in acute myeloid leukemia (AML), but no data are available on the possible effect of concomitant presence of these 2 factors. METHODS: The authors analyzed the outcome of 166 cases of adult AML patients who were homogeneously treated with a fludarabine-based induction therapy. RESULTS: ABCG2 overexpression and FLT3-ITD were detected in 83 (50%) and 47 (28%) patients, respectively. A significant correlation was found between ABCG2 positivity and FLT3 mutation, with 33 (40%) ITD in 83 ABCG2-positive patients compared with 14 (17%) ITD in 83 ABCG2-negative patients (P ¼ .002). Complete remission (CR) after induction therapy was achieved in 95 (57%) patients. Neither ABCG2 overexpression nor FLT3-ITD had any impact on achievement of CR. Relapse occurred in 42 of 95 (44%) patients at a median time of 28 months. Time to relapse was shortened in patients overexpressing ABCG2 (P ¼ .0004). DFS was not affected by FLT3-ITD alone, but FLT3 mutation significantly worsened long-term outcome of ABCG2-positive patients. DFS at 1 and 3 years in patients with overexpression of both ABCG2 and FLT3-ITD was only 36% and 28%, respectively; in ABCG2-positive/FLT3-negative patients, DFS at 1 and 3 years was 65% and 48%, respectively; and in ABCG2-negative cases (regardless of FLT3 status), DFS at 1 and 3 years was greater than 85% and 75%. CONCLUSIONS: Concomitant overexpression of ABCG2 and FLT3-ITD is relatively frequent and identifies a subgroup of AML patients with a significantly worse prognosis. The possible interactions between these 2 prognostic factors need to be defined. Cancer 2011;117:2156-62.

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Section: Discussioncontrasting

confidence: 79%

Section: Discussionmentioning

confidence: 98%

Concomitant ABCG2 overexpression and FLT3‐ITD mutation identify a subset of acute myeloid leukemia patients at high risk of relapse

Tiribelli¹,

Geromin²,

Michelutti³

et al. 2010

Cancer

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“…In addition, it has also been reported that BCRP expression may be a prognostic indicator in certain cancers and is associated with poor response to chemotherapy. 34,35 Overexpression of BCRP has been reported in a number of tumor types including: adenocarcinomas (arising from the digestive tract, the endometrium, and the lung), melanoma, soft tissue sarcomas, 36 hematological malignancies such as acute myeloid leukemia (AML), 37 and acute lymphoblastic leukemia (ALL). 38 Elevated expression of BCRP results in resistance of various cancer cell lines to antitumor drugs including: topotecan, mitoxantrone, daunorubicin, doxorubicin, and bisantrene.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and structure–activity relationship studies on tryprostatin A, an inhibitor of breast cancer resistance protein

Jain

Zhang

Zhou

et al. 2008

Bioorganic & Medicinal Chemistry

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Tryprostatin A is a potent inhibitor of breast cancer resistance protein, consequently a series of structure-activity studies on the cell cycle inhibitory effects of tryprostatin A analogues as potential antitumor antimitotic agents have been carried out. These analogues were assayed for their growth inhibition properties and their ability to perturb the cell cycle in tsFT210 cells. SAR studies resulted in the identification of the essential structural features required for cytotoxic activity. The absolute configuration L-Tyr-L-pro in the diketopiperazine ring along with the presence of the 6-methoxy substituent on the indole moiety of 1 was shown to be essential for dual inhibition of topoisomerase II and tubulin polymerization. Biological evaluation also indicated the presence of the 2-isoprenyl moiety on the indole scaffold of 1 was essential for potent inhibition of cell proliferation. Substitution of the indole N a -H in 1 with various alkyl or aryl groups, incorporation of various L-amino acids into the diketopiperazine ring in place of L-proline, and substitution of the 6-methoxy group in 1 with other functionality provided active analogues. The nature of the substituents present on the indole N a -H or the indole C-2 position influenced the mechanism of action of these analogues. nalogues 68 (IC 50 = 10 μM) and 67 (IC 50 = 19 μM) were 7-fold and 3.5-fold more potent, respectively than 1 (IC 50 = 68 μM) in the inhibition of the growth of tsFT210 cells. Diastereomer-2 of tryprostatin B 8 was a potent inhibitor of the growth of three human carcinoma cell lines: H520 (IC 50 = 11.9 μM), MCF7 (IC 50 = 17.0 μM) and PC3 (IC 50 = 11.1 μM) and was equipotent with etoposide, a clinically used anticancer agent. Isothiocyanate analogue 71 and 6-azido analogue 72 were as potent as 1 in the tsFT210 cell proliferation and may be useful tools in labeling BCRP.

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“…Synergistic effects have been reported when PKC412 was coadministered with mitoxantrone in cell lines harboring FLT3 mutations (43). Although the contribution of ABCG2 to clinical drug resistance is currently under investigation, several studies have reported that ABCG2 expression may play a role in drug resistance in leukemia (25,44). Additionally, Willman et al (45) recently published results from a microarray analysis suggesting that transporter expression is a marker of poor clinical outcome in acute myeloid leukemia.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of ABCG2-mediated transport by protein kinase inhibitors with a bisindolylmaleimide or indolocarbazole structure

Robey

Shukla

Steadman³

et al. 2007

Molecular Cancer Therapeutics

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ABCG2 is a transporter with potential importance in cancer drug resistance, drug oral absorption, and stem cell biology. In an effort to identify novel inhibitors of ABCG2, we examined the ability of commercially available bisindolylmaleimides (BIM) and indolocarbazole protein kinase inhibitors (PKI) to inhibit ABCG2, given the previous demonstration that the indolocarbazole PKI UCN-01 interacted with the transporter. At a concentration of 10 Mmol/L, all of the compounds tested increased intracellular fluorescence of the ABCG2-specific substrate pheophorbide a in ABCG2-transfected HEK-293 cells by 1.3-to 6-fold as measured by flow cytometry; the ABCG2-specific inhibitor fumitremorgin C increased intracellular fluorescence by 6.6-fold. In 4-day cytotoxicity assays, wild-type ABCG2-transfected cells were not more than 2-fold resistant to any of the compounds, suggesting that the PKIs are not significantly transported by ABCG2. BIMs I, II, III, IV, and V, K252c, and arcyriaflavin A were also able to inhibit [ 125 I]iodoarylazidoprazosin labeling of ABCG2 by 65% to 80% at 20 Mmol/L, compared with a 50% to 70% reduction by 20 Mmol/L fumitremorgin C. K252c and arcyriaflavin A were the most potent compounds, with IC 50 values for inhibition of [ 125 I]iodoarylazidoprazosin labeling of 0.37 and 0.23 Mmol/L, respectively. K252c and arcyriaflavin A did not have any effect on the ATPase activity of ABCG2. Four minimally toxic compounds-BIM IV, BIM V, arcyriaflavin A, and K252c-reduced the relative resistance of ABCG2-transfected cells to SN-38 in cytotoxicity assays. We find that indolocarbazole and BIM PKIs directly interact with the ABCG2 protein and may thus increase oral bioavailability of ABCG2 substrates.

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Breast Cancer Resistance Protein and P-Glycoprotein in 149 Adult Acute Myeloid Leukemias

Cited by 163 publications

References 38 publications

Concomitant ABCG2 overexpression and FLT3‐ITD mutation identify a subset of acute myeloid leukemia patients at high risk of relapse

Concomitant ABCG2 overexpression and FLT3‐ITD mutation identify a subset of acute myeloid leukemia patients at high risk of relapse

Synthesis and structure–activity relationship studies on tryprostatin A, an inhibitor of breast cancer resistance protein

Inhibition of ABCG2-mediated transport by protein kinase inhibitors with a bisindolylmaleimide or indolocarbazole structure

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