Decreased Mutation Rate for Cellular Resistance to Doxorubicin and Suppression of mdrl Gene Activation by the Cyclosporin PSC 833

Beketić-Orešković, Lidija; Durán, George E.; Chen, Gang; Dumontet, Charles; Šikić, Branimir I.

doi:10.1093/jnci/87.21.1593

Cited by 75 publications

(47 citation statements)

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“…Doxorubicin and etoposide are structurally different but they are both topoisomerase II inhibitors and this may explain the similarities in the response of cells to selection with these agents; however, further studies will be required to establish this. Others have also investigated the effects of single-step doxorubicin selection on the human sarcoma cell line MES-SA and have reported an increase in ABCB1 expression (Chen et al, 1994;Beketic-Oreskovic et al, 1995); yet previous studies were performed before the identification of ABCG2 as a major ABC transporter in the area of MDR. In addition, the authors used 40 nM doxorubicin for 14 days, nearly two-fold higher than the concentration we employed.…”

Section: Discussionmentioning

confidence: 99%

Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes

Calcagno

Fostel²,

et al. 2008

Br J Cancer

111

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Understanding the mechanisms of multidrug resistance (MDR) could improve clinical drug efficacy. Multidrug resistance is associated with ATP binding cassette (ABC) transporters, but the factors that regulate their expression at clinically relevant drug concentrations are poorly understood. We report that a single-step selection with low doses of anti-cancer agents, similar to concentrations reported in vivo, induces MDR that is mediated exclusively by ABCG2. We selected breast, ovarian and colon cancer cells (MCF-7, IGROV-1 and S-1) after exposure to 14 or 21 nM doxorubicin for only 10 days. We found that these cells overexpress ABCG2 at the mRNA and protein levels. RNA interference analysis confirmed that ABCG2 confers drug resistance. Furthermore, ABCG2 upregulation was facilitated by histone hyperacetylation due to weaker histone deacetylase 1-promoter association, indicating that these epigenetic changes elicit changes in ABCG2 gene expression. These studies indicate that the MDR phenotype arises following low-dose, single-step exposure to doxorubicin, and further suggest that ABCG2 may mediate early stages of MDR development. This is the first report to our knowledge of single-step, low-dose selection leading to overexpression of ABCG2 by epigenetic changes in multiple cancer cell lines.

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Section: Discussionmentioning

confidence: 99%

Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes

Calcagno

Fostel²,

et al. 2008

Br J Cancer

111

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“…Reverse transcription (RT)-PCR analysis of MDR1 and MRP gene expression was performed using two non-overlapping primer pairs, which gave concordant results for each gene in all cell lines (MDR-1: 401-bp product (Futscher et al, 1993); 157-bp product (Bordow et al, 1994); MRP: 565-bp product (Beketic-Oreskovic et al, 1995); 140-bp product (Bordow et al, 1994)). Other primer sets were: topoisomerase II α (topo II α), 322-bp product (Beck et al, 1995), topoisomerase II β (topo II β), 304-bp (Beck et al, 1995), lung-related resistance protein (LRP), 405-bp (Stein et al, 1997), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), 358-bp and β 2 microglobulin (β 2 M), 120-bp (Bordow et al, 1994).…”

Section: Mdr Characterization By Immunocytochemistrymentioning

confidence: 99%

BIRICODAR (VX-710; Incel™): an effective chemosensitizer in neuroblastoma

et al. 1999

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Summary Clinical studies have suggested that both MDR1 and MRP may play a significant role in the chemosensitivity and outcome of neuroblastoma. To clarify the nature of multidrug resistance (MDR) in this tumour a series of six neuroblastoma cell lines have been characterized with regard to P-glycoprotein, MRP and LRP expression using immunocytochemistry and expression of MDR1, MRP, LRP and topoisomerase II genes using reverse transcription polymerase chain reaction (RT-PCR). By RT-PCR, all lines expressed MRP, five expressed LRP and four expressed MDR1, but protein levels of each of these were variable. Chemosensitization to a range of MDR-associated drugs (vincristine, doxorubicin, etoposide, taxotere, topotecan) and non-MDR-associated drugs (cisplatin, melphalan) by three modulating agents, cyclosporin A, PSC 833 and the novel Biricodar (VX-710; Incel™), was evaluated using a colourimetric cytotoxicity assay (MTS). Alteration of daunorubicin efflux by these agents was evaluated using FACS analysis. Clonogenic assay was used to study the influence of these chemosensitizers on vincristine cytotoxicity. Marked sensitization to vincristine was observed in MDR1-positive lines, and a similar but less consistent effect was seen with taxotere, doxorubicin and etoposide. With MRP-positive, MDR-negative lines, only VX-710 caused consistent sensitization. These data confirm MDR1 and MRP expression as contributory factors in chemoresistance in neuroblastoma and indicate that VX-710 may be a useful modulator of both mechanisms and worthy of clinical evaluation in this tumour.

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“…These findings have prompted the interest of many researchers throughout the last two decades to develop P-glycoprotein inhibitors as a way to revert MDR in human cancers (8) or even to prevent the emergence of MDR in cancer patients (9). Many agents that modulate the function of P-glycoprotein are able to restore the cytotoxicity of chemotherapeutic drugs to MDR cells in vitro and in experimental drug-resistant tumors in vivo (10).…”

Section: Introductionmentioning

confidence: 99%

Celastraceae Sesquiterpenes as a New Class of Modulators That Bind Specifically to Human P-Glycoprotein and Reverse Cellular Multidrug Resistance

Muñoz-Martínez

Cortés-Selva

et al. 2004

Cancer Research

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Overexpression of ABCB1 (MDR1) P-glycoprotein, a multidrug efflux pump, is one mechanism by which tumor cells may develop multidrug resistance (MDR), preventing the successful chemotherapeutic treatment of cancer. Sesquiterpenes from Celastraceae family are natural compounds shown previously to reverse MDR in several human cancer cell lines and Leishmania strains. However, their molecular mechanism of reversion has not been characterized. In the present work, we have studied the ability of 28 dihydro-␤-agarofuran sesquiterpenes to reverse the P-glycoprotein-dependent MDR phenotype and elucidated their molecular mechanism of action. Cytotoxicity assays using human MDR1-transfected NIH-3T3 cells allowed us to select the most potent sesquiterpenes reversing the in vitro resistance to daunomycin and vinblastine. Flow cytometry experiments showed that the above active compounds specifically inhibited drug transport activity of P-glycoprotein in a saturable, concentration-dependent manner (K i down to 0.24 ؎ 0.01 mol/L) but not that of ABCC1 (multidrug resistance protein 1; MRP1), ABCC2 (MRP2), and ABCG2 (breast cancer resistance protein; BCRP) transporters. Moreover, sesquiterpenes inhibited at submicromolar concentrations the P-glycoprotein-mediated transport of [ 3 H]colchicine and tetramethylrosamine in plasma membrane from CH R B30 cells and P-glycoproteinenriched proteoliposomes, supporting that P-glycoprotein is their molecular target. Photoaffinity labeling in plasma membrane and fluorescence spectroscopy experiments with purified protein suggested that sesquiterpenes interact with transmembrane domains of P-glycoprotein. Finally, sesquiterpenes modulated P-glycoprotein ATPase-activity in a biphasic, concentration-dependent manner: they stimulated at very low concentrations but inhibited ATPase activity as noncompetitive inhibitors at higher concentrations. Sesquiterpenes from Celastraceae are promising P-glycoprotein modulators with potential applications in cancer chemotherapy because of their MDR reversal potency and specificity for P-glycoprotein.

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Decreased Mutation Rate for Cellular Resistance to Doxorubicin and Suppression of mdrl Gene Activation by the Cyclosporin PSC 833

Abstract: Our results suggest that treatment with multidrug resistance modulators such as PSC 833 together with multidrug resistance-related cytotoxins may suppress the activation of mdr1 and prevent the emergence of resistant cancer cell clones with the multidrug-resistant phenotype.

Cited by 75 publications

References 0 publications

Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes

Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes

BIRICODAR (VX-710; Incel™): an effective chemosensitizer in neuroblastoma

Celastraceae Sesquiterpenes as a New Class of Modulators That Bind Specifically to Human P-Glycoprotein and Reverse Cellular Multidrug Resistance

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