Intracellular ABC transporter A3 confers multidrug resistance in leukemia cells by lysosomal drug sequestration

Chapuy, Björn; Koch, Raphael; Radunski, Ulf K; Corsham, Sabrina; Cheong, Naeun; Inagaki, Nobuya; Ban, Nobuhiro; Wenzel, Dirk; Reinhardt, Dirk; Zapf, Antonia; Schweyer, Stefan; Kosari, Farhad; Klapper, Wolfram; Truemper, Lorenz; Wulf, Gerald

doi:10.1038/leu.2008.103

Cited by 128 publications

(120 citation statements)

References 26 publications

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“…Exosome secretion may yet also contribute to drug resistance. Following initial cell and nuclear penetration tumor cells rapidly sequester drugs, in particular anthracyclines, into subcellular compartments, and from there vesicular transport leads to export of cytostatic drugs via exosomes (13)(14)(15). Thus in leukemia and lymphoma, we found that high levels of ATP-binding cassette (ABC) transporter A3 (ABCA3) are crucial for exosome biogenesis and modulate drug resistance (13,14,16,17).…”

Section: Introductionmentioning

confidence: 99%

“…We previously described ABCA3 expression as crucial for MVB-and exosome biogenesis, contributing to a multidrugresistant phenotype in acute myeloid leukemia (13,14,16). Silencing ABCA3 in lymphoma cells strongly impaired exosome biogenesis, associated with increased susceptibility of lymphoma cells to humoral immunotherapy (16).…”

Section: Trapping Of Anthracyclines In Exosomesmentioning

confidence: 99%

“…For quantification of mRNA, qRT-PCR of hABCA3 and b-actin transcripts was performed in triplicates on a TaqMan cycling machine (ABI Prism 7900HT Sequence Detection System, Applied Biosystems) following previously published protocols (13). Briefly, the SYBR green kit (Qiagen) was used according to the manufacturer's protocols.…”

Section: Translational Relevancementioning

confidence: 99%

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Nuclear Trapping through Inhibition of Exosomal Export by Indomethacin Increases Cytostatic Efficacy of Doxorubicin and Pixantrone

Koch

Aung

Vogel

et al. 2016

Clinical Cancer Research

111

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Purpose: Although R-CHOP-based immunochemotherapy cures significant proportions of patients with aggressive B-cell lymphoma, tumor cell susceptibility to chemotherapy varies, with mostly fatal outcome in cases of resistant disease. We and others have shown before that export of cytostatic drugs contributes to drug resistance. Now we provide a novel approach to overcome exosome-mediated drug resistance in aggressive B-cell lymphomas.Experimental Design: We used well-established centrifugation protocols to purify exosomes from DLBCL cell lines and detected anthracyclines using FACS and HPLC. We used shRNA knockdown of ABCA3 to determine ABCA3 dependence of chemotherapy susceptibility and monitored ABCA3 expression after indomethacin treatment using qPCR. Finally, we established an in vivo assay using a chorioallantoic membrane (CAM) assay to determine the synergy of anthracycline and indomethacin treatment. Results:We show increased efficacy of the anthracycline doxorubicin and the anthracenedione pixantrone by suppression of exosomal drug resistance with indomethacin. B-cell lymphoma cells in vitro efficiently extruded doxorubicin and pixantrone, in part compacted in exosomes. Exosomal biogenesis was critically dependent on the expression of the ATP-transporter A3 (ABCA3). Genetic or chemical depletion of ABCA3 augmented intracellular retention of both drugs and shifted the subcellular drug accumulation to prolonged nuclear retention. Indomethacin increased the cytostatic efficacy of both drugs against DLBCL cell lines in vitro and in vivo in a CAM assay.Conclusions: We propose pretreatment with indomethacin toward enhanced antitumor efficacy of anthracyclines and anthracenediones. Clin Cancer Res; 22(2); 395-404. Ó2015 AACR.

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Section: Introductionmentioning

confidence: 99%

Section: Trapping Of Anthracyclines In Exosomesmentioning

confidence: 99%

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Nuclear Trapping through Inhibition of Exosomal Export by Indomethacin Increases Cytostatic Efficacy of Doxorubicin and Pixantrone

Koch

Aung

Vogel

et al. 2016

Clinical Cancer Research

111

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“…Although the roles of 13 ABC transporters in MDR have been fully characterized, recent studies suggest the involvement of up to 30 members of the 48 encoded in the human genome (16,17). Moreover, besides classical drug efflux, it has also been demonstrated that some of these transporters may mediate the intracellular sequestration of chemotherapeutic drugs (18)(19)(20). This intracellular sequestration is the case for ABCA3, which was recently found to be overexpressed in clinical samples of childhood AML and correlated with poor response to treatment (21).…”

mentioning

confidence: 99%

Redefining the relevance of established cancer cell lines to the study of mechanisms of clinical anti-cancer drug resistance

Gillet

Calcagno

Varma

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

405

322

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Although in vitro models have been a cornerstone of anti-cancer drug development, their direct applicability to clinical cancer research has been uncertain. Using a state-of-the-art Taqman-based quantitative RT-PCR assay, we investigated the multidrug resistance (MDR) transcriptome of six cancer types, in established cancer cell lines (grown in monolayer, 3D scaffold, or in xenograft) and clinical samples, either containing >75% tumor cells or microdissected. The MDR transcriptome was determined a priori based on an extensive curation of the literature published during the last three decades, which led to the enumeration of 380 genes. No correlation was found between clinical samples and established cancer cell lines. As expected, we found up-regulation of genes that would facilitate survival across all cultured cancer cell lines evaluated. More troubling, however, were data showing that all of the cell lines, grown either in vitro or in vivo, bear more resemblance to each other, regardless of the tissue of origin, than to the clinical samples they are supposed to model. Although cultured cells can be used to study many aspects of cancer biology and response of cells to drugs, this study emphasizes the necessity for new in vitro cancer models and the use of primary tumor models in which gene expression can be manipulated and small molecules tested in a setting that more closely mimics the in vivo cancer microenvironment so as to avoid radical changes in gene expression profiles brought on by extended periods of cell culture.

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“…110 The results of Luciani et al 111 are in accord with the above conclusion and demonstrated that lymphoma, adenocarcinoma, and melanoma cells confiscated drugs such as vinblastin, 5-flurouracil, and cisplatin in their endosomal compartments. Further studies revealed that high levels of adenosine triphosphate (ATP)-binding cassette (ABC) transporter A3 (ABCA3) were related to drug resistance, 112,113 especially by drug expulsion which might be modulated by microparticles. 114 As for targeting therapy of B-cell lymphoma exosomes, Aung et al 115 supported this mechanism by showing that exosomes, carrying CD20 and lysosome-related organelleassociated ABCA3, released from B-cell lymphoma, bound to therapeutic anti-CD20 antibody and consumed complement, thereby impairing antibody-dependent cellmediated cytotoxicity (ADCC) and protecting cancer cells from antibody attack.…”

Section: Exosomes As Communicators Of Drug Resistance In Lymphomamentioning

confidence: 99%

Intimate cross-talk between cancer cells and the tumor microenvironment of B-cell lymphomas: The key role of exosomes

Wang

2017

Tumour Biol.

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B-cell lymphomas are composed of tumor cells and the tumor microenvironment, which is conventionally thought to be composed of a mixture of stromal cells, blood vessels, immune cells, and non-cell components, such as extracellular matrix, cytokines, and chemokines. Exosomes, small endocytically derived vesicles that have been proved to be present in a variety of tumor niches and involved in mediating cell signaling networks, are increasingly regarded as important components of tumor microenvironment. In this review, we first focus on the biogenesis, biodistribution, transportation, and other general characteristics of exosomes and then highlight the vital roles of exosomes in lymphomagenesis and disease progression, particularly from the perspective of immune dysfunction, virus infection, and therapeutic resistance mechanisms.

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Intracellular ABC transporter A3 confers multidrug resistance in leukemia cells by lysosomal drug sequestration

Cited by 128 publications

References 26 publications

Nuclear Trapping through Inhibition of Exosomal Export by Indomethacin Increases Cytostatic Efficacy of Doxorubicin and Pixantrone

Nuclear Trapping through Inhibition of Exosomal Export by Indomethacin Increases Cytostatic Efficacy of Doxorubicin and Pixantrone

Redefining the relevance of established cancer cell lines to the study of mechanisms of clinical anti-cancer drug resistance

Intimate cross-talk between cancer cells and the tumor microenvironment of B-cell lymphomas: The key role of exosomes

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