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  Nuclear trapping through inhibition of exosomal export by indomethacin increases cytostatic efficacy of doxorubicin and pixantrone.

Koch, R., Aung, T., Vogel, D., Chapuy, B., Wenzel, D., Becker, S., et al. (2016). Nuclear trapping through inhibition of exosomal export by indomethacin increases cytostatic efficacy of doxorubicin and pixantrone. Clinical Cancer Research, 22(2), 395-404. doi:10.1158/1078-0432.CCR-15-0577.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0029-B00B-F Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-D02A-2
Genre: Journal Article

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2248954.pdf (Publisher version), 2MB
 
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 Creators:
Koch, R., Author
Aung, T., Author
Vogel, D., Author
Chapuy, B., Author
Wenzel, D.1, Author              
Becker, S., Author
Sinzig, U., Author
Venkataramani, V., Author
von Mach, T., Author
Jacob, R., Author
Truemper, L., Author
Wulf, G. G., Author
Affiliations:
1Facility for Electron Microscopy, MPI for biophysical chemistry, Max Planck Society, ou_578615              

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 Abstract: 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. ©2015 AACR.

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Language(s): eng - English
 Dates: 2015-09-142016-01-15
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1158/1078-0432.CCR-15-0577
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Title: Clinical Cancer Research
Source Genre: Journal
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Pages: - Volume / Issue: 22 (2) Sequence Number: - Start / End Page: 395 - 404 Identifier: -