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. 2017 Jun 30;32(1):111–119. doi: 10.1038/leu.2017.182

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Copyright © 2018 The Author(s)

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/

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NER inhibition with spironolactone increases melphalan sensitivity in MM cell lines. (a and b) Spironolactone (sp.) and triptolide inhibit NER in myeloma cells. RPMI8226 cells were incubated with dimethyl sulfoxide (DMSO), spironolactone (10 μM) or triptolide (1 μM) for 6 h before NER evaluation. The figure represents the persistence of DNA-damage signal 150 min after exposure to UV (AFU: arbitrary fluorescent unit). Figure 4a shows representative merged pictures of DAPI and DDB2 proteo-probe signal (b). (c and d) Spironolactone (sp.) and triptolide increase sensitivity to alkylating agents. (c) The left figure represents the impact of spironolactone (10 μM) or triptolide (10 nm) on melphalan (left graph) and melflufen IC₅₀ (right side graph) in RPMI8226 and LR5 MMCL. (d) Sensitivity to melphalan was evaluated in a panel of 20 MM cell lines in context of DMSO or spironolactone. Each dot represents the corresponding melphalan IC₅₀ for a distinct MMCL, in combination with DMSO or spironolactone. IC₅₀ was evaluated by CellTiter-Glo. (e) Spironolactone (sp.) increases sensitivity to melphalan through NER inhibition and ERCC3 downregulation. The figure represents the impact of spironolactone on melphalan sensitivity in GM21148-XPB cell line (green dots), which harbors two mutations in ERCC3, as compared with 20 myeloma cell lines (gray dots). Cell viability was evaluated with CellTiter-Glo. GM21148-XPB cells are not sensitized to melphalan combined with spironolactone. These results were confirmed in three independent experiments. (f and g) Spironolactone (sp.) exposure enhances time-dependant XPB degradation. This western blot shows the impact of 10 μM spironolactone on XPB expression (f) in three MMCLs (JJN3, LP1, NCIH929) after overnight exposure, and over time in the NCIH929 (g). (h and i) Triptolide inhibits transcription. After exposure to triptolide (1 μM), spironolactone (10 μM), actinomycin D (2 μM, transcription inhibitor used as a positive control) or DMSO for 6 h, the global RNA synthesis was evaluated by the measurement of 5-EU incorporation. The figure shows representative merged pictures of DAPI and 5-EU signal. The intensity of the signal was evaluated through fluorescence microscopy (h) and quantified with the CellProfiler Software. Triptolide but not spironolactone inhibits global transcription.