Casagrande, N.; Borghese, C.; Avanzo, M.; Aldinucci, D. In Doxorubicin-Adapted Hodgkin Lymphoma Cells, Acquiring Multidrug Resistance and Improved Immunosuppressive Abilities, Doxorubicin Activity Was Enhanced by Chloroquine and GW4869. Cells2023, 12, 2732.
Casagrande, N.; Borghese, C.; Avanzo, M.; Aldinucci, D. In Doxorubicin-Adapted Hodgkin Lymphoma Cells, Acquiring Multidrug Resistance and Improved Immunosuppressive Abilities, Doxorubicin Activity Was Enhanced by Chloroquine and GW4869. Cells 2023, 12, 2732.
Casagrande, N.; Borghese, C.; Avanzo, M.; Aldinucci, D. In Doxorubicin-Adapted Hodgkin Lymphoma Cells, Acquiring Multidrug Resistance and Improved Immunosuppressive Abilities, Doxorubicin Activity Was Enhanced by Chloroquine and GW4869. Cells2023, 12, 2732.
Casagrande, N.; Borghese, C.; Avanzo, M.; Aldinucci, D. In Doxorubicin-Adapted Hodgkin Lymphoma Cells, Acquiring Multidrug Resistance and Improved Immunosuppressive Abilities, Doxorubicin Activity Was Enhanced by Chloroquine and GW4869. Cells 2023, 12, 2732.
Abstract
Classical Hodgkin lymphoma (cHL) is a highly curable disease (70-80%), even though long-term toxicities, drug resistance, and predicting clinical responses to therapy are major challenges in cHL treatment. To solve these problems, we characterized two cHL cell lines with acquired resistance to doxorubicin, KM-H2dx and HDLM-2dx (HRSdx), generated from KM-H2 and HDLM-2 cells, respectively. HRSdx cells developed cross-resistance to vinblastine, bendamustin, cisplatin, dacarbazine, gem-citabine, brentuximab vedotin (BV), and γ-radiation. Both HDLM-2 and HDLM-2dx cells had an intrinsic resistance to BV but not to the drug MMAE. HDLM-2dx acquired cross-resistance to caelyx. HRSdx cells had in common: decreased CD71, CD80, CD54, cyt-ROS, HLA-DR, DDR1, CD44; increased Bcl-2, CD58, COX2, CD26, CCR5, invasive capability; increased CCL5, TARC, PGE2, TGF-β, and capability to hijack monocytes. In HRSdx cells, less sensitive to DNA damage and oxidative stress, the efflux drug transporters MDR1 and MRP1 were not up-regulated, and doxorubicin accumulated in cytoplasm rather than in nucleus. Both autophagy inhibitor chloroquine and extracellular vesicles (EVs) release inhibitor GW4869 enhanced doxorubicin activity and counteracted doxorubicin resistance. In conclusion, this study identifies common modulated antigens in HRSdx cells, the associated cross-resistance patterns, and new potential therapeutic options to enhance doxorubicin activity and overcome resistance.
Keywords
Hodgkin lymphoma; doxorubicin; drug resistance; cross-resistance; immunosuppression
Subject
Biology and Life Sciences, Cell and Developmental Biology
Copyright:
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