Leiden University Scholarly Publications

Gelder, M.A. van; Li, Y.F.; Wander, D.P.A.; Berlin, I.; Overkleeft, H.S.; Zanden, S.Y. van der; Neefjes, J.J.C. (2024)

Novel N,N-dimethyl-idarubicin analogues are effective cytotoxic agents for ABCB1-overexpressing, doxorubicin-resistant cells

Article / Letter to editor

Anthracyclines comprise one of the most effective anticancer drug classes. Doxorubicin, daunorubicin, epirubicin, and idarubicin have been in clinical use for decades, but their application remains complicated by treatment-related toxicities and drug resistance. We previously demonstrated that the combination of DNA damage and histone eviction exerted by doxorubicin drives its associated adverse effects. However, whether the same properties dictate drug resistance is unclear. In the present study, we evaluate a library of 40 anthracyclines on their cytotoxicity, intracellular uptake, and subcellular localization in K562 wildtype versus ABCB1-transporter-overexpressing, doxorubicin-resistant cells. We identify several highly potent cytotoxic anthracyclines. Among these, N,N-dimethyl-idarubicin and anthracycline (composed of the idarubicin aglycon and the aclarubicin trisaccharide) stand out, due to their histone eviction-mediated cytotoxicity toward doxorubicin-resistant...Show more Anthracyclines comprise one of the most effective anticancer drug classes. Doxorubicin, daunorubicin, epirubicin, and idarubicin have been in clinical use for decades, but their application remains complicated by treatment-related toxicities and drug resistance. We previously demonstrated that the combination of DNA damage and histone eviction exerted by doxorubicin drives its associated adverse effects. However, whether the same properties dictate drug resistance is unclear. In the present study, we evaluate a library of 40 anthracyclines on their cytotoxicity, intracellular uptake, and subcellular localization in K562 wildtype versus ABCB1-transporter-overexpressing, doxorubicin-resistant cells. We identify several highly potent cytotoxic anthracyclines. Among these, N,N-dimethyl-idarubicin and anthracycline (composed of the idarubicin aglycon and the aclarubicin trisaccharide) stand out, due to their histone eviction-mediated cytotoxicity toward doxorubicin-resistant cells. Our findings thus uncover understudied anthracycline variants warranting further investigation in the quest for safer and more effective anticancer agents that circumvent cellular export by ABCB1.
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All authors

Gelder, M.A. van; Li, Y.F.; Wander, D.P.A.; Berlin, I.; Overkleeft, H.S.; Zanden, S.Y. van der; Neefjes, J.J.C.

Date

2024-08-01

Journal

Journal of Medicinal Chemistry

Volume

67

Issue

16

Pages

13802 - 13812

DOI

doi:10.1021/acs.jmedchem.4c00614

Link

https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c00614