Novel -Dimethyl-idarubicin Analogues Are Effective Cytotoxic Agents for ABCB1-Overexpressing, Doxorubicin-Resistant Cells

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2024 Aug 1

PMID 39088428

Authors

Merle A van Gelder

Yufeng Li

Dennis P A Wander

Ilana Berlin

Hermen S Overkleeft

Sabina Y van der Zanden

Jacques J C Neefjes

Affiliations

Soon will be listed here.

Abstract

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, -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.

References

Hanusova V, Bousova I, Skalova L . Possibilities to increase the effectiveness of doxorubicin in cancer cells killing. Drug Metab Rev. 2011; 43(4):540-57. DOI: 10.3109/03602532.2011.609174. View

Daina A, Michielin O, Zoete V . SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017; 7:42717. PMC: 5335600. DOI: 10.1038/srep42717. View

Peter S, Alven S, Maseko R, Aderibigbe B . Doxorubicin-Based Hybrid Compounds as Potential Anticancer Agents: A Review. Molecules. 2022; 27(14). PMC: 9318127. DOI: 10.3390/molecules27144478. View

van Gelder M, van der Zanden S, Vriends M, Wagensveld R, van der Marel G, Codee J . Re-Exploring the Anthracycline Chemical Space for Better Anti-Cancer Compounds. J Med Chem. 2023; 66(16):11390-11398. PMC: 10461226. DOI: 10.1021/acs.jmedchem.3c00853. View

Mattioli R, Ilari A, Colotti B, Mosca L, Fazi F, Colotti G . Doxorubicin and other anthracyclines in cancers: Activity, chemoresistance and its overcoming. Mol Aspects Med. 2023; 93:101205. DOI: 10.1016/j.mam.2023.101205. View

Mortensen S . Aclarubicin: preclinical and clinical data suggesting less chronic cardiotoxicity compared with conventional anthracyclines. Eur J Haematol Suppl. 1987; 47:21-31. DOI: 10.1111/j.1600-0609.1987.tb00019.x. View

van der Zanden S, Qiao X, Neefjes J . New insights into the activities and toxicities of the old anticancer drug doxorubicin. FEBS J. 2020; 288(21):6095-6111. PMC: 8597086. DOI: 10.1111/febs.15583. View

Rothig H, Kraemer H, Sedlacek H . Aclarubicin: experimental and clinical experience. Drugs Exp Clin Res. 1985; 11(2):123-5. View

Wander D, van der Zanden S, van der Marel G, Overkleeft H, Neefjes J, Codee J . Doxorubicin and Aclarubicin: Shuffling Anthracycline Glycans for Improved Anticancer Agents. J Med Chem. 2020; 63(21):12814-12829. PMC: 7667640. DOI: 10.1021/acs.jmedchem.0c01191. View

10.

Huseman E, Byl J, Chapp S, Schley N, Osheroff N, Townsend S . Synthesis and Cytotoxic Evaluation of Arimetamycin A and Its Daunorubicin and Doxorubicin Hybrids. ACS Cent Sci. 2021; 7(8):1327-1337. PMC: 8393218. DOI: 10.1021/acscentsci.1c00040. View

11.

Hodges L, Markova S, Chinn L, Gow J, Kroetz D, Klein T . Very important pharmacogene summary: ABCB1 (MDR1, P-glycoprotein). Pharmacogenet Genomics. 2010; 21(3):152-61. PMC: 3098758. DOI: 10.1097/FPC.0b013e3283385a1c. View

12.

Li Y, Tan M, Sun S, Stea E, Pang B . Targeted CRISPR activation and knockout screenings identify novel doxorubicin transporters. Cell Oncol (Dordr). 2023; 46(6):1807-1820. PMC: 10698112. DOI: 10.1007/s13402-023-00847-0. View

13.

Mirzaei S, Gholami M, Hashemi F, Zabolian A, Farahani M, Hushmandi K . Advances in understanding the role of P-gp in doxorubicin resistance: Molecular pathways, therapeutic strategies, and prospects. Drug Discov Today. 2021; 27(2):436-455. DOI: 10.1016/j.drudis.2021.09.020. View

14.

Battisti R, Zhong Y, Fang L, Gibbs S, Shen J, Nadas J . Modifying the sugar moieties of daunorubicin overcomes P-gp-mediated multidrug resistance. Mol Pharm. 2007; 4(1):140-53. DOI: 10.1021/mp060075v. View

15.

Wander D, van der Zanden S, Vriends M, van Veen B, Vlaming J, Bruyning T . Synthetic (,-Dimethyl)doxorubicin Glycosyl Diastereomers to Dissect Modes of Action of Anthracycline Anticancer Drugs. J Org Chem. 2021; 86(8):5757-5770. PMC: 8056385. DOI: 10.1021/acs.joc.1c00220. View

16.

Kukal S, Guin D, Rawat C, Bora S, Kumar Mishra M, Sharma P . Multidrug efflux transporter ABCG2: expression and regulation. Cell Mol Life Sci. 2021; 78(21-22):6887-6939. PMC: 11072723. DOI: 10.1007/s00018-021-03901-y. View

17.

Qiu Y, Jiang P, Huang Y . Anthracycline-induced cardiotoxicity: mechanisms, monitoring, and prevention. Front Cardiovasc Med. 2024; 10:1242596. PMC: 10762801. DOI: 10.3389/fcvm.2023.1242596. View

18.

Burgess D, Doles J, Zender L, Xue W, Ma B, McCombie W . Topoisomerase levels determine chemotherapy response in vitro and in vivo. Proc Natl Acad Sci U S A. 2008; 105(26):9053-8. PMC: 2435590. DOI: 10.1073/pnas.0803513105. View

19.

Kodan A, Futamata R, Kimura Y, Kioka N, Nakatsu T, Kato H . ABCB1/MDR1/P-gp employs an ATP-dependent twist-and-squeeze mechanism to export hydrophobic drugs. FEBS Lett. 2020; 595(6):707-716. DOI: 10.1002/1873-3468.14018. View

20.

Pang B, Qiao X, Janssen L, Velds A, Groothuis T, Kerkhoven R . Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin. Nat Commun. 2013; 4:1908. PMC: 3674280. DOI: 10.1038/ncomms2921. View