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C8-substituted imidazotetrazine analogs overcome temozolomide resistance by inducing DNA adducts and DNA damage

Yang, Zhikuan; Wei, Danping; Dai, Xiaoli; Stevens, Malcolm F.G.; Bradshaw, Tracey D.; Luo, Ying; Zhang, Jihong

C8-substituted imidazotetrazine analogs overcome temozolomide resistance by inducing DNA adducts and DNA damage Thumbnail


Authors

Zhikuan Yang

Danping Wei

Xiaoli Dai

Malcolm F.G. Stevens

Ying Luo

Jihong Zhang



Abstract

Copyright © 2019 Yang, Wei, Dai, Stevens, Bradshaw, Luo and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Temozolomide (TMZ) is the standard of care chemotherapeutic agent used in the treatment of glioblastoma multiforme. Cytotoxic O6-methylguaine lesions formed by TMZ are repaired by O6-methyl-guanine DNA methyltransferase (MGMT), a DNA repair protein that removes alkyl groups located at the O6-position of guanine. Response to TMZ requires low MGMT expression and functional mismatch repair. Resistance to TMZ conferred by MGMT, and tolerance to O6-methylguanine lesions conferred by deficient MMR severely limit TMZ clinical applications. Therefore, development of new TMZ derivatives that can overcome TMZ-resistance is urgent. In this study, we investigated the anti-tumor mechanism of action of two novel TMZ analogs: C8-imidazolyl (377) and C8-methylimidazole (465) tetrazines. We found that analogs 377 and 465 display good anticancer activity against MGMT-overexpressing glioma T98G and MMR deficient colorectal carcinoma HCT116 cell lines with IC50 value of 62.50, 44.23, 33.09, and 25.37 μM, respectively. Analogs induce cell cycle arrest at G2/M, DNA double strand break damage and apoptosis irrespective of MGMT and MMR status. It was established that analog 377, similar to TMZ, is able to ring-open and hydrolyze under physiological conditions, and its intermediate product is more stable than MTIC. Moreover, DNA adducts of 377 with calf thymus DNA were identified: N7-methylguanine, O6-methylguanine, N3-methyladenine, N3-methylthymine, and N3-methylcytidine deoxynucleotides. We conclude that C8 analogs of TMZ share a mechanism of action similar to TMZ and are able to methylate DNA generating O6-methylguanine adducts, but unlike TMZ are able at least in part to thwart MGMT- and MMR-mediated resistance.

Citation

Yang, Z., Wei, D., Dai, X., Stevens, M. F., Bradshaw, T. D., Luo, Y., & Zhang, J. (2019). C8-substituted imidazotetrazine analogs overcome temozolomide resistance by inducing DNA adducts and DNA damage. Frontiers in Oncology, 9, https://doi.org/10.3389/fonc.2019.00485

Journal Article Type Article
Acceptance Date May 22, 2019
Online Publication Date Jun 11, 2019
Publication Date 2019-06
Deposit Date Nov 20, 2019
Publicly Available Date Mar 28, 2024
Journal Frontiers in Oncology
Electronic ISSN 2234-943X
Publisher Frontiers Media
Peer Reviewed Peer Reviewed
Volume 9
Article Number 485
DOI https://doi.org/10.3389/fonc.2019.00485
Public URL https://nottingham-repository.worktribe.com/output/3345969
Publisher URL https://www.frontiersin.org/articles/10.3389/fonc.2019.00485/full

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