C8-Substituted Imidazotetrazine Analogs Overcome Temozolomide Resistance by Inducing DNA Adducts and DNA Damage

• Published in: Frontiers in oncology 2019-06, Vol.9, p.485-485
• Main Authors: Yang, Zhikuan, Wei, Danping, Dai, Xiaoli, Stevens, Malcolm F G, Bradshaw, Tracey D, Luo, Ying, Zhang, Jihong
• Format: Article
• Language: English
• Subjects: apoptosis; colorectal carcinoma; DNA adducts; glioblastoma; O6-methylguanine-DNA methyltransferase; Oncology
• ISSN: 2234-943X; 2234-943X
• DOI: 10.3389/fonc.2019.00485

Temozolomide (TMZ) is the standard of care chemotherapeutic agent used in the treatment of glioblastoma multiforme. Cytotoxic -methylguaine lesions formed by TMZ are repaired by -methyl-guanine DNA methyltransferase (MGMT), a DNA repair protein that removes alkyl groups located at the -position of guanine. Response to TMZ requires low MGMT expression and functional mismatch repair. Resistance to TMZ conferred by MGMT, and tolerance to -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 IC 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: -methylguanine, -methylguanine, -methyladenine, -methylthymine, and -methylcytidine deoxynucleotides. We conclude that C8 analogs of TMZ share a mechanism of action similar to TMZ and are able to methylate DNA generating -methylguanine adducts, but unlike TMZ are able at least in part to thwart MGMT- and MMR-mediated resistance.