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Novel insights into the molecular regulation of ribonucleotide reductase in adrenocortical carcinoma treatment
Please always quote using this URN: urn:nbn:de:bvb:20-opus-245132
- Current systemic treatment options for patients with adrenocortical carcinomas (ACCs) are far from being satisfactory. DNA damage/repair mechanisms, which involve, e.g., ataxia-telangiectasia-mutated (ATM) and ataxia-telangiectasia/Rad3-related (ATR) protein signaling or ribonucleotide reductase subunits M1/M2 (RRM1/RRM2)-encoded ribonucleotide reductase (RNR) activation, commonly contribute to drug resistance. Moreover, the regulation of RRM2b, the p53-induced alternative to RRM2, is of unclear importance for ACC. Upon extensive drugCurrent systemic treatment options for patients with adrenocortical carcinomas (ACCs) are far from being satisfactory. DNA damage/repair mechanisms, which involve, e.g., ataxia-telangiectasia-mutated (ATM) and ataxia-telangiectasia/Rad3-related (ATR) protein signaling or ribonucleotide reductase subunits M1/M2 (RRM1/RRM2)-encoded ribonucleotide reductase (RNR) activation, commonly contribute to drug resistance. Moreover, the regulation of RRM2b, the p53-induced alternative to RRM2, is of unclear importance for ACC. Upon extensive drug screening, including a large panel of chemotherapies and molecular targeted inhibitors, we provide strong evidence for the anti-tumoral efficacy of combined gemcitabine (G) and cisplatin (C) treatment against the adrenocortical cell lines NCI-H295R and MUC-1. However, accompanying induction of RRM1, RRM2, and RRM2b expression also indicated developing G resistance, a frequent side effect in clinical patient care. Interestingly, this effect was partially reversed upon addition of C. We confirmed our findings for RRM2 protein, RNR-dependent dATP levels, and modulations of related ATM/ATR signaling. Finally, we screened for complementing inhibitors of the DNA damage/repair system targeting RNR, Wee1, CHK1/2, ATR, and ATM. Notably, the combination of G, C, and the dual RRM1/RRM2 inhibitor COH29 resulted in previously unreached total cell killing. In summary, we provide evidence that RNR-modulating therapies might represent a new therapeutic option for ACC.…
Author: | Christina Bothou, Ashish Sharma, Adrian Oo, Baek Kim, Pal Perge, Peter Igaz, Cristina L. Ronchi, Igor Shapiro, Constanze Hantel |
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URN: | urn:nbn:de:bvb:20-opus-245132 |
Document Type: | Journal article |
Faculties: | Medizinische Fakultät / Medizinische Klinik und Poliklinik I |
Language: | English |
Parent Title (English): | Cancers |
ISSN: | 2072-6694 |
Year of Completion: | 2021 |
Volume: | 13 |
Issue: | 16 |
Article Number: | 4200 |
Source: | Cancers (2021) 13:16, 4200. https://doi.org/10.3390/cancers13164200 |
DOI: | https://doi.org/10.3390/cancers13164200 |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Tag: | COH29; RNR; RRM2; adrenocortical carcinoma; adrenocortical cell line |
Release Date: | 2023/05/25 |
Date of first Publication: | 2021/08/20 |
Licence (German): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |