The Implication of Topoisomerase II Inhibitors in Synthetic Lethality for Cancer Therapy
Abstract
:1. Introduction
2. DNA Topoisomerases
3. DNA Topoisomerase Inhibitors
3.1. DNA Topoisomerase II Inhibitors
3.1.1. DNA Topoisomerase II Poisons
3.1.2. DNA Topoisomerase II Catalytic Inhibitors
4. Double-Strand Break (DSB) Repair
4.1. DNA Repair Mechanism
4.1.1. Homologous Recombination
4.1.2. Non-Homologous End-Joining
5. Topoisomerase II inhibition Synergizes with DNA Repair Inhibitors
5.1. PARP Inhibitors
5.2. ATM/ATR Inhibitors
5.3. WEE1/CHK1 Inhibitors
5.4. DNA-PK Inhibitors
6. Chromatin Remodeling and Gene Transcription
6.1. EZH2 and Topoisomerase II
6.2. Myc and Topoisomerase II
7. Top2 Catalytic Inhibitors and Synthetic Lethality
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Type | Subfamily | Mechanism | Human Proteins | Function | Co-Factor | Substrate |
---|---|---|---|---|---|---|
I | IA | Strand passage | Top3a | Relaxed DNA Sc, decatenation activity | Mg2+ | DNA Sc, hemicatenanes, double Holliday junctions, and D loops. |
Top3b | Relaxed DNA Sc, RNA helicase activity | DNA HSc, RNA knots, and R loops. | ||||
IB | Controlled rotation | Top1 | Relaxed negative and positive DNA Sc | None | DNA positive and negative Sc. | |
Top1mt | ||||||
IC | Not found in humans | |||||
II | IIA | Strand passage | Top2a | Relaxed negative and positive DNA Sc, potent decatenation activity | Mg2+, ATP | DNA positive and negative Sc, DNA knots, and DNA catenanes. |
Top2b | ||||||
IIB | Not found in humans |
Name | Mechanism of Action | Mode of Inhibition | Application | Refs. |
---|---|---|---|---|
Aclarubicin | Prevents binding of Top2 to DNA | Catalytic | Acute myeloid leukemia | [31] |
T638 (T60) | Inhibition compared to etoposide with less cytotoxicity in K562 cancer cells and xenografts | [32,33,34] | ||
Novobiocin | Binds to ATP binding site | BRCA-deficient tumors with acquired PARP inhibitor resistance | [35] | |
Merbarone | Blocks DNA Cleavage | Limitations due to nephrotoxicity | [36] | |
ICRF-193 (ICRF-187) | Blocks ATP hydrolysis and traps enzymes in the closed clamp | Addresses cardiotoxicity caused by Top2 poison | [37] | |
Etoposide | Stabilizes covalent cleavage complexes | Poison | Small cell lung cancer, lymphomas, refractory testicular tumors | [38] |
Doxorubicin | Leukemia, ovarian and breast carcinomas | [39] | ||
Amsacrine | Acute myeloid leukemia | [40] |
DNA Repair Protein | Inhibitor | Application | Clinical Trial | Refs. |
---|---|---|---|---|
PARP | Olaparib | BRCA or HR+ ovarian cancer mutations | NCT02476968 NCT03286842 | [92,93] |
ATM | AZD0156 | Advanced solid tumors | NCT02588105 | [94] |
AZD1390 | Non-small cell lung cancer and brain cancer | NCT03423628 NCT04550104 | [95,96] | |
ATR | M6620 | Metastatic urothelial cancer and solid tumors | NCT02589522 NCT02567409 | [97,98] |
CHK1 | AZD7762 | Refractory solid tumors | NCT00937664 | [99] |
WEE1 | AZD1775 | Glioblastoma and refractory solid tumors | NCT02095132 NCT01849146 | [100,101] |
DNA-PK | VX-984 | Advanced solid tumors | NCT02644278 | [102] |
M3814 | Advanced rectal cancer | NCT03770689 | [103] |
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Matias-Barrios, V.M.; Dong, X. The Implication of Topoisomerase II Inhibitors in Synthetic Lethality for Cancer Therapy. Pharmaceuticals 2023, 16, 94. https://doi.org/10.3390/ph16010094
Matias-Barrios VM, Dong X. The Implication of Topoisomerase II Inhibitors in Synthetic Lethality for Cancer Therapy. Pharmaceuticals. 2023; 16(1):94. https://doi.org/10.3390/ph16010094
Chicago/Turabian StyleMatias-Barrios, Victor M., and Xuesen Dong. 2023. "The Implication of Topoisomerase II Inhibitors in Synthetic Lethality for Cancer Therapy" Pharmaceuticals 16, no. 1: 94. https://doi.org/10.3390/ph16010094