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Topoisomerase II as a target for anticancer drugs: when enzymes stop being nice
1Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Abstract:
Topoisomerase II is an essential enzyme that plays a role in virtually every cellular DNA process. This enzyme interconverts different topological forms of DNA by passing one nucleic acid segment through a transient double-stranded break generated in a second segment. By virtue of its double-stranded DNA passage reaction, topoisomerase II is able to regulate DNA over- and underwinding, and can resolve knots and tangles in the genetic material. Beyond the critical physiological functions of the eukaryotic enzyme, topoisomerase II is the target for some of the most successful anticancer drugs used to treat human malignancies. These agents are referred to as topoisomerase II poisons, because they transform the enzyme into a potent cellular toxin. Topoisomerase II poisons act by increasing the concentration of covalent enzyme-cleaved DNA complexes that normally are fleeting intermediates in the catalytic cycle of topoisomerase II. As a result of their action, these drugs generate high levels of enzyme-mediated breaks in the genetic material of treated cells and ultimately trigger cell death pathways. Topoisomerase II is also the target for a second category of drugs referred to as catalytic inhibitors. Compounds in this category prevent topoisomerase II from carrying out its required physiological functions. Drugs from both categories vary widely in their mechanisms of actions. This review focuses on topoisomerase II function and how drugs alter the catalytic cycle of this important enzyme.
Insights
Topoisomerase II (an enzyme crucial for DNA management) is a key target for anticancer drugs. These drugs, acting as poisons or inhibitors, disrupt the enzyme
Area of Science:
- Molecular Biology
- Biochemistry
- Genetics
Background:
- Topoisomerase II is vital for DNA topology regulation, essential for cellular processes.
- It resolves DNA tangles and manages supercoiling by transiently breaking and rejoining DNA strands.
- The enzyme is a critical target for anticancer therapies.
Purpose of the Study:
- To review the function of Topoisomerase II.
- To explore how anticancer drugs interact with and alter the enzyme's catalytic cycle.
- To differentiate between Topoisomerase II poisons and catalytic inhibitors.
Main Methods:
- Literature review of Topoisomerase II function and drug interactions.
- Analysis of the mechanisms of action for Topoisomerase II poisons and catalytic inhibitors.
- Focus on how drugs affect the enzyme's catalytic cycle and DNA cleavage complexes.
Main Results:
- Topoisomerase II poisons stabilize enzyme-DNA cleavage complexes, leading to DNA breaks and cell death.
- Catalytic inhibitors block the essential functions of Topoisomerase II.
- Both drug classes exhibit diverse mechanisms but target the same essential enzyme.
Conclusions:
- Topoisomerase II is a critical target for anticancer drug development due to its essential cellular role.
- Understanding drug interactions with Topoisomerase II is key to developing effective cancer treatments.
- The review highlights the distinct mechanisms of Topoisomerase II poisons and inhibitors.