Topoisomerase inhibitor

Topoisomerase inhibitors are agents designed to interfere with the action of topoisomerase enzymes^[1] (topoisomerase I and II), which are enzymes that control the changes in DNA structure^[2] by catalyzing the breaking and rejoining of the phosphodiester backbone of DNA strands during the normal cell cycle.

In recent years, topoisomerases have become popular targets for cancer chemotherapy treatments. It is thought that topoisomerase inhibitors block the ligation step of the cell cycle, generating single and double stranded breaks that harm the integrity of the genome. Introduction of these breaks subsequently lead to apoptosis and cell death.

Topoisomerase inhibitors can also function as antibacterial agents.^[3] Quinolones have this function.^[4]

Classification

Topoisomerase inhibitors are often divided according to which type of enzyme it inhibits.

• Topoisomerase I inhibitors: irinotecan, topotecan, camptothecin and lamellarin D all target type IB topoisomerases,
• Topoisomerase II inhibitors: etoposide (VP-16), teniposide, aurintricarboxylic acid,^[5] and HU-331, a quinolone synthesized from cannabidiol.

A numerous plant derived natural phenols (ex. EGCG,^{[6][7][8][9][10]} genistein, quercetin, resveratrol) possess strong topoisomerase inhibitory properties affecting both types of enzymes. They may express function of phytoalexins - compounds produced by plants to combat vermin and pests.

Use of topoisomerase inhibitors for antineoplastic treatments may lead to secondary neoplasms because of DNA damaging properties of the compounds. Also plant derived polyphenols shows signs of carcinogenity, especially in feuses and neonates who do not detoxify the compounds sufficiently.^[11][12][13] An association between high intake of tea (containing polyphenols) during pregnancy and elevated risk of childhood malignant central nervous system (CNS) tumours has been found.^[14][15]

Compounds that target Type II topoisomerase

These inhibitors are split into two main classes: topoisomerase poisons, which target the topoisomerase-DNA complex, and topoisomerase inhibitors, which disrupt catalytic turnover.

Topo II poisons

Examples of topoisomerase poisons include the following:

• eukaryotic type II topoisomerase inhibitors (topo II): amsacrine, etoposide, etoposide phosphate, teniposide and doxorubicin. These drugs are anti-cancer therapies.
• bacterial type II topoisomerase inhibitors (gyrase and topo IV): fluoroquinolones. These are antibacterials and include such fluoroquinolones as ciprofloxacin.

Some of these poisons encourage the forward cleavage reaction (fluoroquinolones), while other poisons prevent the re-ligation of DNA (etoposide and teniposide).

Interestingly, poisons of type IIA topoisomerases can target prokaryotic and eukaryotic enzymes preferentially, making them attractive drug candidates. Ciprofloxacin targets prokaryotes in excess of a thousandfold more than it targets eukaryotic topo IIs. The mechanism for this specificity is unknown, but drug-resistant mutants cluster in regions around the active site.

Topo II inhibitors

These inhibitors target the N-terminal ATPase domain of topo II and prevent topo II from turning over.

Examples of topoisomerase inhibitors include :

• ICRF-193.^[16] The structure of this compound bound to the ATPase domain was solved by Classen (Proceedings of the National Academy of Science, 2004) showing that the drug binds in a non-competitive manner and locks down the dimerization of the ATPase domain.^[17]

• genistein.

References