Topoisomerase inhibitor
Encyclopedia
Topoisomerase inhibitors are agents designed to interfere with the action of topoisomerase
enzymes (topoisomerase I and II), which are enzymes that control the changes in DNA
structure 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. Quinolone
s have this function.
A numerous plant derived natural phenol
s (ex. EGCG
, genistein
, quercetin
, resveratrol
) possess strong topoisomerase inhibitory properties affecting both types of enzymes. They may express function of phytoalexin
s - compounds produced by plants to combat vermin and pests.
Use of topoisomerase inhibitors for antineoplastic treatments may lead to secondary neoplasm
s 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. An association between high intake of tea
(containing polyphenol
s) during pregnancy and elevated risk of childhood malignant central nervous system (CNS) tumours has been found.
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.
Examples of topoisomerase inhibitors include :
Topoisomerase
Topoisomerases are enzymes that regulate the overwinding or underwinding of DNA. The winding problem of DNA arises due to the intertwined nature of its double helical structure. For example, during DNA replication, DNA becomes overwound ahead of a replication fork...
enzymes (topoisomerase I and II), which are enzymes that control the changes in DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
structure by catalyzing
Enzyme catalysis
Enzyme catalysis is the catalysis of chemical reactions by specialized proteins known as enzymes. Catalysis of biochemical reactions in the cell is vital due to the very low reaction rates of the uncatalysed reactions....
the breaking and rejoining of the phosphodiester backbone of DNA strands during the normal cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
.
In recent years, topoisomerases have become popular targets for cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
chemotherapy treatments. It is thought that topoisomerase inhibitors block the ligation
Ligation
Ligation may refer to:* In molecular biology, the covalent linking of two ends of DNA molecules using DNA ligase* In medicine, the making of a ligature * Chemical ligation, the production of peptides from amino acids...
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. Quinolone
Quinolone
The quinolones are a family of synthetic broad-spectrum antibiotics. The term quinolone refers to potent synthetic chemotherapeutic antibacterials....
s have this function.
Classification
Topoisomerase inhibitors are often divided according to which type of enzyme it inhibits.- Topoisomerase I inhibitors: irinotecanIrinotecanIrinotecan is a drug used for the treatment of cancer.Irinotecan prevents DNA from unwinding by inhibition of topoisomerase 1. In chemical terms, it is a semisynthetic analogue of the natural alkaloid camptothecin....
, topotecanTopotecanTopotecan hydrochloride is a chemotherapy agent that is a topoisomerase I inhibitor. It is the water-soluble derivative of camptothecin...
, camptothecinCamptothecinCamptothecin is a cytotoxic quinoline alkaloid which inhibits the DNA enzyme topoisomerase I . It was discovered in 1966 by M. E. Wall and M. C. Wani in systematic screening of natural products for anticancer drugs. It was isolated from the bark and stem of Camptotheca acuminata , a tree native to...
and lamellarin D all target type IB topoisomerases, - Topoisomerase II inhibitors: etoposideEtoposideEtoposide phosphate is an anti-cancer agent. It is known in the laboratory as a topoisomerase poison. Etoposide is often incorrectly referred to as a topoisomerase inhibitor in order to avoid using the term "poison" in a clinical setting...
(VP-16), teniposideTeniposideTeniposide is a chemotherapeutic medication mainly used in the treatment of childhood acute lymphocytic leukemia . It is in a class of drugs known as podophyllotoxin derivatives and slows the growth of cancer cells in the body....
, aurintricarboxylic acidAurintricarboxylic acidAurintricarboxylic acid is a chemical compound that readily polymerizes in aqueous solution, forming a stable free radical that inhibits protein-nucleic acid interactions. It is a potent inhibitor of ribonuclease and topoisomerase II by preventing the binding of the nucleic acid to the enzyme...
, and HU-331HU-331HU-331 is a quinone anticarcinogenic drug synthesized from cannabidiol, a cannabinoid in the Cannabis sativa plant. It showed a great efficacy against oncogenic human cells. HU-331 does not cause arrest in cell cycle, cell apoptosis or caspase activation...
, a quinolone synthesized from cannabidiolCannabidiolCannabidiol is a cannabinoid found in Cannabis. It is a major constituent of the plant, representing up to 40% in its extracts.It has displayed sedative effects in animal tests...
.
A numerous plant derived natural phenol
Natural phenol
Natural phenols, bioavailable phenols, plant phenolics, low molecular weight phenols or phenoloids are a class of natural products. They are small molecules containing one or more phenolic group. These molecules are smaller in size than polyphenols, containing less than 12 phenolic groups...
s (ex. EGCG
Epigallocatechin gallate
Epigallocatechin gallate , also known as epigallocatechin 3-gallate, is the ester of epigallocatechin and gallic acid, and is a type of catechin....
, genistein
Genistein
Genistein is one of several known isoflavones. Isoflavones, such as genistein and daidzein, are found in a number of plants including lupin, fava beans, soybeans, kudzu, and psoralea being the primary food source, also in the medicinal plant, Flemingia vestita and coffee Besides functioning as...
, quercetin
Quercetin
Quercetin , a flavonol, is a plant-derived flavonoid found in fruits, vegetables, leaves and grains. It also may be used as an ingredient in supplements, beverages or foods.-Occurrence:...
, resveratrol
Resveratrol
Resveratrol is a stilbenoid, a type of natural phenol, and a phytoalexin produced naturally by several plants when under attack by pathogens such as bacteria or fungi....
) possess strong topoisomerase inhibitory properties affecting both types of enzymes. They may express function of phytoalexin
Phytoalexin
Phytoalexins are antimicrobial substances synthesized de novo by plants that accumulate rapidly at areas of incompatible pathogen infection. They are broad spectrum inhibitors and are chemically diverse with different types characteristic of particular plant species...
s - compounds produced by plants to combat vermin and pests.
Use of topoisomerase inhibitors for antineoplastic treatments may lead to secondary neoplasm
Secondary neoplasm
A secondary neoplasm refers to any of a class of cancerous tumors that are either metastatic offshoots of a primary tumor, or apparently unrelated tumors that increase in frequency following certain cancer treatments, including chemotherapy or radiotherapy....
s 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. An association between high intake of tea
Tea
Tea is an aromatic beverage prepared by adding cured leaves of the Camellia sinensis plant to hot water. The term also refers to the plant itself. After water, tea is the most widely consumed beverage in the world...
(containing polyphenol
Polyphenol
Polyphenols are a structural class of natural, synthetic, and semisynthetic organic chemicals characterized by the presence of large multiples of phenol structural units...
s) during pregnancy and elevated risk of childhood malignant central nervous system (CNS) tumours has been found.
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): amsacrineAmsacrineAmsacrine is an antineoplastic agent.It has been used in acute lymphoblastic leukemia.-Mechanism:Its planar fused ring system can intercalate into the DNA of tumor cells, thereby altering the major and minor groove proportions...
, etoposideEtoposideEtoposide phosphate is an anti-cancer agent. It is known in the laboratory as a topoisomerase poison. Etoposide is often incorrectly referred to as a topoisomerase inhibitor in order to avoid using the term "poison" in a clinical setting...
, etoposide phosphate, teniposideTeniposideTeniposide is a chemotherapeutic medication mainly used in the treatment of childhood acute lymphocytic leukemia . It is in a class of drugs known as podophyllotoxin derivatives and slows the growth of cancer cells in the body....
and doxorubicinDoxorubicinDoxorubicin INN is a drug used in cancer chemotherapy. It is an anthracycline antibiotic, closely related to the natural product daunomycin, and like all anthracyclines, it works by intercalating DNA....
. 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
Ciprofloxacin
Ciprofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class.It is a second-generation fluoroquinolone antibacterial. It kills bacteria by interfering with the enzymes that cause DNA to rewind after being copied, which stops synthesis of DNA and of...
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. 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.
- genisteinGenisteinGenistein is one of several known isoflavones. Isoflavones, such as genistein and daidzein, are found in a number of plants including lupin, fava beans, soybeans, kudzu, and psoralea being the primary food source, also in the medicinal plant, Flemingia vestita and coffee Besides functioning as...
.