Topoisomerase II and leukemia

Abstract

Type II topoisomerases are essential enzymes that modulate DNA under- and overwinding, knotting, and tangling. Beyond their critical physiological functions, these enzymes are the targets for some of the most widely prescribed anticancer drugs (topoisomerase II poisons) in clinical use. Topoisomerase II poisons kill cells by increasing levels of covalent enzyme-cleaved DNA complexes that are normal reaction intermediates. Drugs such as etoposide, doxorubicin, and mitoxantrone are frontline therapies for a variety of solid tumors and hematological malignancies. Unfortunately, their use is also associated with the development of specific leukemias. Regimens that include etoposide or doxorubicin are linked to the occurrence of acute myeloid leukemias that feature rearrangements at chromosomal band 11q23. Similar rearrangements are seen in infant leukemias and are associated with gestational diets that are high in naturally occurring topoisomerase II–active compounds. Finally, regimens that include mitoxantrone and epirubicin are linked to acute promyelocytic leukemias that feature t(15;17) rearrangements. The first part of this article will focus on type II topoisomerases and describe the mechanism of enzyme and drug action. The second part will discuss how topoisomerase II poisons trigger chromosomal breaks that lead to leukemia and potential approaches for dissociating the actions of drugs from their leukemogenic potential.

Treatment of Mice with Naringin Alleviates the Doxorubicin-Induced Oxidative Stress in the Liver of Swiss Albino Mice

“…However, it produces deleterious effects on several normal tissues that may result in the production of second malignancies in the long term survivors. 53 The induction of secondary neoplasia is a major stumbling block in realizing its full potential in treating various malignant diseases. The doxorubicin acts by intercalating into the cellular DNA and also by inhibiting the enzyme topoisomerase II, which plays a central role during DNA replication.…”

Genome-wide TOP2A DNA cleavage is biased toward translocated and highly transcribed loci

“…It also is a member of the BAF complex that decatenates newly replicated sister chromatids during mitosis (Dykhuizen et al 2013). TOP2B expression is cell cycle independent (Pendleton et al 2014).…”

“…Each subunit of the TOP2 homodimer forms a phosphodiester bond with the base 3 ′ to the cleavage, creating the cleavage complex, a covalent intermediate with four-base staggered DNA ends tethered by the enzyme (Pendleton et al 2014). TOP2A increases during cell growth and is required for replication (Pendleton et al 2014). It also is a member of the BAF complex that decatenates newly replicated sister chromatids during mitosis (Dykhuizen et al 2013).…”

“…They relax, unknot, and untangle DNA by transiently cleaving and religating both strands of the double helix. Each subunit of the TOP2 homodimer forms a phosphodiester bond with the base 3 ′ to the cleavage, creating the cleavage complex, a covalent intermediate with four-base staggered DNA ends tethered by the enzyme (Pendleton et al 2014). TOP2A increases during cell growth and is required for replication (Pendleton et al 2014).…”

Theoretical and experimental studies on anticancer drug mitoxantrone

“…Anthracycline drugs are known to exert their cytotoxic effects through interaction with DNA resulting in modification of its structure hence inhibition of its replication [9]. Mitoxantrone is known inhibitor to topoisomerase II [10]. Mitoxantrone shows covalent and noncovalent interactions with many biological macromolecules [9].…”