DNA Topoisomerase II Enzymes as Molecular Targets for Cancer Chemotherapy

Abstract

DNA topoisomerase II enzymes regulate essential cellular processes by altering the topology of chromosomal DNA. These enzymes function by creating transient double-stranded breaks in the DNA molecule that allow the DNA strands to pass through each other and unwind or unknot tangled DNA. Because of the integral role of topoisomerases in regulating DNA metabolism, these enzymes are vital for cell survival. Several clinically active antitumor agents target these enzymes. Mammalian cells contain two topoisomerase II isozymes that are encoded by different genes: topoisomerase IIα and IIβ. Although, both isozymes are homologous and exhibit similar catalytic activity, they are differentially regulated and are involved in distinct biological functions. The topoisomerase IIα and topoisomerase IIβ enzymes are regulated by post-translational modifications, including sumoylation, ubiquitination and phosphorylation. These post-translational modifications influence the biologic and catalytic activity of the enzyme and affect sensitivity of cells to topoisomerase II-targeted drugs. In this review, we describe how the catalytic and biologic activity of the topoisomerase II enzyme is regulated and discuss the mechanisms by which chemotherapeutic agents that target these enzymes function. Given the potential importance of site-specific modifications, in particular phosphorylation, in regulating sensitivity to topoisomerase II-targeted drugs, we discuss the potential role of altered topoisomerase II phosphorylation in development of drug resistance, which is often a limiting factor in the treatment of cancer.

Riccardin D, a novel macrocyclic bisbibenzyl, induces apoptosis of human leukemia cells by targeting DNA topoisomerase II

“…3c, the supercoiled DNA was completely converted to the relaxed DNA in the presence of the nuclear extracts from untreated K562 (lane 2), indicating the constitutive activities of topoisomerases in the nuclei. However, only part of the supercoiled DNA was converted to the relaxed DNA in the presence of the nuclear extracts from riccardin D-treated K562 cells (lanes [3][4][5]. This result suggested that topo II activity in riccardin D-treated K562 cells was suppressed.…”

“…Currently available topo II targeted drugs include topo II poisons and catalytic inhibitors. Topo II poisons such as etoposide, doxorubicin, anthracyclines, ciprofloxacin, and m-AMSA induce topo II-DNA complexes, inhibit resealing of DNA breaks and then trigger cell death [2,3]. Catalytic inhibitors, such as aclarubicin, inhibit the enzyme's binding to its DNA substrate or lock the homodimeric topo II in the form of a closed bracelet surrounding DNA at the post-religation step [4,5].…”

Phytochemicals in Cancer Prevention: A Review of the Evidence

“…These compounds take part in cancer inhibition via prevention of enzyme topoisomerase activity which is involved in DNA imitation, inducing apoptosis and expression of p53 gene (61,62). However, alkaloids have long been existed before humans; some of them are structurally similar to neurotransmitters present in the central nervous system of humans.…”

Regulation of Hepatic Cholesteryl Ester Transfer Protein Expression and Reverse Cholesterol Transport by Inhibition of DNA Topoisomerase II

“…Topo II is vital for cell survival, and tumor cells always exert an abnormal Topo II activity. Thus, Topo II is a promising molecular target for cancer chemotherapy (10). In fact, some Topo II inhibitors, such as etoposide (VP-16) and teniposide (VM-26), have been used to treat various cancers for many years (11).…”