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Review
. 2018 Jan 23;475(2):373-398.
doi: 10.1042/BCJ20160583.

Topoisomerases as Anticancer Targets

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Free PMC article
Review

Topoisomerases as Anticancer Targets

Justine L Delgado et al. Biochem J. .
Free PMC article

Abstract

Many cancer type-specific anticancer agents have been developed and significant advances have been made toward precision medicine in cancer treatment. However, traditional or nonspecific anticancer drugs are still important for the treatment of many cancer patients whose cancers either do not respond to or have developed resistance to cancer-specific anticancer agents. DNA topoisomerases, especially type IIA topoisomerases, are proved therapeutic targets of anticancer and antibacterial drugs. Clinically successful topoisomerase-targeting anticancer drugs act through topoisomerase poisoning, which leads to replication fork arrest and double-strand break formation. Unfortunately, this unique mode of action is associated with the development of secondary cancers and cardiotoxicity. Structures of topoisomerase-drug-DNA ternary complexes have revealed the exact binding sites and mechanisms of topoisomerase poisons. Recent advances in the field have suggested a possibility of designing isoform-specific human topoisomerase II poisons, which may be developed as safer anticancer drugs. It may also be possible to design catalytic inhibitors of topoisomerases by targeting certain inactive conformations of these enzymes. Furthermore, identification of various new bacterial topoisomerase inhibitors and regulatory proteins may inspire the discovery of novel human topoisomerase inhibitors. Thus, topoisomerases remain as important therapeutic targets of anticancer agents.

Keywords: anticancer agents; chemotherapy; topoisomerase I; topoisomerase II; topoisomerase inhibitors; topoisomerase poisoning.

Conflict of interest statement

Declarations of Interest

The Authors declare no competing interests associated with the manuscript.

Figures

Figure 1.
Figure 1.. Relaxation reaction catalyzed by hTop 1 and the effect of camptothecin class of anticancer agents.
Type IB topoisomerases cleave one strand of supercoiled DNA via the formation of a protein-linked phosphotyrosyl bond between the catalytic tyrosine (purple sticks) and the 3′-phosphate group. While the DNA duplex upstream of the break (red) is bound tightly by hTop 1, very few interactions are present between the downstream DNA duplex (blue) and the enzyme, which allows both positive and negative superhelical tension in DNA to be released by the rotation of downstream DNA duplex about the break. The insertion of camptothecin class of anticancer agents (green ellipsoid) stabilizes the hTop 1-mediated DNA strand break and inhibits the enzyme’s relaxation activity. The cartoon representation of hTop 1 (PDBid: 1RRJ [137]) was generated using PyMol (http://pymol.org).
Figure 2.
Figure 2.. Catalytic cycle and inhibitors of type IIA topoisomerases.
The catalytic cycle of type IIA topoisomerases starts from the entry of G-segment DNA (blue) through an opened N-gate. Binding of two ATP molecules induces closure of the N-gate to facilitate the capture of T-segment DNA (green). The Cleavage of the G-segment followed by pulling the broken DNA ends apart creates a path that allows the T-segment to go through. This duplex passage event is likely driven by the hydrolysis of one ATP and a clockwise rotation of the N-gate, which not only pushes the T-segment through the DNA-gate but also causes the upper cavity enclosed by the N-gate to collapse to prevent the T-segment from moving backward. The religation of the cleaved G-segment is expected to shrink the bottom cavity and thus induces opening of the C-terminal exit gate and the release of the T-segment. The second ATP hydrolysis event then takes place to reset the enzyme for next catalytic cycle. The turnover of type IIA topoisomerases may be blocked by arresting the enzyme at different intermediate states upon the binding of small molecule inhibitors or regulatory proteins. The ATPase, transducer, Toprim, and the remaining C-terminal fragment (from WHD to C-gate) are in yellow, orange, red, and cyan, respectively. The domains of the second protomer are colored grey and light blue. The design of this figure was inspired by Larsen et al. [345].
Figure 3.
Figure 3.. Structures of topoisomerase inhibitors.
A. Type IIA topoisomerase (Top 2) poisons. B. Type IIA topoisomerase (Top 2) catalytic inhibitors. C. Type IB topoisomerase (Top 1) poisons.
Figure 4.
Figure 4.. Targeting sites and binding modes of selected type IIA topoisomerase inhibitors and regulatory proteins.
Functional modulation of type IIA topoisomerases can be achieved by the binding of small molecules and regulatory proteins to various sites in the enzyme. The crystal structures of type IIA topoisomerases in complexes with small molecules {ICRF-187 (PDBid: 1QZR [117]), novobiocin (PDBid: 4URO [346]), GSK299423 (PDBid: 2XCS [191]), etoposide (PDBid: 3QX3 [42]), simocyclinone D8 (PDBid: 2Y3P [233])} and regulatory proteins {YacG (PDBid: 4TMA [228]), CcdB toxin (PDBid: 1X75 [240])} were generated using PyMol (http://pymol.org). The structural model of MfpA-bound GyrA was constructed by manual docking of the MfpA (PDBid: 2BM4 [222]) to the N-terminal fragment of GyrA (PDBid: 1AB4 [107]) followed by stereochemical idealization.

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