Topoisomerases are enzymes that regulate the overwinding or underwinding of DNA. The double stranded nature of DNA creates a special set of problems for processes that require strand unwinding such as transcription and replication. The unwinding that occurs during these processes creates a topological problem because the unwinding must be compensated by overwinding elsewhere in the DNA molecule. The winding problem of DNA arises due to the intertwined nature of its double-helical structure. DNA topoisomerases are enzymes that solve these difficulties by introducing transient breaks in DNA. The transient breaks allow changes in DNA topology that eliminate the overwinding.

Topoisomerases are isomerase enzymes that act on the topology of DNA. Type I topoisomerase cuts one strand of a DNA double helix, relaxation occurs, and then the cut strand is reannealed. Type I topoisomerases has two subclasses: type IA topoisomerases, which share many structural and mechanistic features with the type II topoisomerases, and type IB topoisomerases, which utilize a controlled rotary mechanism. Meanwhile, type II topoisomerase cuts both strands of one DNA double helix, pass another unbroken DNA helix through it, and then reanneal the cut strands. This class is also split into two subclasses: type IIA and type IIB topoisomerases, which possess similar structure and mechanisms.

MSN8C is a novel catalytic inhibitor of human DNA topoisomerase II

MSN8C, an analog of mansonone E, is a novel catalytic inhibitor of human DNA topoisomerase II. Even at high drug concentrations, MSN8C inhibits Topo II activity without causing broken DNA or inducing DNA damage markers γH2AX (S139) at cellular levels. MSN8C shows significant antiproliferative activity against eleven human tumor cell lines in vitro. It is particularly effective against the HL-60/MX2 cell line, which is resistant to Topo II poisons. Meanwhile, MSN8C induces cancer cell apoptosis. Furthermore, MSN8C exhibits potent antitumor efficacy in the A549 tumor xenograft model. Although it was not as active as doxorubicin in animal experiments, it had a better safety profile.

All in all, MSN8C is a novel catalytic inhibitor of human DNA topoisomerase II that has potential for the research of cancer.


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[2] Ou JB, et, al. Molecules. 2023 Jul 24;28(14):5598.