Topoisomerase Inhibitors in Cancer

Topoisomerases are nuclear enzymes involved in DNA replication, transcription, chromosomal segregation, and recombination. There are two types of topoisomerases found in all cells: type I enzymes that cut single-stranded DNA and type II enzymes that cut and pass double-stranded DNA. Topo2 is involved in endoreduplication as well as mitotic chromosomal segregation following replication. Inhibiting topo2 in cells may cause a cascade of events ranging from endoreduplication and polyploidy to cell death. Etoposide is employed as an anticancer drug by targeting the topo2-DNA complex, however, its induction of the DNA strand break-stable complex may result in chromosomal translocation and, ultimately, a particular kind of leukaemia.

There are two types of topoisomerase 2 inhibitors. Class 1 chemicals, such as etoposide and doxorubicin, are known as classical poisons because they stabilise the DNA-Topo 2 complex by producing lesions with broken DNA strands and protein covalently bound to them. Class 2 chemicals are known as catalytic inhibitors because they reduce the catalytic activity of topo2, which is required by cells. Earlier in-vitro research revealed that tumour cells expressing greater levels of topo2 are more sensitive to topo2 inhibitors than tumour cells expressing low levels of topo2. Using siRNA investigations, researchers discovered that cells with little or no topo2 expression were resistant to topo2 inhibitors, with comparable in-vivo outcomes. Topo2 sensitivity was discovered to be a recessive allele in yeast and mammalian cells, which could not confer resistance to cells when heterozygous. Targeting cells with high erbb2 (her2/neu) expression also demonstrated enhanced sensitivity to anti topo 2 medicines (particularly anthracyclines), which might be due to the topo2-alpha gene's near proximity to the erbb2 gene on chromosome 17, which could lead to co-amplification of both genes. While the effects of antimitotic drugs on topo2 expression remain unknown.

Topo2a overexpression is associated with the development of prostatic cancer, and greater expression may result in a more invasive (aggressive) phenotype owing to genomic rearrangements. Anti-androgen medications were ineffective in killing cells expressing topo2. Aside from that, the combined action of topo2 inhibitor and anti-androgen medication was enough to limit growth. Topo2 is also involved in the transcription of androgen sensitive genes, which increases androgen expression. Topo2's actions promote cancer development and increase medication sensitivity.



References

Schaefer-Klein, J. L., Murphy, S. J., Johnson, S. H., Vasmatzis, G., & Kovtun, I. V. (2015). Topoisomerase 2 alpha cooperates with androgen receptors to contribute to prostate cancer progression. PloS one, 10(11), e0142327.

Targeting DNA topoisomerase II in cancer chemotherapy John L. Nitiss Molecular Pharmacology Dept., St. Jude Children's Research Hospital -

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