- Topoisomerases are well-established drug targets, particularly in cancer therapy, due to their essential roles in DNA metabolism and the maintenance of genomic stability.
- These enzymes resolve topological stress during processes such as DNA replication, transcription, recombination, and chromosome segregation.
- Because rapidly dividing cells, such as cancer cells, heavily depend on topoisomerase activity, inhibiting these enzymes can selectively disrupt tumor growth by inducing DNA damage and triggering cell death.
- There are two major classes of topoisomerases targeted by drugs: topoisomerase I (TOP1) and topoisomerase II (TOP2).
- TOP1 inhibitors, such as camptothecin and its clinically used derivatives topotecan and irinotecan, stabilize the TOP1-DNA cleavage complex. Normally, TOP1 creates transient single-strand breaks to relieve supercoiling and then reseals the break. However, these inhibitors trap the enzyme in its cleaved state, leading to the accumulation of single-strand breaks. When the replication fork encounters these breaks, they are converted into irreversible double-strand breaks, resulting in replication stress, genomic instability, and ultimately, cell death.
- TOP2 inhibitors work through a similar mechanism but target the enzyme that introduces double-strand breaks. Drugs like etoposide, teniposide, and doxorubicin bind to the TOP2-DNA complex and prevent re-ligation of the DNA strands. This leads to persistent double-strand breaks that are toxic to cells. These agents are widely used in treating various cancers, including leukemias, lymphomas, and solid tumors such as breast and lung cancer.
- However, the use of topoisomerase inhibitors is associated with certain challenges. One major issue is drug resistance, which can arise from multiple mechanisms: decreased expression or mutation of the topoisomerase target, increased drug efflux via ABC transporters (e.g., P-glycoprotein), and enhanced DNA repair mechanisms. In addition, topoisomerase inhibitors can cause dose-limiting toxicities, especially myelosuppression and secondary malignancies such as therapy-related leukemias, due to their impact on normal proliferating cells and genomic integrity.
- To overcome these limitations, research is focused on improving topoisomerase-targeted therapies. Efforts include developing novel inhibitors with greater specificity and reduced toxicity, dual-function drugs that inhibit both TOP1 and TOP2, and nanoparticle-based delivery systems that improve tumor targeting. Moreover, there is growing interest in biomarker-guided therapy, where the expression levels of TOP1 or TOP2A and associated gene mutations are used to predict patient response and personalize treatment.
