- Topoisomerases are essential enzymes that regulate the overwinding and tangling of DNA that occur during processes such as replication, transcription, recombination, and chromatin remodeling.
- In cancer biology, these enzymes play a critical role because of their involvement in maintaining genomic integrity. When their function becomes dysregulated, it can lead to genomic instability—a hallmark of cancer.
- There are two major classes of topoisomerases in humans: topoisomerase I (TOP1), which induces transient single-strand breaks, and topoisomerase II (TOP2), which induces transient double-strand breaks to resolve DNA supercoils and untangle DNA during cell division.
- In many types of cancer, topoisomerases are overexpressed to support the high replication demands of rapidly dividing tumor cells.
- For instance, TOP2A is often found to be upregulated in aggressive tumors such as breast, lung, and prostate cancers, where its expression is associated with poor prognosis.
- Similarly, increased expression of TOP1 has been observed in colorectal and ovarian cancers.
- These enzymes help cancer cells manage replication stress and are thus indispensable for tumor progression. However, their elevated activity also makes cancer cells particularly vulnerable to topoisomerase-targeting drugs.
- Topoisomerases are the targets of several widely used chemotherapeutic agents.
- Inhibitors of TOP1 include camptothecin derivatives such as topotecan and irinotecan, which are used to treat ovarian and colorectal cancers, respectively. These drugs work by stabilizing the TOP1-DNA cleavage complex, preventing DNA re-ligation, and ultimately leading to lethal DNA breaks during replication.
- TOP2 inhibitors include drugs such as etoposide, teniposide, and the anthracyclines (e.g., doxorubicin), which similarly stabilize the enzyme-DNA complex to induce double-strand breaks.
- These agents are effective across a wide range of cancers, including leukemias, lymphomas, and solid tumors.
- Despite their efficacy, resistance to topoisomerase inhibitors is a significant clinical problem.
- Cancer cells can develop resistance through several mechanisms, including
- mutations in the topoisomerase genes that reduce drug binding,
- overexpression of drug-efflux pumps (e.g., P-glycoprotein), and
- upregulation of DNA repair pathways that mitigate drug-induced damage.
- In some cases, reduced expression of the topoisomerase itself can also lead to decreased sensitivity to inhibitors.
- These challenges highlight the importance of identifying biomarkers to predict drug response and developing strategies to overcome resistance.
- Cancer cells can develop resistance through several mechanisms, including
- In recent years, research has focused on improving the efficacy of topoisomerase-targeted therapies. Biomarker-driven approaches are being developed to better stratify patients who are most likely to benefit from these drugs. For example, amplification of the TOP2A gene may predict sensitivity to anthracyclines, while high TOP1 expression could be used to guide the use of camptothecin derivatives.
- Novel approaches include the development of dual TOP1/TOP2 inhibitors, combination therapies with PARP inhibitors or immunotherapies, and the use of nanoparticle-based drug delivery systems to improve tumor targeting and reduce systemic toxicity.
