Cancer Therapies and Cardiac Dysfunction
Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler in Heart Failure, 2023
Anthracyclines are a class of chemotherapeutics used in the management of many solid and hematologic cancers, most prominently for breast cancer. These drugs, including doxorubicin, daunorubicin, epirubicin, and idarubicin, are responsible for the earliest described form of chemotherapy-induced cardiotoxicity and as such are the most well studied. Anthracyclines rapidly localize to the nucleus where they integrate with DNA, thus disrupting RNA production and DNA metabolism (Figure 29.1). Their cytotoxicity is primarily due to inhibition of topoisomerase II, which then prevents DNA repair and results in apoptosis.29 There are two isozymes of topoisomerase, Top IIa, which is expressed in rapidly dividing cells, and Top IIb, which is expressed in quiescent cells like cardiac myocytes.30 The non-selective nature of anthracyclines results in binding of these agents to Top IIb, resulting in myocyte death.31 Anthracyclines also cause oxidative stress through the formation of reactive oxygen species (ROS), which result in fibrosis and lipid peroxidation of cardiac membranes,32 and may directly impair proliferation of cardiac progenitor cells, thus impairing recovery from stressors and inhibiting pro-survival signaling.33,34
Nucleic Acids as Therapeutic Targets and Agents
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
In order to relieve the topological stress caused by the supercoiling, the enzymes topoisomerase I and II (Topo I and II) produce single or double-strand breaks, respectively, followed by re-sealing, thus reducing the tension in the DNA strand without leaving damaging nicks. Topoisomerase I works by breaking only one strand of DNA, followed by attachment of the free phosphate residue of the broken strand to a tyrosine residue of the enzyme. The complex then rotates, relieving the supercoiled tension of the DNA, and the two ends are then re-sealed. Topoisomerase II works in a related manner but cleaves both strands of double-stranded DNA simultaneously, passing a complete duplex strand through the cut, followed by re-sealing of both strands. The topoisomerase inhibitors are agents that affect the activity of Topo I and II, with most acting to block the re-sealing process which leads to cell death through apoptosis (see Figure 5.47 for mechanism of Topo I inhibitors). Mechanism of the formation of DNA breaks and resulting cell death induced by Topoisomerase I inhibitors.
Cancer Research Is Leading the Way
Rebecca A. Krimins in Learning from Disease in Pets, 2020
DNA topoisomerase 1 (TOP1) is an enzyme that induces single strand breaks in supercoiled DNA permitting relaxation and remodeling, which is essential for transcription, replication, and repair. TOP1 is dysregulated in a variety of cancers. Two TOP1 inhibitors, irinotecan and topotecan, have been FDA approved for use in ovarian, small cell-lung, cervical, colorectal, and/or gastric cancers (Pommier 2006). Both FDA-approved TOP1 inhibitors are in the camptothecin class, and these compounds have significant limitations including chemical instability, short half-life, susceptibility to efflux mediated drug-resistance, and dose-limiting diarrhea (Burton et al. 2018). To bypass these limitations, novel chemical classes of TOP1 inhibitors have been developed. The indenoisoquinoline class of TOP1 inhibitors is one alternate class of compounds which displays nanomolar potency and has enhanced chemical stability and drug efflux properties (Burton et al. 2018). Three indenoisoquinoline TOP1 inhibitors with varying pharmacokinetic properties were examined in a comparative oncology trial in dogs with NHL. While all three compounds displayed objective therapeutic activity, a single compound was identified as having significantly enhanced tumor accumulation and retention relative to the others (Burton et al. 2018). This trial demonstrated not only that indenoisoquinoline TOP1 inhibitors may be therapeutically relevant in the treatment of canine NHL, but importantly also allowed for identification of a clinical lead compound, LMP744, that is currently under evaluation in human clinical trials (Burton et al. 2018).
Novel topoisomerase II/EGFR dual inhibitors: design, synthesis and docking studies of naphtho[2′,3′:4,5]thiazolo[3,2-a]pyrimidine hybrids as potential anticancer agents with apoptosis inducing activity
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Mai A. E. Mourad, Ayman Abo Elmaaty, Islam Zaki, Ahmed A. E. Mourad, Amal Hofni, Ahmed E. Khodir, Esam M. Aboubakr, Ahmed Elkamhawy, Eun Joo Roh, Ahmed A. Al-Karmalawy
DNA topoisomerases are essential nuclear enzymes that maintain the topological changes of DNA and play key role in catalysing DNA replication, proliferation, transcription, recombination, repair, chromosome condensation and segregation4,7,8. Additionally, most of available anticancer regimens based on using at least one member of topoisomerase inhibitors6. However, DNA topoisomerases are generally classified into topoisomerase I (topo I) and topoisomerase II (topo II)9. Topo I possesses its functions by cleaving only one strand of DNA, while type II cleaves both DNA strands10. In the same context, topo II catalysis requires two cofactors ATP and Mg+2 in order to carry out its double-stranded DNA passage reaction11.
Current and emerging treatment options for Angelman syndrome
Published in Expert Review of Neurotherapeutics, 2023
Christopher J. Keary, Christopher J. McDougle
Efforts to block the expression of UBE3A-ATS through various mechanisms have been explored. Topoisomerase inhibitors block processes that allow for transcription elongation and ultimate gene expression. The topoisomerase inhibitor, topotecan, was found to reduce murine Ube3a-ATS with a resulting dose-dependent increase in activation of mouse Ube3a gene in brain regions of the AS mouse model [79]. The risk of suppression of multiple long genes (such as that for UBE3A-ATS) by topotecan [80] raises concerns for clinical use. Its effects in gene expression may not be specific to just the unique genetic deficit of AS. CRISPR/Cas9 has been used in preclinical mouse model studies of AS to mutate the region encoding for Ube3a-ATS, thereby blocking its expression and resulting in upregulation of mouse Ube3a gene [81]. These findings demonstrate the potential value of targeting UBE3A-ATS expression in developing therapeutics for AS.
A patent review of topoisomerase I inhibitors (2016–present)
Published in Expert Opinion on Therapeutic Patents, 2021
Asier Selas, Endika Martin-Encinas, Maria Fuertes, Carme Masdeu, Gloria Rubiales, Francisco Palacios, Concepción Alonso
DNA topoisomerases are DNA modifying enzymes that solve DNA topological stress originated in vital cell events such as replication, transcription or recombination. These enzymes accomplish this fact by means of a catalytic cycle which in all cases involves binding to the corresponding substrate (a double stranded DNA), followed by a nucleophilic attack to a DNA phosphodiester group by a catalytic tyrosine residue (cleavage step). This reaction results in a covalent topoisomerase-DNA cleavage complex (Topcc) that allows the strand passage. The mentioned transesterification is highly reversible and after strand passage, the hydroxyl group of the cleaved phosphodiester backbone performs a nucleophilic attack to the phosphotyrosyl bond (the inverse reaction to the cleavage), resulting in a religation of the DNA (religation step) and a subsequent releasing of the enzyme [8–11].
Related Knowledge Centers
- Dexamethasone
- DNA
- DNA Gyrase
- DNA Replication
- Immediate Early Gene
- Insulin
- Estradiol
- DNA
- DNA Replication
- Transcription
- DNA Gyrase
- Enzyme Commission Number
- Serum