scholarly journals Topoisomerases as anticancer targets

2018 ◽  
Vol 475 (2) ◽  
pp. 373-398 ◽  
Author(s):  
Justine L. Delgado ◽  
Chao-Ming Hsieh ◽  
Nei-Li Chan ◽  
Hiroshi Hiasa
Keyword(s):  
Anticancer Drugs ◽  
Anticancer Agents ◽  
Topoisomerase Ii ◽  
Therapeutic Targets ◽  
Strand Break ◽  
Cancer Type ◽  
Topoisomerase Inhibitors ◽  
Topoisomerase Ii Poisons ◽  
Topoisomerase Poisons ◽  
Replication Fork Arrest

Many cancer type-specific anticancer agents have been developed and significant advances have been made toward precision medicine in cancer treatment. However, traditional or nonspecific anticancer drugs are still important for the treatment of many cancer patients whose cancers either do not respond to or have developed resistance to cancer-specific anticancer agents. DNA topoisomerases, especially type IIA topoisomerases, are proved therapeutic targets of anticancer and antibacterial drugs. Clinically successful topoisomerase-targeting anticancer drugs act through topoisomerase poisoning, which leads to replication fork arrest and double-strand break formation. Unfortunately, this unique mode of action is associated with the development of secondary cancers and cardiotoxicity. Structures of topoisomerase–drug–DNA ternary complexes have revealed the exact binding sites and mechanisms of topoisomerase poisons. Recent advances in the field have suggested a possibility of designing isoform-specific human topoisomerase II poisons, which may be developed as safer anticancer drugs. It may also be possible to design catalytic inhibitors of topoisomerases by targeting certain inactive conformations of these enzymes. Furthermore, identification of various new bacterial topoisomerase inhibitors and regulatory proteins may inspire the discovery of novel human topoisomerase inhibitors. Thus, topoisomerases remain as important therapeutic targets of anticancer agents.

scholarly journals Drug resistance in topoisomerase-targeting therapy

2018 ◽  
Vol 72 ◽  
pp. 1073-1083 ◽  
Author(s):  
Karol Wtorek ◽  
Angelika Długosz ◽  
Anna Janecka
Keyword(s):  
Drug Resistance ◽  
Cancer Cells ◽  
Anticancer Drugs ◽  
Anticancer Agents ◽  
Topoisomerase I ◽  
Topoisomerase Ii ◽  
Catalytic Domain ◽  
Cancer Drug ◽  
Anthracycline Antibiotics ◽  
Targeting Therapy

Drug resistance is a well-known phenomenon that occurs when initially responsive to chemotherapy cancer cells become tolerant and elude further effectiveness of anticancer drugs. Based on their mechanism of action, anticancer drugs can be divided into cytotoxic-based agents and target-based agents. An important role among the therapeutics of the second group is played by drugs targeting topoisomerases, nuclear enzymes critical to DNA function and cell survival. These enzymes are cellular targets of several groups of anticancer agents which generate DNA damage in rapidly proliferating cancer cells. Drugs targeting topoisomerase I are mostly analogs of camtothecin, a natural compound isolated from the bark of a tree growing in China. Drugs targeting topoisomerase II are divided into poisons, such as anthracycline antibiotics, whose action is based on intercalation between DNA bases, and catalytic inhibitors that block topoisomerase II at different stages of the catalytic cycle. Unfortunately, chemotherapy is often limited by the induction of drug resistance. Identifying mechanisms that promote drug resistance is critical for the improvement of patient prognosis. Cancer drug resistance is a complex phenomenon that may be influenced by many factors. Here we discuss various mechanisms by which cancer cells can develop resistance to topoisomerase-directed drugs, which include enhanced drug efflux, mutations in topoisomerase genes, hypophosphorylation of topoisomerase II catalytic domain, activation of NF-κB transcription factor and drug inactivation. All these events may lead to the ineffective induction of cancer cell death. Attempts at circumventing drug resistance through the inhibition of cellular efflux pumps, use of silencing RNAs or inhibition of some important mechanisms, which can allow cancer cells to survive therapy, are also presented.

Topoisomerase II Inhibitors in Cancer Treatment

2011 ◽  
Vol 3 (4) ◽  
pp. 1173-1181
Author(s):  
Devendra Singh Thakur
Keyword(s):  
Anticancer Agents ◽  
Topoisomerase Ii ◽  
Double Helix ◽  
Clinical Use ◽  
Topoisomerase Inhibitors ◽  
Dna Double Strand Breaks ◽  
Metabolic Processes ◽  
Strand Breaks ◽  
Cellular Target ◽  
Dna Double Helix

Topoisomerase II constitutes a family of nuclear enzymes essential to all living cells. These enzymes are capable of transferring one DNA double helix through a transient break in another DNA double helix. Type II topoisomerases play important roles in DNA metabolic processes, in which they are involved in DNA replication, transcription, chromosome condensation and de-condensation. Topoisomerase II is also the cellular target for a number of widely used anticancer agents currently in clinical use, such as the anthracyclines (daunorubicin and doxorubicin), the epipodophyllotoxins (etoposide and teniposide), and the aminoacridines. These agents stimulate the topoisomerase II-cleavable complex, which is a transient configuration of topoisomerase II on DNA in which topoisomerase II is covalently attached to DNA. This causes the accumulation of cytotoxic nonreversible DNA double-strand breaks generated by the processing of such complexes by DNA metabolic processes. As of present, the clinical use of catalytic topoisomerase inhibitors as antineoplastic agents is limited to aclarubicin and MST-16. Both of these compounds are preferentially active toward hematological malignancies and show limited activity toward solid tumors. This review explains the role of topoisomerase inhibitors in cancer therapy.

Recent Design and Structure-Activity Relationship Studies on Modifications of DHFR Inhibitors as Anticancer Agents

2019 ◽  
Vol 26 ◽  
Author(s):  
Agnieszka Wróbel ◽  
Danuta Drozdowska
Keyword(s):  
Anticancer Activity ◽  
Anticancer Drugs ◽  
Anticancer Agents ◽  
Physicochemical Characterization ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Biological Research ◽  
Structure Activity ◽  
Dhfr Inhibitors

Background: Dihydrofolate reductase (DHFR) has been known for decades as a molecular target for antibacterial, antifungal and anti-malarial treatments. This enzyme is becoming increasingly important in the design of new anticancer drugs, which is confirmed by numerous studies including modelling, synthesis and in vitro biological research. This review aims to present and discuss some remarkable recent advances on the research of new DHFR inhibitors with potential anticancer activity. Methods: The scientific literature of the last decade on the different types of DHFR inhibitors has been searched. The studies on design, synthesis and investigation structure-activity relationship were summarized and divided into several subsections depending on the leading molecule and its structural modification. Various methods of synthesis, potential anticancer activity and possible practical applications as DHFR inhibitors of new chemical compounds were described and discussed. <p> Results: This review presents the current state of knowledge on the modification of known DHFR inhibitors and the structures and searching for over eighty new molecules, designed as potential anticancer drugs. In addition, DHFR inhibitors acting on thymidylate synthase (TS), carbon anhydrase (CA) and even DNA-binding are presented in this paper. <p> Conclusion: Thorough physicochemical characterization and biological investigations it is possible to understand structure-activity relationship of DHFR inhibitors. This will enable even better design and synthesis of active compounds, which would have the expected mechanism of action and the desired activity.

In Vitro Antitumor Evaluation of Some Hybrid Molecules Containing Coumarin and Quinolinone Moieties

2020 ◽  
Vol 19 (16) ◽  
pp. 2010-2018
Author(s):  
Youstina W. Rizzk ◽  
Ibrahim M. El-Deen ◽  
Faten Z. Mohammed ◽  
Moustafa S. Abdelhamid ◽  
Amgad I.M. Khedr
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Cancer Cell ◽  
Anticancer Agents ◽  
Topoisomerase Ii ◽  
Cancer Cell Lines ◽  
Bax Protein ◽  
Hybrid Molecules ◽  
Mcf 7

Background: Hybrid molecules furnished by merging two or more pharmacophores is an emerging concept in the field of medicinal chemistry and drug discovery. Currently, coumarin hybrids have attracted the keen attention of researchers to discover their therapeutic capability against cancer. Objective: The present study aimed to evaluate the in vitro antitumor activity of a new series of hybrid molecules containing coumarin and quinolinone moieties 4 and 5 against four cancer cell lines. Materials and Methods: A new series of hybrid molecules containing coumarin and quinolinone moieties, 4a-c and 5a-c, were synthesized and screened for their cytotoxicity against prostate PC-3, breast MCF-7, colon HCT- 116 and liver HepG2 cancer cell lines as well as normal breast Hs-371 T. Results: All the synthesized compounds were assessed for their in vitro antiproliferative activity against four cancer cell lines and several compounds were found to be active. Further in vitro cell cycle study of compounds 4a and 5a revealed MCF-7 cells arrest at G2 /M phase of the cell cycle profile and induction apoptosis at pre-G1 phase. The apoptosis-inducing activity was evidenced by up-regulation of Bax protein together with the downregulation of the expression of Bcl-2 protein. The mechanism of cytotoxic activity of compounds 4a and 5a correlated to its topoisomerase II inhibitory activity. Conclusion: Hybrid molecules containing coumarin and quinolinone moieties represents a scaffold for further optimization to obtain promising anticancer agents.

scholarly journals Activity of Indenoisoquinolines against African Trypanosomes

2008 ◽  
Vol 53 (1) ◽  
pp. 123-128 ◽  
Author(s):  
Rahul P. Bakshi ◽  
Dongpei Sang ◽  
Andrew Morrell ◽  
Mark Cushman ◽  
Theresa A. Shapiro
Keyword(s):  
Anticancer Agents ◽  
Mammalian Cells ◽  
Sleeping Sickness ◽  
Water Soluble ◽  
African Trypanosomes ◽  
In Vivo Experiments ◽  
Topoisomerase Ib ◽  
Topoisomerase Poisons

ABSTRACT African trypanosomiasis (sleeping sickness), caused by protozoan Trypanosoma brucei species, is a debilitating disease that is lethal if untreated. Available drugs are antiquated, toxic, and compromised by emerging resistance. The indenoisoquinolines are a class of noncamptothecin topoisomerase IB poisons that are under development as anticancer agents. We tested a variety of indenoisoquinolines for their ability to kill T. brucei. Indenoisoquinolines proved trypanocidal at submicromolar concentrations in vitro. Structure-activity analysis yielded motifs that enhanced potency, including alkylamino substitutions on N-6, methoxy groups on C-2 and C-3, and a methylenedioxy bridge between C-8 and C-9. Detailed analysis of eight water-soluble indenoisoquinolines demonstrated that in trypanosomes the compounds inhibited DNA synthesis and acted as topoisomerase poisons. Testing these compounds on L1210 mouse leukemia cells revealed that all eight were more effective against trypanosomes than against mammalian cells. In preliminary in vivo experiments one compound delayed parasitemia and extended survival in mice subjected to a lethal trypanosome challenge. The indenoisoquinolines provide a promising lead for the development of drugs against sleeping sickness.

scholarly journals Newly Identified Antibacterial Compounds Are Topoisomerase Poisons in African Trypanosomes

2009 ◽  
Vol 54 (2) ◽  
pp. 620-626 ◽  
Author(s):  
Sonya C. Tang ◽  
Theresa A. Shapiro
Keyword(s):  
Topoisomerase Ii ◽  
Protozoan Parasite ◽  
New Drugs ◽  
Chemical Library ◽  
African Trypanosomes ◽  
Topoisomerase Poisons ◽  
Type Ia ◽  
Library Screen ◽  
Circular Dnas ◽  
Current Therapies

ABSTRACT Human African trypanosomiasis, caused by the Trypanosoma brucei protozoan parasite, is fatal when left untreated. Current therapies are antiquated, and there is a need for new pharmacologic agents against T. brucei targets that have no human ortholog. Trypanosomes have a single mitochondrion with a unique mitochondrial DNA, known as kinetoplast DNA (kDNA), a topologically complex network that contains thousands of interlocking circular DNAs, termed minicircles (∼1 kb) and maxicircles (∼23 kb). Replication of kDNA depends on topoisomerases, enzymes that catalyze reactions that change DNA topology. T. brucei has an unusual type IA topoisomerase that is dedicated to kDNA metabolism. This enzyme has no ortholog in humans, and RNA interference (RNAi) studies have shown that it is essential for parasite survival, making it an ideal drug target. In a large chemical library screen, two compounds were recently identified as poisons of bacterial topoisomerase IA. We found that these compounds are trypanocidal in the low micromolar range and that they promote the formation of linearized minicircles covalently bound to protein on the 5′ end, consistent with the poisoning of mitochondrial topoisomerase IA. Surprisingly, however, band depletion studies showed that it is topoisomerase IImt, and not topoisomerase IAmt, that is trapped. Both compounds are planar aromatic polycyclic structures that intercalate into and unwind DNA. These findings reinforce the utility of topoisomerase IImt as a target for development of new drugs for African sleeping sickness.

Gelation of the genome by topoisomerase II targeting anticancer agents

Soft Matter ◽  
2013 ◽  
Vol 9 (5) ◽  
pp. 1656-1663 ◽  
Author(s):  
Yun Soo Kim ◽  
Binu Kundukad ◽  
Abdollah Allahverdi ◽  
Lars Nordensköld ◽  
Patrick S. Doyle ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Topoisomerase Ii
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