Spontaneous neoplasm metastasis, a fatalist pathological feature of cancer, is a long-evolving, multi-steps process that can now only be treated or controlled by drugs or immuno-modulators. As we have previously hypothesized, each drug or immuno-modulator might act differently within various stages of a metastasis. Therefore any researches helping to determine these differences will be beneficial for updating therapeutics for metastasis. In this work, we have testified this hypothesis by using a series of well-known anti-metastatic agents â Bisdioxopiperazine compounds.
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http://dx.doi.org/10.3797/scipharm.0910-16 | DOI Listing |
Cardiovasc Hematol Agents Med Chem
January 2023
Center for Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector- 62, Noida 201307, Uttar Pradesh, India.
Chemotherapy-induced cardiotoxicity is an increasing concern and it is critical to avoid heart dysfunction induced by medications used in various cancers. Dysregulated cardiomyocyte homeostasis is a critical phenomenon of drug-induced cardiotoxicity, which hinders the cardiac tissue's natural physiological function. Drug-induced cardiotoxicity is responsible for various heart disorders such as myocardial infarction, myocardial hypertrophy, and arrhythmia, among others.
View Article and Find Full Text PDFClin Sci (Lond)
August 2021
Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic.
The anthracycline (ANT) anticancer drugs such as doxorubicin or daunorubicin (DAU) can cause serious myocardial injury and chronic cardiac dysfunction in cancer survivors. A bisdioxopiperazine agent dexrazoxane (DEX) has been developed as a cardioprotective drug to prevent these adverse events, but it is uncertain whether it is the best representative of the class. The present study used a rabbit model of chronic ANT cardiotoxicity to examine another bisdioxopiperazine compound called GK-667 (meso-(butane-2,3-diylbis(2,6-dioxopiperazine-4,1-diyl))bis(methylene)-bis(2-aminoacetate) hydrochloride), a water-soluble prodrug of ICRF-193 (meso-4,4'-(butan-2,3-diyl)bis(piperazine-2,6-dione)), as a potential cardioprotectant.
View Article and Find Full Text PDFJ Med Chem
April 2021
Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 50005 Hradec Králové, Czech Republic.
Cardioprotective activity of dexrazoxane (ICRF-187), the only clinically approved drug against anthracycline-induced cardiotoxicity, has traditionally been attributed to its iron-chelating metabolite. However, recent experimental evidence suggested that the inhibition and/or depletion of topoisomerase IIβ (TOP2B) by dexrazoxane could be cardioprotective. Hence, we evaluated a series of dexrazoxane analogues and found that their cardioprotective activity strongly correlated with their interaction with TOP2B in cardiomyocytes, but was independent of their iron chelation ability.
View Article and Find Full Text PDFToxicol Appl Pharmacol
July 2020
College of Pharmacy, Apotex Centre, University of Manitoba, Winnipeg, Manitoba R3E 0T5, Canada.
The cardiotoxicity caused by doxorubicin and extravasation injury caused by anthracyclines is reduced by the clinically approved bisdioxopiperazine drug dexrazoxane. Dexrazoxane is a rings-closed analog of EDTA and is hydrolyzed in vivo to a form that strongly binds iron. Its protective effects were originally thought to be due to the ability of its metabolite to remove iron from the iron-doxorubicin complex, thereby preventing oxygen radical damage to cellular components.
View Article and Find Full Text PDFJ Pharmacol Exp Ther
June 2020
Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
Bisdioxopiperazine agent dexrazoxane (ICRF-187) has been the only effective and approved drug for prevention of chronic anthracycline cardiotoxicity. However, the structure-activity relationships (SARs) of its cardioprotective effects remain obscure owing to limited investigation of its derivatives/analogs and uncertainties about its mechanism of action. To fill these knowledge gaps, we tested the hypothesis that dexrazoxane derivatives exert cardioprotection via metal chelation and/or modulation of topoisomerase II (Top2B) activity in chronic anthracycline cardiotoxicity.
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