The Role of the Metabolism of Anticancer Drugs in Their Induced-Cardiotoxicity

Reis-Mendes, Ana; Sousa, Emília; Bastos, Maria de Lourdes; Costa, Vera Marisa

doi:10.2174/1389200216666151103114926

Cited by 37 publications

(49 citation statements)

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“…In bile, about 30% is excreted in form of conjugates, although their structures were not yet elucidated (Crombag et al, 2016). Doxorubicinol (DOXol, 8) (Scheme 2) is formed from DOX (1) by a two-electron reduction of the side chain at C-13 carbonyl group of DOX (1) by nicotinamide adenine dinucleotide phosphate (NADPH)-dependent cytoplasmic aldo/ketoses or carbonyl reductases (Menna et al, 2012, Reis-Mendes et al, 2016b. DOXol (8), an alcohol metabolite of DOX…”

Section: Conventional Cytotoxic Drugsmentioning

confidence: 99%

“…DOXol (8) also inhibits the calcium pump of the heart and skeletal muscle and the proton pump of cardiac mitochondria (Boucek Jr et al, 1987, Olson et al, 1988. DOXol (8) is less effective in killing cancer cells but it is more potent than its parent compound in impairing the myocardial cell (Menna et al, 2012, Reis-Mendes et al, 2016b. When DOX (1) is administered, the concentration of DOXol (8) gradually prevails over that of DOX (1) concentration over time, making DOXol (8) the most toxic species at the time when late stage cardiomyopathy is developed (Menna et al, 2012).…”

Section: Conventional Cytotoxic Drugsmentioning

confidence: 99%

“…A study showed that the aglycones 9, 11, and 14 can be reliably detected and can also significantly contribute to the (cardiac) toxicity of DOX (1) (Joerger et al, 2005). In fact, aglycones are shown to be powerful mitochondrial toxins therefore largely affecting the heart (Reis-Mendes et al, 2016b).…”

Section: Conventional Cytotoxic Drugsmentioning

confidence: 99%

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The importance of drug metabolites synthesis: the case-study of cardiotoxic anticancer drugs

Hrynchak

Sousa

Pinto

et al. 2017

Drug Metabolism Reviews

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Anticancer drugs are presently guarantying more survivors as a result of more powerful drugs or combinations of drugs used in therapy. Thus, it has become more crucial to study and overcome the side effects of these therapies. Cardiotoxicity is one of the most relevant side effects on the long-term cancer survivors, because of its high social and economic impact. Drug metabolism can result in active metabolites or toxic metabolites that can lead to important side effects. The metabolites of anticancer drugs are possible culprits of cardiotoxicity; however, the cardiotoxicity of many of the metabolites in several drug classes was not yet suitably studied so far. On the other hand, the use of prodrugs that are bioactivated through metabolism can be a good alternative to obtain more cardio safe drugs. In this review, the methods to obtain and study metabolites are summarized and their application to the study of a group of anticancer drugs with acknowledged cardiotoxicity is highlighted. In this group of drugs, doxorubicin (DOX, 1), mitoxantrone (MTX, 2), cyclophosphamide (CTX, 3) and 5-fluorouracil (5-FU, 4) are included, as well as the tyrosine kinase inhibitors, such as imatinib (5), sunitinib (6) and sorafenib (7). Only with the synthesis and purification of considerable amounts of the metabolites can reliable studies be performed, either in vitro or in vivo that allow accurate conclusions regarding the cardiotoxicity of anticancer drug metabolites and then pharmacological prevention or treatment of the cardiac side effects can be done.

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Section: Conventional Cytotoxic Drugsmentioning

confidence: 99%

Section: Conventional Cytotoxic Drugsmentioning

confidence: 99%

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The importance of drug metabolites synthesis: the case-study of cardiotoxic anticancer drugs

Hrynchak

Sousa

Pinto

et al. 2017

Drug Metabolism Reviews

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“…Anticancer drugs, however, lack total selectivity, which results in serious side effects (Hrynchak et al ., 2017; Reis-Mendes et al ., 2015). Cardiotoxicity is one of the most worrying side effect found in patients treated with anticancer drugs of several pharmacological groups, like anthracyclines [ e.g .…”

Section: Introductionmentioning

confidence: 99%

“…doxorubicin (DOX)] and anthracenediones [ e.g. mitoxantrone (MTX)] (Hrynchak et al ., 2017; Reis-Mendes et al ., 2015). DOX has been used for almost 50 years, but cardiotoxicity has been a critical and limiting side effect in its clinical use.…”

Section: Introductionmentioning

confidence: 99%

Pixantrone, a new anticancer drug with the same old cardiac problems? An in vitro study with differentiated and non-differentiated H9c2 cells

Reis-Mendes

Alves

Carvalho

et al. 2018

Interdisciplinary Toxicology

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Pixantrone (PIX) is an anticancer drug approved for the treatment of multiple relapsed or refractory aggressive B-cell non-Hodgkin's lymphoma. It is an aza-anthracenedione synthesized to have the same anticancer activity as its predecessors, anthracyclines (e.g. doxorubicin) and anthracenediones (e.g. mitoxantrone), with lower cardiotoxicity. However, published data regarding its possible cardiotoxicity are scarce. Therefore, this work aimed to assess the potential cytotoxicity of PIX, at clinically relevant concentrations (0.1; 1; and 10 μM) in both non-differentiated and 7-day differentiated H9c2 cells. Cells were exposed to PIX for 48 h and cytotoxicity was evaluated through phase contrast microscopy, Hoescht staining and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) reduction and neutral red (NR) uptake assays. Cytotoxicity was observed in differentiated and non-differentiated H9c2 cells, with detached cells and round cells evidenced by phase contrast microscopy, mainly at the highest concentration tested (10 μM). In the Hoechst staining, PIX 10 μM showed a marked decrease in the number of cells when compared to control but with no signs of nuclear condensation. Furthermore, significant concentration-dependent mitochondrial dysfunction was observed through the MTT reduction assay. The NR assay showed similar results to those obtained in the MTT reduction assay in both differentiated and non-differentiated H9c2 cells. The differentiation state of the cells was not crucial to PIX effects, although PIX toxicity was slightly higher in differentiated H9c2 cells. To the best of our knowledge, this was the first in vitro study performed with PIX in H9c2 cells and it discloses worrying cytotoxicity at clinically relevant concentrations.

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Acrolein and Unsaturated Aldehydes

Bein¹,

Leikauf²

2020

Environmental Toxicants

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The Role of the Metabolism of Anticancer Drugs in Their Induced-Cardiotoxicity

Cited by 37 publications

References 0 publications

The importance of drug metabolites synthesis: the case-study of cardiotoxic anticancer drugs

The importance of drug metabolites synthesis: the case-study of cardiotoxic anticancer drugs

Pixantrone, a new anticancer drug with the same old cardiac problems? An in vitro study with differentiated and non-differentiated H9c2 cells

Acrolein and Unsaturated Aldehydes

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