The major adverse effects of the antineoplastic drug doxorubicin (DOX) are acute and chronic cardiotoxicity/cardiomyopathy. DOX use is limited by cumulative, dose-related, progressive myocardial damage that may lead to congestive heart failure (CHF) [Article:12767102]. The cardiotoxicity induced by DOX appears to be a multi-factorial process and many mechanisms have been proposed and studied [Article:15169927]. The mechanisms of the therapeutic effects of DOX are thought to be different from those of the mechanisms of its cardiotoxicity. We describe below two mechanism of cardiotoxicity: oxidative stress placed on cardiac myocytes by free radicals involving DOX and DOX metabolites, processes that involve iron [Articles:15038979, 15038980, 9777314] and the deleterious effects of the drug on mitochondrial bioenergetics [Articles:17652813, 16278810].
DOX, ROS and iron
DOX is metabolized to doxorubicinol (DOXol) and this metabolite has been implicated in cardiotoxicity. The metabolism has been reported to occur via aldo-keto reductase (AKR) 1C3 [Articles:18616992, 18635746], aldehyde reductase (AKR1A1) [Article:12963485], and carbonyl reductases CBR1 [Article:18635746] and CBR3 [Article:20007405]. However, others have reported that AKR1C3 did not metabolize DOX to DOXol [Article:12963485]. DOXol also appears to perturb the iron homeostatic processes that are associated with aconitase- iron regulatory protein-1 (ACO1), possibly causing cardiotoxicity [Article:9576481]. Dexrazoxane, an iron chelator, demonstrated clear cardioprotective properties in clinical studies when administrated before or with DOX [Articles:15038979, 9777314, 9193324, 9193323, 18425895]. In addition, the glycosidic DOX bond can be cleaved to yield 7-deoxydoxorubicinone, again yielding ROS and hydrogen peroxide [Article:15169927]. And DOX itself has also been shown to form a complex with iron that forms radicals [Article:3533644]. In addition to ROS, reactive nitrogen species (RNS) are also implicated in DOX cardiotoxicity [Article:15054088] via the disruption of nitric oxide (NO) regulation. Rodents treated with DOX showed heart dysfunction from the production of peroxynitrite formed from the rapid reaction of nitric oxide (NO) and superoxide (O2-) [Articles:10871338, 12591762], in a mechanism involving nitric oxide synthases (NOS1, NOS2, NOS3) [Articles:10871338, 12591762].
One reason why cardiomyocytes may be more susceptible than other tissues is because the heart, compared to the liver, has a much lower concentration of enzymatic defenses (CAT, SOD1) against free radical attack and sustains a drug-related depression in cardiac glutathione peroxidase activity (another anti-oxidating enzyme) after exposure to doxorubicin [Article:7350193] (rat), [Article:2496064] (rat). DOX has been shown to decrease the protein levels and activity of SOD1 [Article:12030376].
Note that the association of DOX, iron and ROS is not without controversy [Article:19307704]. Since other iron chelators, such as deferasirox, fail to exert the protective effects of dexrazoxane 14642395 an alternative mechanism suggested is via interaction with TOP2B that prevents DOX from inducing DNA damage [Articles:17875725, 19442138].
More recently, it has been suggested that the primary mechanism for cardiotoxicity is mitochondrial dysfunction [Articles:16278810, 17652813], possibly via an interference with calcium homeostasis [Article:17652813] (rat), [Article:12498738] (rat). Mitochondria are abundant in cardiac tissue (up to 35% of the cell volume), relying upon ATP to sustain contractile function, and interference with this function is likely to cause the cardio-selective toxicity [Article:17652813]. DOX and other anthracyclines have been shown to be reduced to the semiquinone form at Complex I of the mitochondrial electron transport chain and to form free radicals [Articles:3005279, 3456345]. DOX aglycones have been shown to accumulate in the inner mitochondrial membrane where they interfered with electron carriers of the respiratory chain and can cause release of cytochrome c (CYCS) [Article:12894526] and DOX aglycone semiquinones emerging from an interaction with complex I of the mitochondria were found to form hydroxyl radicals causing oxidative stress [Article:9618942]. 5-Iminodaunorubicin, a structurally related analog that is has diminished cardiotoxicity, does not liberate oxygen free radicals and has no effect on mitochondrial respiration [Articles:3005279, 3456345]. Furthermore, DOX has been shown to inhibit the net accumulation of calcium by isolated cardiac mitochondria in in vivo rat studies [Article:7527602]. DOXol, the DOX metabolite, has been shown to interfere with the calcium pump of sarcoplasmic reticulum (ATP2A2) the Na+ /K+ pump of sarcolemma (RYR2) and the F0F1, proton pump of mitochondria (EC 220.127.116.11) [Articles:2897122, 19442138].
Historically, only cumulative anthracycline dose has been confirmed as a significant risk factor for DOX-induced cardiotoxicity [Article:6651020]. Variants in ABCC1 (rs45511401), ABCC2 (rs8187694, rs8187710), CAT (rs10836235), CBR3 (rs1056892), CYBA (rs4673), NCF4 (rs1883112) and RAC2 (rs13058338) have been associated with cardiotoxicity in vivo [Articles:16330681, 19448608, 18457324, 19863340].
Wojnowski et al, in a study of SNPs from 82 genes from 1697 patients, 3.2% of whom developed either acute or chronic DOX-induced cardiotoxicity, found 5 significant associations between cardiotoxicity and polymorphisms of the NAD(P)H oxidase complex (CYBA, NCF4 and RAC2), as well as DOX transporters [Article:16330681]. Consistent with this, mice deficient in NAD(P)H oxidase activity, unlike wild-type mice, were resistant to chronic doxorubicin treatment [Article:16330681]. A recent study by Rossi et al in lymphoma patients treated with DOX-containing chemotherapy showed an association of CYBA (rs4673) and NCF4 (rs1883112) with toxicity [Article:19448608].
Blanco et al, suggested the CBR3 Val244Met polymorphism (rs1056892) may have an impact on the risk of anthracycline-related CHF among childhood cancer survivors, although acknowledged that a larger study is needed [Article:18457324]. This variant was also associated with higher doxorubicinol AUC and higher CBR3 expression in tumor tissue from Asian breast cancer patients [Article:18551042]. However, the in vitro studies of this variant are somewhat conflicting with some showing decreased activity of variant protein with DOX as a substrate [Articles:18457324, 20007405] and others showing increased activity using menadione as a substrate [Article:15537833].
Other studies have examined a variety of variants and phenotypes both in vivo and in vitro, see Genetics Tab for further details. The majority of DOX PGx studies still need to be validated.
Thorn Caroline F, Oshiro Connie, Marsh Sharon, Hernandez-Boussard Tina, McLeod Howard, Klein Teri E, Altman Russ B. "Doxorubicin pathways: pharmacodynamics and adverse effects" Pharmacogenetics and genomics (2010).
If you would like to reproduce this PharmGKB pathway diagram:
Entities in the Pathway
Drugs/Drug Classes (2)
Relationships in the Pathway
|Arrow From||Arrow To||Controllers||PMID|
|ATP5A1, ATP5B, ATP5C1, ATP5C1P1, ATP5D, ATP5E, ATP5F1, ATP5H, ATP5I||ATP5A1, ATP5B, ATP5C1, ATP5C1P1, ATP5D, ATP5E, ATP5F1, ATP5H, ATP5I||doxorubicinol||19442138, 2897122|
|doxorubicin||7-deoxy-doxorubicinone, reactive oxygen species||15169927|
|doxorubicin||doxorubicinol||AKR1A1, AKR1C3, CBR1, CBR3||12963485, 18616992, 18635746, 20007405|
|doxorubicin||reactive nitrogen species||NOS1, NOS2, NOS3||10871338, 12591762, 15054088|
|doxorubicin||reactive oxygen species||CYBA, NCF4, RAC2||16278810, 16330681, 17652813|
|doxorubicin-Iron (II) complex ()||doxorubicin-Iron (II) complex ()||dexrazoxane||15038979, 18425895, 9193323, 9193324, 9777314|
|doxorubicin||doxorubicin-Iron (II) complex ()||3533644|
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