The use of doxorubicin (Adriamycin), a widely used antineoplastic drug effective against several types of cancer, is limited by its cardiac toxicity, particularly in patients with concurrent risk factors for heart disease, including metabolic syndrome (MetS).Ogonowski et al report that a single moderate dose of doxorubicin produced significant cardiac toxicity in a rat dietary fructose model of MetS compared to rats on a standard diet.1 Before the administration of doxorubicin, the fructose-fed rats had hypertension, significantly elevated plasma triglycerides, and increased indices of lipid peroxidation and oxidative stress, but lower P-glycoprotein, expression and superoxide dismutase activity in their hearts. The fructose-fed rats were not obese, nor did they have significant hyperglycemia or echocardiographic evidence of cardiac dysfunction. However 3 days after doxorubicin treatment, ejection fraction and fractional shortening were significantly decreased only in the MetS rats and cardiac lipid peroxidation was further increased.1 Although the definition of MetS varies, hypertension, dyslipidemia, and increased inflammation and oxidative stress observed in these fructose-fed rats are criteria common to all.2 The relevance of this study is augmented by the use of a moderate model of MetS and dose of doxorubicin reflective of many patients who develop cardiotoxicity despite being relatively healthy before initiating doxorubicin treatment.
P-glycoprotein, also called multiple drug-resistant protein1 and ATP-binding cassette (ABC) transporter 1, is responsible for the active transport of endogenous and exogenous compounds, including doxorubicin, out of cells. P-glycoprotein measured by western blot was decreased by 30% in the hearts of the fructose-fed rat before challenge with doxorubicin and was not altered after its administration (Ogonowski et al). The effect of inflammation on the expression of P-glycoprotein or its gene, ABCB1 (multiple drug resistant protein1), depends on the cell type.3,4 It is suppressed in hepatocytes and vascular and intestinal endothelial cells forming barriers of the brain and gut, yet increased in renal tubules. In a mouse model of lipopolysaccharide inflammation, the excretion of doxorubicin was decreased in the bile, but increased in the urine.5
The cardiotoxicity of doxorubicin is attributed primarily to its main metabolite doxorubicinol, which is ineffective as an antineoplastic agent. As circulating doxorubicinol does not cross the vascular endothelial barrier, its accumulation and toxicity in cardiomyocytes depends on enzymatic formation from doxorubicin within the heart.6 The short-chain alcohol dehydrogenases 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) and carbonyl reductase1 are the primary enzymes responsible for catalyzing the formation of doxorubicinol from doxorubicin.7 Although most often associated with the reduction of the inactive steroids cortisone and 11-dehydrocorticosterone to the endogenous glucocorticoids cortisol and corticosterone, 11βHSD1 is an important reductase of diverse carbonyl-bearing xenobiotics, including doxorubicin,7 for entry into phase 1 biotransformation.8 11βHSD1 is expressed in many cells including cardiomyocytes, in addition to hepatocytes and the endothelial cells of barrier tissues such as the gut and vessels.9
Expression of 11β-HSD1 is increased in a variety of inflammatory conditions from arthritis to dementia, including MetS.9 Inflammatory cytokines promote TNF-α induced 11βHSD1 transcription, thus increasing activation of endogenous glucocorticoids that activate glucocorticoid receptor, a nuclear transcription factor that modulates diverse anti-inflammatory responses, including the transcription of 11βHSD1.9 Tissue inflammation associated with MetS targets the heart, vessels, and fat in particular; accordingly, 11βHSD1 is significantly increased in the heart in patients and animals with MetS.10,11 The same Th1 cell-associated inflammatory cytokines that increase the expression of 11βHSD1 also suppress P-glycoprotein expression and action.12 Tissue levels of doxorubicin or doxorubicinol were not measured for the Ogonowski study; nor was 11βHSD1. Notwithstanding, the authors' premise that the decrease in P-glycoprotein in the heart allowed more doxorubicin to enter the heart, is likely to be correct. Similarly, 11βHSD1 is expressed in the heart and increases in MetS;10,11 thus, it is likely that the conversion of doxorubicin to doxorubicinol was greater in the rats with MetS rats, resulting in increased toxicity.
The use of selective inhibitors of carbonyl reductase1 and 11βHSD1 with doxorubicin to improve its therapeutic index has been suggested.7 Although selective inhibitors of 11βHSD1 exist, targeting enzymes with such wide substrate and tissue distributions and essential functions has been problematic. Despite promising preclinical studies, results of multiple clinical trials of the efficacy of selective inhibitors of 11βHSD1 in the treatment of a variety of conditions associated with chronic inflammation, including MetS, have been equivocal.13 However, these trials were for the treatment of chronic conditions and focused on reducing the impact of inappropriate glucocorticoid-mediated pathology, perhaps without adequate consideration of the many other 11βHSD1 substrates.9 Acute use of a selective 11βHSD1 inhibitor concurrent with doxorubicin treatment would decrease doxorubicin inactivation in the liver, thereby reducing the total dose required for treatment,7 and decrease its conversion to doxorubicinol within the heart, thus the cardiotoxicity seen more often in patients with underlying inflammatory conditions such as MetS.
1. Ogonowski N, Rukavina M, Lucia N, et al. Cardiotoxic effects of the antineoplastic doxorubicin in a model of metabolic syndrome: oxidative stress and transporters expression in the heart. J Cardiovasc Pharmacol. 2021 doi: 10.1097/FJC.0000000000001137.
2. Stekkinger E, Scholten RR, Heidema WM, et al. Comparison of three definitions of metabolic syndrome and relation to risk of recurrent preeclampsia. Hypertens Pregnancy. 2021;40:97–108.
3. Liu J, Zhou F, Chen Q, et al. Chronic inflammation up-regulates P-glycoprotein in peripheral mononuclear blood cells via the STAT3/Nf-kappab pathway in 2,4,6-trinitrobenzene sulfonic acid-induced colitis mice. Scientific Rep. 2015;5:13558.
4. Teng S, Piquette-Miller M. Regulation of transporters by nuclear hormone receptors: implications during inflammation. Mol Pharm. 2008;5:67–76.
5. Hartmann G, Vassileva V, Piquette-Miller M. Impact of endotoxin-induced changes in P-glycoprotein expression on disposition of doxorubicin in mice. Drug Metab Dispos. 2005;33:820–828.
6. Zeng X, Cai H, Yang J, et al. Pharmacokinetics and cardiotoxicity of doxorubicin and its secondary alcohol metabolite in rats. Biomed Pharmacother. 2019;116:108964.
7. Yang X, Hua W, Ryu S, et al. 11beta-Hydroxysteroid dehydrogenase 1 human tissue distribution, selective inhibitor, and role in doxorubicin metabolism. Drug Metab Dispos. 2018;46:1023–1029.
8. Odermatt A, Klusonova P. 11beta-Hydroxysteroid dehydrogenase 1: regeneration of active glucocorticoids is only part of the story. J Steroid Biochem Mol Biol. 2015;151:85–92.
9. Gomez-Sanchez EP, Gomez-Sanchez CE. 11beta-hydroxysteroid dehydrogenases: a growing multi-tasking family. Mol Cell Endocrinol. 2021;526:111210.
10. Frey FJ, Odermatt A, Frey BM. Glucocorticoid-mediated mineralocorticoid receptor activation and hypertension. Curr Opin Nephrol Hypertens. 2004;13:451–458.
11. Takeshita Y, Watanabe S, Hattori T, et al. Blockade of glucocorticoid receptors with RU486 attenuates cardiac damage and adipose tissue inflammation in a rat model of metabolic syndrome. Hypertens Res. 2015;38:741–750.
12. Fernandez C, Buyse M, German-Fattal M, et al. Influence of the pro-inflammatory cytokines on P-glycoprotein expression and functionality. J Pharm Pharm Sci. 2004;7:359–371.
13. Gregory S, Hill D, Grey B, et al. 11beta-hydroxysteroid dehydrogenase type 1 inhibitor use in human disease-a systematic review and narrative synthesis. Metab Clin Exp. 2020;108:154246.