Paclitaxel and Docetaxel Stimulation of Doxorubicinol Formation in the Human Heart: Implications for Cardiotoxicity of Doxorubicin-Taxane Chemotherapies

Abstract

Antitumor therapy with the anthracycline doxorubicin is limited by a dose-related cardiotoxicity that is aggravated by a concomitant administration of the taxane paclitaxel. Previous limited studies with isolated human heart cytosol showed that paclitaxel was able to stimulate an NADPH-dependent reduction of doxorubicin to its toxic secondary alcohol metabolite doxorubicinol. Here we characterized that 0.25 to 2.5 M paclitaxel caused allosteric effects that increased doxorubicinol formation in human heart cytosol, whereas 5 to 10 M paclitaxel decreased doxorubicinol formation. The closely related taxane docetaxel caused similar effects. Basal or taxane-stimulated doxorubicinol formation was blunted by 2,7-difluorospirofluorene-9,5Ј-imidazolidine-2Ј,4Ј-dione (AL1576), a specific inhibitor of aldehyde reductases. Doxorubicinol was measured also in the cytosol of human myocardial strips incubated in plasma and exposed to doxorubicin in the absence or presence of paclitaxel or docetaxel and their clinical vehicles Cremophor EL or polysorbate 80. Low concentrations of taxanes stimulated doxorubicinol formation, whereas high concentrations decreased it. Doxorubicinol formation reached its maximum on adding plasma with 6 M paclitaxel or docetaxel; this corresponded to the partitioning of 1.5 to 2.5 M taxanes in the cytosol of the strips. Taxane-stimulated doxorubicinol formation was not mediated by vehicles, nor was it caused by increased doxorubicin uptake or de novo protein synthesis; however, doxorubicinol formation was blunted by AL1576. These results show that allosteric interactions with cytoplasmic aldehyde reductases enable paclitaxel or docetaxel to stimulate doxorubicinol formation in human heart. This information serves metabolic insights into the risk of cardiotoxicity induced by doxorubicin-taxane therapies.The anthracycline doxorubicin and the taxane paclitaxel are both highly active in breast cancer. Doxorubicin and paclitaxel exhibit different mechanisms of action (DNA intercalation and topoisomerase II inhibition versus microtubule stabilization), nonoverlapping toxicities (cardiomyopathy versus neuropathy), and incomplete cross-resistance;

Long-term Cardiovascular Toxicity in Children, Adolescents, and Young Adults Who Receive Cancer Therapy: Pathophysiology, Course, Monitoring, Management, Prevention, and Research Directions

“…• Introduction of extended-field high-dose (35)(36)(37)(38)(39)(40)(41)(42)(43)(44) The types of chemotherapy-induced cardiovascular alterations reported primarily, but not exclusively, in adults include the following: Acute cardiac rhythm abnormalities (arrhythmias including QT prolongation), myocardial ischemia or infarction, hypertension, and significant left ventricular (LV) contractile dysfunction. 37,38 The pathogenesis of these diverse cardiovascular effects varies and may involve multiple mechanisms.…”

CBR1 and CBR3 pharmacogenetics and their influence on doxorubicin disposition in Asian breast cancer patients

“…(37) Taxanes, such as paclitaxel, have been shown to increase the intracellular conversion of doxorubicin to doxorubicinol by binding to the regulatory allosteric and catalytic sites of CBR enzymes, thereby influencing the efficacy and toxicity of combination chemotherapy regimens. (38) CBR-mediated intracellular conversion of doxorubicin to doxorubicinol has also been proposed to be important in the development of anthracycline cardiotoxicity. (39) In vitro studies have shown a higher potency of doxorubicinol than doxorubicin in depressing myocardial contractility and inhibiting ion channel pumps, (40) whereas studies on transgenic mice overexpressing CBR1 in the heart showed higher intracardiac levels of doxorubicinol and increased signs of myocardial damage after doxorubicin administration.…”

2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines

“…Taksany zmniejszają eliminację doksorubicyny, co powoduje wzrost jej stężenia w osoczu [274], a także sprzyjają jej metabolizmowi w mięśniu sercowym do bardziej toksycznych metabolitów [275]. Paklitaksel stosowany w połączeniu z antracyklinami zwiększa ich kardiotoksyczność [276].…”