title: 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 microM paclitaxel caused allosteric effects that increased doxorubicinol formation in human heart cytosol, whereas 5 to 10 microM paclitaxel decreased doxorubicinol formation. The closely related taxane docetaxel caused similar effects. Basal or taxane-stimulated doxorubicinol formation was blunted by 2,7-difluorospirofluorene-9,5'-imidazolidine-2',4'-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 microM paclitaxel or docetaxel; this corresponded to the partitioning of 1.5 to 2.5 microM 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.
authors.affiliation: Department of Drug Sciences and Center of Excellence on Aging, G. d'Annunzio University School of Medicine, Via dei Vestini, 66013 Chieti, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Salvatorelli
authors.forename: Pierantonio
authors.initials: P
authors.lastname: Menna
authors.forename: Sabrina
authors.initials: S
authors.lastname: Cascegna
authors.forename: Giovanni
authors.initials: G
authors.lastname: Liberi
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Calafiore
authors.forename: Luca
authors.initials: L
authors.lastname: Gianni
authors.forename: Giorgio
authors.initials: G
authors.lastname: Minotti
mesh_terms: D000368:Aged; D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000970:Antineoplastic Agents / Q000378:metabolism / Q000633:toxicity; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D017239:Paclitaxel / Q000378:metabolism / Q000633:toxicity*; D043823:Taxoids / Q000378:metabolism / Q000633:toxicity*
chemical_list: D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D004317:Doxorubicin; C010013:adriamycinol; D017239:Paclitaxel