Emanuela Salvatorelli

LIUCBM Libera Università Campus Bio-Medico di Roma, Roma, Latium, Italy

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Publications (33)139.52 Total impact

  • Journal of Viral Hepatitis 06/2014; · 3.08 Impact Factor
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    ABSTRACT: Whether tumor necrosis factor-alpha (TNFα) caused beneficial or detrimental cardiovascular effects remains poorly defined. Anti-TNFα agents improved cardiac end points in chronic rheumatic diseases characterized by progressive deterioration of cardiac function. In contrast, anti-TNFα agents did not always improve but actually worsened cardiac function in non-rheumatic patients with heart failure (HF), in spite of that HF usually accompanies with high circulating levels of TNFα. To shed light on these mixed findings, we characterized the effects of TNFα in H9c2 cardiomyocytes. Cells were incubated for 24 h with increasing concentrations of TNFα, hydrogen peroxide, aminotriazole, or etoposide. Posttreatment cell viability was assessed by antimycin A-inhibitable reduction of 3-(4,dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, and the IC50 value of each test compound was defined. H9c2 cells were also preconditioned with a low non-toxic concentration of TNFα and then re-challenged with increasing concentrations of TNFα and other stressor agents. In re-challenge experiments, all of the IC50 values increased significantly, with the IC50 value of TNFα increasing approximately 16-fold. TNFα preconditioning increased cardiomyocytes shedding of the external portion of transmembrane type 1 and type 2 TNFα receptors [(soluble TNFα receptors (sTNFR)]. Levels of survival-oriented soluble TNFR2 (sTNFR2) always exceeded those of death-oriented sTNFR1. When exposed to TNFα at its IC50 value, preconditioned cardiomyocytes showed an increased release of sTNFR2 but not sTNFR1. These results denoted that preconditioning by "low TNFα" helped cardiomyocyte to withstand toxicity from "high TNFα" or other agents. These results also suggested that beneficial or detrimental effects of anti-TNFα agents might well depend on whether these agents spared or intercepted discrete amounts of TNFα that preconditioned cardiomyocytes and made them more resistant to high concentrations of TNFα.
    Cardiovascular toxicology 05/2014; · 2.56 Impact Factor
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    ABSTRACT: Preclinical mechanisms and clinical correlates of cardiotoxicity are pillars of contemporary Cardio-Oncology. The first session of the International Colloquium on Cardio-Oncology (Rome, March 12-14, 2014) asked a provocative question, what is cardiotoxicity? Here we introduce and comment on what the speakers said at that session and discuss in details in separate articles. In summarizing the strengths and weaknesses of preclinical models and of clinical definitions of cardiotoxicity, we join the experts in concluding that a universal and clinically-integrated definition of cardiotoxicity is in fact lacking. After many years of inquisitive efforts, molecular paths to “cardiotoxicity” remain inadequately characterized. Old generation chemotherapeutics, like anthracyclines, are intuitively different from newer classes of drugs like small-molecule kinase inhibitors. In both cases, however, reported mechanisms of cardiotoxicity need to be put in a wider context that accommodates genetic predisposition or individual modifiable risk factors. In clinical settings, available imaging or biomarkers of cardiotoxicity do not always correlate with patients’ cardiac outcome and need to be validated in properly designed studies. Making clinical decisions to change treatment based on one or another biomarker may cause erroneous initiatives that place patients at risk of undertreating the cancer and poor oncologic efficacy. New pragmatic approaches, as exemplified by the concept of actionable cardiotoxicity, should be built on risk:benefit ratio and on balancing oncologic efficacy with cardiac outcomes. Yet, answering the question “what is cardiotoxicity?” remains problematic.
    Progress in Pediatric Cardiology 01/2014;
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    ABSTRACT: Cardiotoxicity from the antitumor anthracycline, doxorubicin, correlates with doxorubicin cardiac levels, redox activation to superoxide anion (O(2)(._)) and hydrogen peroxide (H(2)O(2)), formation of the long-lived secondary alcohol metabolite, doxorubicinol. Cardiotoxicity may first manifest during salvage therapy with other drugs, such as the anthracenedione mitoxantrone. Minimal evidence for cardiotoxicity in anthracycline-pretreated patients with refractory-relapsed non Hodgkin's lymphoma was observed with the novel anthracenedione, pixantrone. We characterized whether pixantrone and mitoxantrone caused different effects on doxorubicin levels, redox activation, doxorubicinol formation. Pixantrone and mitoxantrone were probed in a validated ex vivo human myocardial strip model that was either doxorubicin-naïve or preliminarily subjected to doxorubicin loading and washouts to mimic doxorubicin treatment and elimination in the clinical setting. In doxorubicin-naive strips, pixantrone showed higher uptake than mitoxantrone; however, neither drug formed O(2)(._) or H(2)O(2). In doxorubicin-pretreated strips, pixantrone or mitoxantrone did not alter the distribution and clearance of residual doxorubicin. Mitoxantrone showed an unchanged uptake, lacked effects on doxorubicin levels, but synergized with doxorubicin to form more O(2)(._) and H(2)O(2), as evidenced by O(2)(._) -dependent inactivation of mitochondrial aconitase or mitoxantrone oxidation by H(2)O(2) -activated peroxidases. In contrast, pixantrone uptake was reduced by prior doxorubicin exposure; moreover, pixantrone lacked redox synergism with doxorubicin, and formed an N-dealkylated product that inhibited metabolism of residual doxorubicin to doxorubicinol. Redox inactivity and inhibition of doxorubicinol formation correlate with the cardiac safety of pixantrone in doxorubicin-pretreated patients. Redox inactivity in the face of high cardiac uptake suggests that pixantrone might be safe also in doxorubicin-naive patients.
    Journal of Pharmacology and Experimental Therapeutics 11/2012; · 3.89 Impact Factor
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    ABSTRACT: The pharmacokinetics of pegylated liposomal doxorubicin (PLD) were investigated in seventeen women undergoing intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) for advanced ovarian cancer and peritoneal carcinomatosis. HIPEC was performed immediately after completing debulking surgery, which included a number of peritonectomy procedures. PLD was injected and allowed to equilibrate in peritoneal cavity filled with 4 liters of physiologic solution and stabilized at 42 °C; next, the outflow line was opened and perfusion proceeded for 1h. PLD was stable in peritoneal perfusate and plasma. During HIPEC, PLD peritoneal perfusate:plasma gradients averaged ≈600 or ≥1000 for C(max) or AUC. After HIPEC, PLD plasma levels remained stable or decreased. Biopsies of residual normal peritoneum or ovarian carcinomatosis were collected at the end of HIPEC and were shown to contain free doxorubicin. Correlating PLD decrements in peritoneal perfusate with plasma exposure to PLD or peritoneal deposition of free doxorubicin, showed that the former occurred during preperfusional equilibration of PLD in peritoneal cavity, while the latter occurred during 1h perfusion. Plasma exposure to PLD correlated negatively with the number of peritonectomy procedures performed during surgery, while peritoneal deposition of free doxorubicin correlated positively. Collectively, these results show that PLD administered by intraoperative HIPEC undergoes limited systemic diffusion and releases active free doxorubicin in peritoneum exposed to ovarian carcinomatosis. PLD pharmacokinetics seem to be influenced by peritonectomy procedures.
    Drug metabolism and disposition: the biological fate of chemicals 09/2012; · 3.74 Impact Factor
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    ABSTRACT: Antitumor anthracyclines such as doxorubicin and epirubicin are known to cause cardiotoxicity that correlates with anthracycline accumulation in the heart. The anthracycline amrubicin [(7S,9S)-9-acetyl-9-amino-7-[(2-deoxy-β-d-erythro-pentopyranosyl)oxy]-7,8,9,10-tetrahydro-6,11-dihydroxy-5,12-napthacenedione hydrochloride] has not shown cardiotoxicity in laboratory animals or patients in approved or investigational settings; therefore, we conducted preclinical work to characterize whether amrubicin attained lower levels than doxorubicin or epirubicin in the heart. Anthracyclines were evaluated in ex vivo human myocardial strips incubated in plasma to which anthracycline concentrations of 3 or 10 μM were added. Four-hour incubations were performed to characterize myocardial anthracycline accumulation derived from anthracycline uptake in equilibrium with anthracycline clearance. Short-term incubations followed by multiple washouts were performed to obtain independent measurements of anthracycline uptake or clearance. In comparison with doxorubicin or epirubicin, amrubicin attained very low levels in the soluble and membrane fractions of human myocardial strips. This occurred at both 3 and 10 μM anthracycline concentrations and was caused primarily by a highly favorable clearance of amrubicin. Amrubicin clearance was facilitated by formation and elimination of sizeable levels of 9-deaminoamrubicin and 9-deaminoamrubicinol. Amrubicin clearance was not mediated by P glycoprotein or other drug efflux pumps, as judged from the lack of effect of verapamil on the partitioning of amrubicin and its deaminated metabolites across myocardial strips and plasma. Limited accumulation of amrubicin in an ex vivo human myocardial strip model may therefore correlate with the improved cardiac tolerability observed with the use of amrubicin in preclinical or clinical settings.
    Journal of Pharmacology and Experimental Therapeutics 02/2012; 341(2):464-73. · 3.89 Impact Factor
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    ABSTRACT: Anthracycline-related cardiotoxicity correlates with cardiac anthracycline accumulation and bioactivation to secondary alcohol metabolites or reactive oxygen species (ROS), such as superoxide anion (O₂·⁻) and hydrogen peroxide H₂O₂). We reported that in an ex vivo human myocardial strip model, 3 or 10 μM amrubicin [(7S,9S)-9-acetyl-9-amino-7-[(2-deoxy-β-D-erythro-pentopyranosyl)oxy]-7,8,9,10-tetrahydro-6,11-dihydroxy-5,12-napthacenedione hydrochloride] accumulated to a lower level compared with equimolar doxorubicin or epirubicin (J Pharmacol Exp Ther 341:464-473, 2012). We have characterized how amrubicin converted to ROS or secondary alcohol metabolite in comparison with doxorubicin (that formed both toxic species) or epirubicin (that lacked ROS formation and showed an impaired conversion to alcohol metabolite). Amrubicin and doxorubicin partitioned to mitochondria and caused similar elevations of H₂O₂, but the mechanisms of H₂O₂ formation were different. Amrubicin produced H₂O₂ by enzymatic reduction-oxidation of its quinone moiety, whereas doxorubicin acted by inducing mitochondrial uncoupling. Moreover, mitochondrial aconitase assays showed that 3 μM amrubicin caused an O₂·⁻-dependent reversible inactivation, whereas doxorubicin always caused an irreversible inactivation. Low concentrations of amrubicin therefore proved similar to epirubicin in sparing mitochondrial aconitase from irreversible inactivation. The soluble fraction of human myocardial strips converted doxorubicin and epirubicin to secondary alcohol metabolites that irreversibly inactivated cytoplasmic aconitase; in contrast, strips exposed to amrubicin failed to generate its secondary alcohol metabolite, amrubicinol, and only occasionally exhibited an irreversible inactivation of cytoplasmic aconitase. This was caused by competing pathways that favored formation and complete or near-to-complete elimination of 9-deaminoamrubicinol. These results characterize amrubicin metabolic advantages over doxorubicin and epirubicin, which may correlate with amrubicin cardiac safety in preclinical or clinical settings.
    Journal of Pharmacology and Experimental Therapeutics 02/2012; 341(2):474-83. · 3.89 Impact Factor
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    ABSTRACT: INTRODUCTION: Anthracyclines are widely prescribed anticancer agents that cause a dose-related cardiotoxicity, often aggravated by nonanthracycline chemotherapeutics or new generation targeted drugs. Anthracycline cardiotoxicity may occur anytime in the life of cancer survivors. Understanding the molecular mechanisms and clinical correlates of cardiotoxicity is necessary to improve the therapeutic index of anthracyclines or to identify active, but less cardiotoxic analogs. AREAS COVERED: The authors review the pharmacokinetic, pharmacodynamic and biochemical mechanisms of anthracycline cardiotoxicity and correlate them to clinical phenotypes of cardiac dysfunction. Attention is paid to bioactivation mechanisms that converted anthracyclines to reactive oxygen species (ROS) or long-lived secondary alcohol metabolites. Preclinical aspects and clinical implications of the "oxidative stress" or "secondary alcohol metabolite" hypotheses are discussed on the basis of literature that cuts across bench and evidence-based medicine. Interactions of anthracyclines with comorbidities or unfavorable lifestyle choices were identified as important cofactors of the lifetime risk of cardiotoxicity and as possible targets of preventative strategies. EXPERT OPINION: Anthracycline cardiotoxicity is a multifactorial process that needs to be incorporated in a translational framework, where individual genetic background, comorbidities, lifestyles and other drugs play an equally important role. Fears for cardiotoxicity should not discourage from using anthracyclines in many oncologic settings. Cardioprotective strategies are available and should be used more pragmatically in routine clinical practice.
    Expert Opinion on Drug Safety 06/2011; 11 Suppl 1:S21-36. · 2.74 Impact Factor
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    ABSTRACT: Tumor necrosis factor alpha (TNFa) plays a central role in the pathogenesis of both rheumatoid arthritis (RA) and heart failure (HF). Over the last years RA could benefit from TNFa inhibitors that mitigated disease activity, decreased structural damage, and prevented cardiovascular events. Contraindications to clinical use of TNFa inhibitors may include infections, autoimmune disorders, demyelinating disease, cancer, and heart failure. Overall, these pathological conditions do not appear to increase significantly during treatment with TNFa antagonists compared to placebo. Clinical trials probed these drugs in non RA HF patients produced disappointing results and formed the basis to contraindicate TNFa inhibitors in patients with moderate-severe HF. Although National Registries provide apparently encouraging data about HF safety of anti-TNFa therapies, they cannot adequately assess the actual risk, as these drugs are administered to patients with no cardiac dysfunction. These findings introduced a "rheumatological dilemma" in the clinical management of RA with anti-TNFa. Probably, in RA patients anti-TNFa agents would intercept TNFa and prevent its toxic effects on heart function, while in patients with advanced heart damage (NYHA class III-IV HF), anti-TNFa agents would interfere with the beneficial preconditioning effects of TNFa.
    Autoimmunity reviews 04/2011; 10(10):631-5. · 6.37 Impact Factor
  • Molecular Interventions 04/2011; 11(2):79-87. · 4.59 Impact Factor
  • Cardiotoxicity of Non-Cardiovascular Drugs, 04/2010: pages 223 - 256; , ISBN: 9780470660379
  • Giorgio Minotti, Emanuela Salvatorelli, Pierantonio Menna
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    ABSTRACT: Anthracyclines and many other antitumor drugs induce cardiotoxicity that occurs "on treatment" or long after completing chemotherapy. Dose reductions limit the incidence of early cardiac events but not that of delayed sequelae, possibly indicating that any dose level of antitumor drugs would prime the heart to damage from sequential stressors. Drugs targeted at tumor-specific moieties raised hope for improving the cardiovascular safety of antitumor therapies; unfortunately, however, many such drugs proved unable to spare the heart, aggravated cardiotoxicity induced by anthracyclines, or were safe in selected patients of clinical trials but not in the general population. Cardio-oncology is the discipline aimed at monitoring the cardiovascular safety of antitumor therapies. Although popularly perceived as a clinical discipline that brings oncologists and cardiologists working together, cardio-oncology is in fact a pharmacology-oriented translational discipline. The cardiovascular performance of survivors of cancer will only improve if clinicians joined pharmacologists in the search for new predictive models of cardiotoxicity or mechanistic approaches to explain how a given drug might switch from causing systolic failure to inducing ischemia. The lifetime risk of cardiotoxicity from antitumor drugs needs to be reconciled with the identification of long-lasting pharmacological signatures that overlap with comorbidities. Research on targeted drugs should be reshaped to appreciate that the terminal ballistics of new "magic bullets" might involve cardiomyocytes as innocent bystanders. Finally, the concepts of prevention and treatment need to be tailored to the notion that late-onset cardiotoxicity builds on early asymptomatic cardiotoxicity. The heart of cardio-oncology rests with such pharmacological foundations.
    Journal of Pharmacology and Experimental Therapeutics 03/2010; 334(1):2-8. · 3.89 Impact Factor
  • Pierantonio Menna, Emanuela Salvatorelli, Giorgio Minotti
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    ABSTRACT: The clinical use of doxorubicin (DOX) and other quinone-hydroquinone antitumor anthracyclines is limited by dose-related cardiotoxicity. One-electron redox cycling of the quinone moiety has long been known to form reactive oxygen species (ROS) in excess of the limited antioxidant defenses of cardiomyocytes; therefore, anthracycline cardiotoxicity was perceived as a one-way process in which redox cycling of the quinone always primed cardiomyocytes to oxidant stress and death. The past few years witnessed a growing interest in an alternative process in which peroxidases and quinone-derived hydrogen peroxide were able to oxidize the hydroquinone moiety of anthracyclines. Such a process was initially thought to amplify the cardiotoxicity induced by anthracyclines. Here, we briefly review how oxyferrous myoglobin could be subsequently identified as the primary catalyst of anthracycline oxidation in cardiomyocytes and be shown to induce an anthracycline chemical degradation that diminished the cellular levels and toxicity of active parent compounds. Many aspects of anthracycline degradation remain obscure or only partially understood; nevertheless, it is not too naive to conclude that anthracyclines are degraded and inactivated as a result of ROS production from their own redox cycling. Anthracycline redox reactions might therefore be viewed as two-way processes in which oxidative stress mediated both the death and survival of cardiomyocytes.
    Chemical Research in Toxicology 12/2009; 23(1):6-10. · 3.67 Impact Factor
  • Pierantonio Menna, Emanuela Salvatorelli, Giorgio Minotti
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    ABSTRACT: Cardiotoxicity limits the clinical use of doxorubicin (DOX) and other quinone-hydroquinone antitumor anthracyclines. One-electron reduction of the quinone moiety is followed by the formation of reactive oxygen species (ROS) that have been proposed to induce cardiotoxicity through an oxidative stress; conversely, one-electron oxidation of the hydroquinone moiety by hydrogen peroxide (H(2)O(2)) and oxyferrous myoglobin (Mb(II)O(2)) is followed by an anthracycline degradation process that has been proposed to limit cardiotoxicity. We previously reported that tert-butoxycarbonyl-alanine (t-BA) impeded DOX oxidation/degradation by H(2)O(2)/Mb(II)O(2) in a cell-free system; accordingly, t-BA increased the levels of DOX, its conversion to ROS, and its concentration-related toxicity in cardiomyocytes. To re-explore methodological and toxicological aspects of anthracycline degradation, we used 4'-epidoxorubicin (EPI), an anthracycline analogue that is very similar to DOX but undergoes protonation-sequestration in cytoplasmic acidic organelles. t-BA lacked an effect on H9c2 cardiomyocytes exposed to EPI; however, blocking the protonation-sequestration mechanism with the vacuolar H(+)-ATPase inhibitor, bafilomycin A1 (BFL), enabled t-BA to increase the cellular levels of EPI, its conversion to ROS, and its concentration-related toxicity. This suggested that t-BA was specific enough to increase the cellular levels and toxicity of only those anthracyclines that were liable to oxidation/degradation by H(2)O(2)/Mb(II)O(2). By exposing cardiomyocytes to nontoxic concentrations of DOX or EPI and by increasing their cellular levels by means of appropriate combinations with t-BA, BFL, or t-BA+BFL, we nonetheless found that the loss of cardiomyocyte viability correlated with the accumulation of undegraded anthrayclines but not with their ability to form ROS or to induce lipid peroxidation. This suggested that an accumulation of undegraded anthracyclines might induce cardiotoxicity also by mechanisms independent of ROS and oxidative stress. Thus, EPI proved useful to refine the value of t-BA in the studies of anthracycline degradation and to reappraise the role of anthracycline degradation in cardiotoxicity.
    Chemical Research in Toxicology 05/2009; 22(6):978-83. · 3.67 Impact Factor
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    ABSTRACT: Secondary alcohol metabolites and reactive oxygen species mediate cardiomyopathy induced by cumulative doses of antitumor anthracyclines, such as doxorubicin and epirubicin. Epirubicin exhibits a defective conversion to both toxic species, thereby inducing cardiotoxicity at doses higher than equiactive to doxorubicin; however, the gain in cardiac tolerability seems to be marginal compared with the magnitude of the metabolic defects of epirubicin. Cardiomyopathy may occur independent of toxic metabolites if a given anthracycline tends to accumulate in the heart; therefore, we characterized whether epirubicin showed an unusual accumulation in human myocardial strips incubated in plasma. Epirubicin exhibited a higher uptake and reached myocardial levels 2 times higher than those of doxorubicin. Epirubicin also showed a unique metabolization to doxorubicinolone, the product of epirubicin deglycosidation and carbonyl reduction. In diffusing from the strips to plasma, doxorubicinolone caused membrane permeation effects that augmented epirubicin elimination. Experiments with purified doxorubicinolone showed that the efflux of 1 mol doxorubicinolone promoted the concomitant elimination of as many as approximately 40 mol epirubicin. Doxorubicinolone could also diffuse from plasma back to the strips, causing a permeation effect that promoted epirubicin reuptake; however, this reverse process was slower and less potent. On balance, doxorubicinolone efflux diminished the epirubicin to doxorubicin accumulation ratio to approximately 1.5. These results suggest that the cardiac tolerability of epirubicin is limited by its accumulation in the heart and that such accumulation would be even higher in the absence of doxorubicinolone formation and efflux. These results may also serve guidelines for developing noncardiotoxic anthracyclines.
    Journal of Pharmacology and Experimental Therapeutics 02/2009; 329(1):175-84. · 3.89 Impact Factor
  • Pierantonio Menna, Emanuela Salvatorelli, Giorgio Minotti
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    ABSTRACT: Many antitumor drugs cause "on treatment" cardiotoxicity or introduce a measurable risk of delayed cardiovascular events. Doxorubicin and other anthracyclines cause congestive heart failure that develops in a dose-dependent manner and reflects the formation of toxic drug metabolites in the heart. Cardiovascular events may occur also with other chemotherapeutics, but the dose or metabolism dependence of such events are less obvious and predictable. Drugs targeted to tumor-specific receptors or metabolic routes were hoped to offer a therapeutic gain while also sparing the heart and other healthy tissues; nonetheless, many such drugs still cause moderate to severe cardiotoxicity. Targeted drugs may also engage a cardiotoxic synergism with "old-fashioned" chemotherapeutics, as shown by the higher than expected incidence of anthracycline-related congestive heart failure that occurred in patients treated with doxorubicin and the anti HER2 antibody Trastuzumab. Mechanism-based considerations and retrospective analyses of clinical trials now form the basis for a new classification of cardiotoxicity, type I for anthracyclines vs type II for Trastuzumab. Such a classification may serve a template to accommodate other paradigms of cardiotoxicity induced by new drugs and combination therapies. Of note, laboratory animal models did not always anticipate the mechanisms and/or metabolic determinants of cardiotoxicity induced by antitumor drugs or combination therapies. Toxicologists and regulatory agencies and clinicians should therefore join in collaborative efforts that improve the early identification of cardiotoxicity and minimize the risks of cardiac events in patients.
    Chemical Research in Toxicology 06/2008; 21(5):978-89. · 3.67 Impact Factor
  • Ejc Supplements - EJC SUPPL. 01/2008; 6(9):31-31.
  • Pierantonio Menna, Emanuela Salvatorelli, Luca Gianni, Giorgio Minotti
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    ABSTRACT: The clinical use of doxorubicin and other quinone-hydroquinone anticancer anthracyclines is limitedby a dose-related cardiotoxicity. Here, we review the correlation of cardiotoxicity of doxorubicinwith its peak plasma concentration and diffusion in the heart, followed by reductive bioactivation or oxidativeinactivation. One-electron quinone reduction and two-electron side chain carbonyl reduction are accompaniedby iron and free radical reactions that are responsible for many aspects of anthracycline cardiotoxicity.In contrast, one-electron hydroquinone oxidation serves as a salvage pathway for degrading and detoxifyinganthracyclines. Mechanism-based cardioprotective strategies therefore involve replacing bolus administrationwith slow infusions (to reduce the drug's plasma peak), encapsulating anthracyclines in liposomes (to reducethe drug's cardiac diffusion), and administering antioxidants or iron chelators. Preclinical modellingand clinical studies suggest that eliminating the side chain carbonyl group reduction warranted a satisfactorydegree of cardioprotection. Approved or investigational anthracyclines that lacked the carbonyl group orshowed an inherent resistance to carbonyl reduction might prove safer than doxorubicin, particularly whenadministered with new generation drugs that otherwise caused a toxic synergism with doxorubicin.
    Topics in current chemistry 01/2008; 283:21-44. · 8.46 Impact Factor
  • Pierantonio Menna, Emanuela Salvatorelli, Giorgio Minotti
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    ABSTRACT: Antitumor therapy with the anthracycline doxorubicin is limited by a severe cardiotoxicity, which seems to correlate with the cardiac levels of doxorubicin and its metabolization to reactive oxygen species. Previous biochemical studies showed that hydrogen peroxide-activated myoglobin caused an oxidative degradation of doxorubicin; however, a pharmacological evaluation of this metabolic pathway was precluded by the lack of safe and specific inhibitors of doxorubicin degradation. We found that tert-butoxycarbonyl-alanine inhibited doxorubicin degradation induced in vitro by hydrogen peroxide-activated oxyferrous myoglobin. When assessed in H9c2 cardiomyocytes, tert-butoxycarbonyl-alanine neither stimulated the cellular uptake of doxorubicin nor diminished its efflux; moreover, tert-butoxycarbonyl-alanine did not cause toxicity per se nor did it augment the toxicity induced by hydrogen peroxide or chemical agents that increased the cellular levels of reactive oxygen species. Nonetheless, tert-butoxycarbonyl-alanine increased the cellular levels of doxorubicin, its conversion to reactive oxygen species, and its concentration-related toxicity. tert-Butoxycarbonyl-alanine also aggravated the toxicity of a degradation-prone anthracycline analog, daunorubicin, but it caused a minor effect on the toxicity of a degradation-resistant analog, aclarubicin. These results suggested that tert-butoxycarbonyl-alanine increased the cellular levels and toxicity of doxorubicin by inhibiting its oxidative degradation to harmless products. Accordingly, doxorubicin samples that had been oxidized in vitro with hydrogen peroxide and oxyferrous myoglobin lacked toxicity to cardiomyocytes. The effects of tert-butoxycarbonyl-alanine were most evident at 0.1 to 1 microM doxorubicin, which may be relevant to clinical conditions. These studies identify an oxidative degradation of doxorubicin as a possible salvage mechanism for diminishing its levels and toxicity in cardiomyocytes.
    Journal of Pharmacology and Experimental Therapeutics 08/2007; 322(1):408-19. · 3.89 Impact Factor
  • Emanuela Salvatorelli, Pierantonio Menna, Luca Gianni, Giorgio Minotti
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    ABSTRACT: The antitumor anthracycline doxorubicin induces a dose-related cardiotoxicity that correlates with the myocardial levels of its secondary alcohol metabolite doxorubicinol. Combining doxorubicin with taxanes such as paclitaxel or docetaxel may aggravate cardiotoxicity, presumably because the taxanes cause an allosteric-like stimulation of cytoplasmic aldehyde reductases that convert doxorubicin to doxorubicinol in the heart. A less severe aggravation of cardiotoxicity was observed on combining taxanes with epirubicin, a closely related analog of doxorubicin; therefore, we characterized whether the cardiac tolerability of epirubicin-taxane therapies could be due to a defective taxane stimulation of the conversion of epirubicin to its secondary alcohol metabolite epirubicinol. Comparisons between doxorubicin and epirubicin in isolated human heart cytosol showed that epirubicin exhibited a lower V(max)/K(m) value for reaction with aldehyde reductases and a defective stimulation of epirubicinol formation by paclitaxel or docetaxel. A similar pattern occurred in the soluble fraction of human myocardial strips incubated in plasma with anthracyclines and paclitaxel or docetaxel, formulated in their clinical vehicles Cremophor EL or polysorbate 80. Doxorubicin, but not epirubicin, was also able to generate reactive oxygen species in the membrane fraction of myocardial strips; however, the levels of doxorubicin-derived reactive oxygen species were not further augmented by paclitaxel. These results support the notion that taxanes might aggravate the cardiotoxicity of doxorubicin through a specific stimulation of doxorubicinol formation. The failure of paclitaxel or docetaxel to stimulate epirubicinol formation therefore uncovers an important determinant of the improved cardiac tolerability of epirubicin-taxane combinations.
    Journal of Pharmacology and Experimental Therapeutics 03/2007; 320(2):790-800. · 3.89 Impact Factor

Publication Stats

1k Citations
139.52 Total Impact Points

Institutions

  • 2008–2012
    • LIUCBM Libera Università Campus Bio-Medico di Roma
      • Integrated Research Center (CIR)
      Roma, Latium, Italy
  • 2002–2008
    • Università degli Studi G. d'Annunzio Chieti e Pescara
      • Center for Aging Sciences CESI
      Pescara, Abruzzo, Italy
  • 2007
    • Fondazione IRCCS Istituto Nazionale dei Tumori di Milano
      • s.c. Medicina Oncologica 1
      Milano, Lombardy, Italy