Emanuela Salvatorelli

Bio: Emanuela Salvatorelli is an academic researcher from Università Campus Bio-Medico. The author has contributed to research in topics: Cardiotoxicity & Anthracycline. The author has an hindex of 21, co-authored 47 publications receiving 4437 citations. Previous affiliations of Emanuela Salvatorelli include University of Chieti-Pescara & University of Rome Tor Vergata.

Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

Abstract: The clinical use of anthracyclines like doxorubicin and daunorubicin can be viewed as a sort of double-edged sword. On the one hand, anthracyclines play an undisputed key role in the treatment of many neoplastic diseases; on the other hand, chronic administration of anthracyclines induces cardiomyopathy and congestive heart failure usually refractory to common medications. Second-generation analogs like epirubicin or idarubicin exhibit improvements in their therapeutic index, but the risk of inducing cardiomyopathy is not abated. It is because of their janus behavior (activity in tumors vis-a-vis toxicity in cardiomyocytes) that anthracyclines continue to attract the interest of preclinical and clinical investigations despite their longer-than-40-year record of longevity. Here we review recent progresses that may serve as a framework for reappraising the activity and toxicity of anthracyclines on basic and clinical pharmacology grounds. We review 1) new aspects of anthracycline-induced DNA damage in cancer cells; 2) the role of iron and free radicals as causative factors of apoptosis or other forms of cardiac damage; 3) molecular mechanisms of cardiotoxic synergism between anthracyclines and other anticancer agents; 4) the pharmacologic rationale and clinical recommendations for using cardioprotectants while not interfering with tumor response; 5) the development of tumor-targeted anthracycline formulations; and 6) the designing of third-generation analogs and their assessment in preclinical or clinical settings. An overview of these issues confirms that anthracyclines remain "evergreen" drugs with broad clinical indications but have still an improvable therapeutic index.

Doxorubicin Irreversibly Inactivates Iron Regulatory Proteins 1 and 2 in Cardiomyocytes Evidence for Distinct Metabolic Pathways and Implications for Iron-mediated Cardiotoxicity of Antitumor Therapy

Abstract: Changes in iron homeostasis have been implicated in cardiotoxicity induced by the anticancer anthracycline doxorubicin (DOX). Certain products of DOX metabolism, like the secondary alcohol doxorubicinol (DOXol) or reactive oxygen species (ROS), may contribute to cardiotoxicity by inactivating iron regulatory proteins (IRP) that modulate the fate of mRNAs for transferrin receptor and ferritin. It is important to know whether DOXol and ROS act by independent or combined mechanisms. Therefore, we monitored IRP activities in H9c2 rat embryo cardiomyocytes exposed to DOX or to analogues which were selected to achieve a higher formation of secondary alcohol metabolite (daunorubicin), a concomitant increase of alcohol metabolite and decrease of ROS (5-iminodaunorubicin), or a defective conversion to alcohol metabolite (mitoxantrone). On the basis of such multiple comparisons, we characterized that DOXol was able to remove iron from the catalytic Fe-S cluster of cytoplasmic aconitase, making this enzyme switch to the cluster-free IRP-1. ROS were not involved in this step, but they converted the IRP-1 produced by DOXol into a null protein which did not bind to mRNA, nor was it able to switch back to aconitase. DOX was also shown to inactivate IRP-2, which does not assemble or disassemble a Fe-S cluster. Comparisons between DOX and the analogues revealed that IRP-2 was inactivated only by ROS. Thus, DOX can inactivate both IRP through a sequential action of DOXol and ROS on IRP-1 or an independent action of ROS on IRP-2. This information serves guidelines for designing anthracyclines that spare iron homeostasis and induce less severe cardiotoxicity.

Cardiotoxicity of antitumor drugs.

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.

Anthracycline cardiotoxicity in breast cancer patients: synergism with trastuzumab and taxanes.

Abstract: Doxorubicin is known to cause cardiomyopathy and congestive heart failure (CHF) upon chronic administration. A major obstacle to doxorubicin-containing multiagent therapies pertains to the possible development of cardiomyopathy and CHF at lower than expected cumulative doses of doxorubicin. For example, the cardiac toxicity of doxorubicin is aggravated by the anti-HER2 antibody Trastuzumab or by the tubulin-active taxane paclitaxel; however, the mechanisms by which Trastuzumab and paclitaxel aggravate doxorubicin-induced cardiotoxicity are mechanistically distinct: Trastuzumab interferes with cardiac-specific survival factors that help the heart to withstand stressor agents like anthracyclines, while paclitaxel acts by stimulating the formation of anthracycline metabolites that play a key role in the mechanism of cardiac failure. Here, we briefly review the molecular mechanisms of the cardiotoxic synergism of Trastuzumab or paclitaxel with doxorubicin, and we attempt to briefly outline how the mechanistic know-how translates into the clinical strategies for improving the safety of anthracycline-based multiagent therapies.

Doxorubicin cardiotoxicity and the control of iron metabolism: quinone-dependent and independent mechanisms.

Abstract: Publisher Summary This chapter reviews an experimental evidence suggesting that Doxorubicin (DOX) and other anthracyclines can act at an intracellular level, perhaps by altering the function of iron regulatory proteins (IRP) that serve to maintain low molecular weight iron pool (often referred to as the labile iron pool, LIP) within physiologic concentrations. DOX is the leading compound of a broad family of extractive or pharmaceutically engineered anticancer anthracyclines. Since its introduction in several investigational and approved chemotherapy regimens, DOX has contributed to the improved life expectancy of countless patients affected by carcinomas, sarcomas, or lymphomas. The activity of DOX against tumors is nonetheless accompanied by acute and chronic toxicities to the heart. The acute toxicity develops immediately after initiation of DOX treatment and consists of arrhythmias or hypotensive episodes, which do not represent an indication to discontinue the anthracycline regimen. The unique reactivity of DOXol toward aconitase/IRP-1 and the precise mechanisms of null protein formation clearly call for validation in clinical settings or proper animal models of in vivo cardiotoxicity. Likewise, preliminary observations that DOX-sensitive or DOX-resistant tumor cells exhibit different ratios of aconitase to IRP-1 might anticipate a possibility to target iron trafficking in sensitive cells while not affecting iron homeostasis in the heart. Research efforts are now going in this direction.

Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

Abstract: The clinical use of anthracyclines like doxorubicin and daunorubicin can be viewed as a sort of double-edged sword. On the one hand, anthracyclines play an undisputed key role in the treatment of many neoplastic diseases; on the other hand, chronic administration of anthracyclines induces cardiomyopathy and congestive heart failure usually refractory to common medications. Second-generation analogs like epirubicin or idarubicin exhibit improvements in their therapeutic index, but the risk of inducing cardiomyopathy is not abated. It is because of their janus behavior (activity in tumors vis-a-vis toxicity in cardiomyocytes) that anthracyclines continue to attract the interest of preclinical and clinical investigations despite their longer-than-40-year record of longevity. Here we review recent progresses that may serve as a framework for reappraising the activity and toxicity of anthracyclines on basic and clinical pharmacology grounds. We review 1) new aspects of anthracycline-induced DNA damage in cancer cells; 2) the role of iron and free radicals as causative factors of apoptosis or other forms of cardiac damage; 3) molecular mechanisms of cardiotoxic synergism between anthracyclines and other anticancer agents; 4) the pharmacologic rationale and clinical recommendations for using cardioprotectants while not interfering with tumor response; 5) the development of tumor-targeted anthracycline formulations; and 6) the designing of third-generation analogs and their assessment in preclinical or clinical settings. An overview of these issues confirms that anthracyclines remain "evergreen" drugs with broad clinical indications but have still an improvable therapeutic index.

Mitochondrial Reactive Oxygen Species (ROS) and ROS-Induced ROS Release

Abstract: Byproducts of normal mitochondrial metabolism and homeostasis include the buildup of potentially damaging levels of reactive oxygen species (ROS), Ca2+, etc., which must be normalized. Evidence suggests that brief mitochondrial permeability transition pore (mPTP) openings play an important physiological role maintaining healthy mitochondria homeostasis. Adaptive and maladaptive responses to redox stress may involve mitochondrial channels such as mPTP and inner membrane anion channel (IMAC). Their activation causes intra- and intermitochondrial redox-environment changes leading to ROS release. This regenerative cycle of mitochondrial ROS formation and release was named ROS-induced ROS release (RIRR). Brief, reversible mPTP opening-associated ROS release apparently constitutes an adaptive housekeeping function by the timely release from mitochondria of accumulated potentially toxic levels of ROS (and Ca2+). At higher ROS levels, longer mPTP openings may release a ROS burst leading to destruction of mitochondria, and if propagated from mitochondrion to mitochondrion, of the cell itself. The destructive function of RIRR may serve a physiological role by removal of unwanted cells or damaged mitochondria, or cause the pathological elimination of vital and essential mitochondria and cells. The adaptive release of sufficient ROS into the vicinity of mitochondria may also activate local pools of redox-sensitive enzymes involved in protective signaling pathways that limit ischemic damage to mitochondria and cells in that area. Maladaptive mPTP- or IMAC-related RIRR may also be playing a role in aging. Because the mechanism of mitochondrial RIRR highlights the central role of mitochondria-formed ROS, we discuss all of the known ROS-producing sites (shown in vitro) and their relevance to the mitochondrial ROS production in vivo.

Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems

Abstract: Objectives The frontline drug doxorubicin has been used for treating cancer for over 30 years. While providing a cure in select cases, doxorubicin causes toxicity to most major organs, especially life-threatening cardiotoxicity, which forces the treatment to become dose-limiting. Key findings Doxorubicin is known to bind to DNA-associated enzymes, intercalate with DNA base pairs, and target multiple molecular targets to produce a range of cytotoxic effects. For instance, it causes the activation of various molecular signals from AMPK (AMP-activated protein kinase inducing apoptosis) to influence the Bcl-2/Bax apoptosis pathway. By altering the Bcl-2/Bax ratio, downstream activation of different caspases can occur resulting in apoptosis. Doxorubicin also induces apoptosis and necrosis in healthy tissue causing toxicity in the brain, liver, kidney and heart. Over the years, many studies have been conducted to devise a drug delivery system that would eliminate these adverse affects including liposomes, hydrogel and nanoparticulate systems, and we highlight the pros and cons of these drug delivery systems. Summary Overall the future for the continued use of doxorubicin clinically against cancer looks set to be prolonged, provided certain enhancements as listed above are made to its chemistry, delivery and toxicity. Increased efficacy depends on these three aims being met satisfactorily as discussed in turn in this review.

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

Abstract: 2-D : two-dimensional 3-D : three-dimensional 5-FU : 5-fluorouracil ACE : angiotensin-converting enzyme ARB : angiotensin II receptor blocker ASE : American Society of Echocardiography BNP : B-type natriuretic peptide CABG : coronary artery bypass graft CAD : coronary artery