Cardiotoxic Side Effects Research Articles

Free radical induced activity of an anthracycline analogue and its MnII complex on biological targets through in situ electrochemical generation of semiquinone

Cytotoxicity by anthracycline antibiotics is attributed to several pathways. Important among them are formation of free-radical intermediates. However, their generation makes anthracyclines cardiotoxic which is a concern on their use as anticancer agents. Hence, any change in redox behavior that address cardiotoxicity is welcome. Modulation of redox behavior raises the fear that cytotoxicity could be compromised. Regarding the generation of free radical intermediates on anthracyclines, a lot depends on the surrounding environment (oxic or anoxic), polarity and pH of the medium. In case of anthracyclines, one-electron reduction to semiquinone or two-electron reduction to quinone-dianion are crucial both for cytotoxicity and for cardiotoxic side effects. The disproportion-comproportionation equilibria at play between quinone-dianion, free quinone and semiquinone control biological activity. Whatever is the form of reduction, semiquinones are generated as a consequence of the presence of anthracyclines and these interact with a biological target. Alizarin, a simpler anthracycline analogue and its MnII complex were subjected to electrochemical reduction to realize what happens when anthracyclines are reduced by compounds present in cells as members of the electron transport chain. Glassy carbon electrode maintained at the pre-determined reduction potential of a compound was used for reduction of the compounds. Nucleobases and calf thymus DNA that were maintained in immediate vicinity of such radical generation were used as biological targets. Changes due to the generated species under aerated/de-aerated conditions on nucleobases and on DNA helps one to realize the process by which alizarin and its MnII complex might affect DNA. The study reveals alizarin was more effective on nucleobases than the complex in the free radical pathway. Difference in damage caused by alizarin and the MnII complex on DNA is comparatively less than that observed on nucleobases; the complex makes up for any inefficacy in the free radical pathway by its other attributes.

Treatment of Cardiovascular Dysfunction With PDE5-Inhibitors - Temperature Dependent Effects on Transport and Metabolism of cAMP and cGMP.

IntroductionCardiovascular dysfunction is a potentially lethal complication of hypothermia. Due to a knowledge gap, pharmacological interventions are not recommended at core temperatures below 30°C. Yet, further cooling is induced in surgical procedures and survival of accidental hypothermia is reported after rewarming from below 15°C, advocating a need for evidence-based treatment guidelines. In vivo studies have proposed vasodilation and afterload reduction through arteriole smooth muscle cGMP-elevation as a favorable strategy to prevent cardiovascular dysfunction in hypothermia. Further development of treatment guidelines demand information about temperature-dependent changes in pharmacological effects of clinically relevant vasodilators.Materials and MethodsHuman phosphodiesterase-enzymes and inverted erythrocytes were utilized to evaluate how vasodilators sildenafil and vardenafil affected cellular efflux and enzymatic breakdown of cAMP and cGMP, at 37°C, 34°C, 32°C, 28°C, 24°C, and 20°C. The ability of both drugs to reach their cytosolic site of action was assessed at the same temperatures. IC50- and Ki-values were calculated from dose–response curves at all temperatures, to evaluate temperature-dependent effects of both drugs.ResultsBoth drugs were able to reach the intracellular space at all hypothermic temperatures, with no reduction compared to normothermia. Sildenafil IC50 and Ki-values increased during hypothermia for enzymatic breakdown of both cAMP (IC50: 122 ± 18.9 μM at 37°C vs. 269 ± 14.7 μM at 20°C, p < 0.05) and cGMP (IC50: 0.009 ± 0.000 μM at 37°C vs. 0.024 ± 0.004 μM at 32°C, p < 0.05), while no significant changes were detected for vardenafil. Neither of the drugs showed significant hypothermia-induced changes in IC50 and Ki–values for inhibition of cellular cAMP and cGMP efflux.ConclusionSildenafil and particularly vardenafil were ableto inhibit elimination of cGMP down to 20°C. As the cellular effects of these drugs can cause afterload reduction, they show potential in treating cardiovascular dysfunction during hypothermia. As in normothermia, both drugs showed higher selectivity for inhibition of cGMP-elimination than cAMP-elimination at low core temperatures, indicating that risk for cardiotoxic side effects is not increased by hypothermia.

The Human Fetal and Adult Stem Cell Secretome Can Exert Cardioprotective Paracrine Effects against Cardiotoxicity and Oxidative Stress from Cancer Treatment.

Simple SummaryAnthracyclines, such as doxorubicin (Dox), are an important class of chemotherapeutic drugs. However, their use is hampered by the risk of developing heart failure. The aim of this study was to assess and compare the cardioprotective effects exerted by a set of factors, collectively named secretomes, secreted by either adult or fetal human stem cells. Both secretome formulations were effective in counteracting Dox-induced apoptosis and mitochondrial impairment in cardiomyocytes and cardiac fibroblasts. In vivo experiments in a mouse model of Dox-induced cardiomyopathy (DIC) indicated that early administration of both secretomes during Dox treatment exerted beneficial long-term effects, preserving cardiac function and body mass. These findings suggest that the stem cell secretome could represent a feasible option for future paracrine cardioprotective therapy against Dox-related cardiotoxicity during cancer treatment.Cardiovascular side effects are major shortcomings of cancer treatments causing cardiotoxicity and late-onset cardiomyopathy. While doxorubicin (Dox) has been reported as an effective chemotherapy agent, unspecific impairment in cardiomyocyte mitochondria activity has been documented. We demonstrated that the human fetal amniotic fluid-stem cell (hAFS) secretome, namely the secreted paracrine factors within the hAFS-conditioned medium (hAFS-CM), exerts pro-survival effects on Dox-exposed cardiomyocytes. Here, we provide a detailed comparison of the cardioprotective potential of hAFS-CM over the secretome of mesenchymal stromal cells from adipose tissue (hMSC-CM). hAFS and hMSC were preconditioned under hypoxia to enrich their secretome. The cardioprotective effects of hAFS/hMSC-CM were evaluated on murine neonatal ventricular cardiomyocytes (mNVCM) and on their fibroblast counterpart (mNVFib), and their long-term paracrine effects were investigated in a mouse model of Dox-induced cardiomyopathy. Both secretomes significantly contributed to preserving mitochondrial metabolism within Dox-injured cardiac cells. hAFS-CM and hMSC-CM inhibited body weight loss, improved myocardial function, reduced lipid peroxidation and counteracted the impairment of mitochondrial complex I activity, oxygen consumption, and ATP synthesis induced by Dox. The hAFS and hMSC secretomes can be exploited for inhibiting cardiotoxic detrimental side effects of Dox during cancer therapy, thus ensuring cardioprotection via combinatorial paracrine therapy in association with standard oncological treatments.

Shenlijia Attenuates Doxorubicin-Induced Chronic Heart Failure by Inhibiting Cardiac Fibrosis.

Application of the anticancer drug doxorubicin (DOX) is restricted due to its adverse, cardiotoxic side effects, which ultimately result in heart failure. Moreover, there are a limited number of chemical agents for the clinical prevention of DOX-induced cardiotoxicity. Based on the theories of traditional Chinese medicine (TCM) on chronic heart failure (CHF), Shenlijia (SLJ), a new TCM compound, has been developed to fulfill multiple functions, including improving cardiac function and inhibiting cardiac fibrosis. In the present study, the protective effects and molecular mechanisms of SLJ on DOX-induced CHF rats were investigated. The CHF rat model was induced by intraperitoneal injection of DOX for six weeks with the cumulative dose of 15 mg/kg. All rats were then randomly divided into the control, CHF, CHF + SLJ (3.0 g/kg per day), and CHF + captopril (3.8 mg/kg per day) groups and treated for further four weeks. Echocardiography and the assessment of hemodynamic parameters were performed to evaluate heart function. A protein chip was applied to identify proteins with diagnostic values that were differentially expressed following SLJ treatment. The data from these investigations showed that SLJ treatment significantly improved cardiac function by increasing the left ventricular ejection fraction, improving the hemodynamic index, and inhibiting interstitial fibrosis. Protein chip analysis revealed that SLJ upregulated MCP-1, MDC, neuropilin-2, TGF-β3, thrombospondin, TIE-2, EG-VEGF/PK1, and TIMP-1/2/3 expressions and downregulated that of MMP-13. In addition, immunohistochemistry and western blot results further confirmed that SLJ promoted TIMP-1/2/3 and inhibited MMP-13 expression. The results of the present study suggest that SLJ was effective against DOX-induced CHF rats and is related to the improvement of heart function and ultrastructure and the inhibition of myocardial fibrosis.

Immunomodulatory mAbs as Tools to Investigate on Cis-Interaction of PD-1/PD-L1 on Tumor Cells and to Set Up Methods for Early Screening of Safe and Potent Combinatorial Treatments.

Simple SummaryA novel challenge in cancer immunotherapy is the identification of the most potent combinations of immunomodulatory mAbs that are capable of maximizing therapeutic benefits while minimizing irAEs. We set up an in vitro system to quickly predict the efficacy and eventual cardiotoxic side effects of combinatorial treatments, thus allowing for the early screening of most potent and safe combinatorial therapeutic regimens for both validated and emerging immunomodulatory mAbs against different immune checkpoints (ICs). Furthermore, we provide for the first time evidence on cis-interactions of ICs in tumor cells.Antibodies targeting Immune Checkpoints (IC) on tumor infiltrating lymphocytes improve immune responses against cancer. Recently, the expression of some ICs has also been reported on cancer cells. We used the clinically validated Ipilimumab and Nivolumab and other novel human antibodies targeting Cytotoxic T- lymphocyte-antigen 4 (CTLA-4), Programmed Death receptor-1 (PD-1) and Programmed Death Ligand 1 (PD-L1) to shed light on the functions of these ICs in cancer cells. We show here for the first time that all these antagonistic mAbs are able to reduce Erk phosphorylation and, unexpectedly, to induce a significant increase of ICs expression on tumor cells, involving a hyperphosphorylation of NF-kB. On the contrary, agonistic PD-L1 and PD-1 recombinant proteins showed opposite effects by leading to a significant reduction of PD-1 and PD-L1, thus also suggesting the existence of a crosstalk in tumor cells between multiple ICs. Since the immunomodulatory mAbs show their higher anti-tumor efficacy by activating lymphocytes against cancer cells, we also investigated whether it was possible to identify the most efficient combinations of immunomodulatory mAbs for achieving potent anti-tumor efficacy associated with the lowest adverse side effects by setting up novel simple and predictive in vitro models based on co-cultures of tumor cells or human fetal cardiomyocytes with lymphocytes. We demonstrate here that novel combinations of immunomodulatory mAbs with more potent anti-cancer activity than Ipilimumab and Nivolumab combination can be identified with no or lower cardiotoxic side effects. Thus, we propose these co-cultures-based assays as useful tools to test also other combinatorial treatments of emerging immunomodulatory mAbs against different ICs for the early screening of most potent and safe combinatorial therapeutic regimens.

Use of strain rate imaging for early detection of epirubicin-induced cardiotoxicity in patients with breast cancer.

e12531 Background: Although epirubicin has improved outcome in breast cancer (BC) patients, its application is limited by its cardiotoxicity . Assessment of left ventricular (LV) ejection fraction (EF) is performed to demonstrate cardiac dysfunction. Changes in cardiac function induced by this therapy, however, are difficult to quantitate by conventional echocacardiography. Tissue Doppler myocardial imaging (TDI) derived wall motion velocity, and strain rate (SR) have been shown to sensitively quantify abnormalities in cardiac function. The aim of this study was to determine if sensitive indices of LV dysfunction, would be useful for addressing the early detection of cardiotoxic side effects of epirubicin. Methods: BC patients (N = 45 median age 60.2years) without cardiovascular risk factors were prospectively included. All patients received epirubicin. Twenty patients received further trastuzumab. Conventional and TDI echocardiography were obtained at baseline , every 2cycles of treatment and 3 months after chemotherapy. Segmental peak systolic longitudinal and radial velocity, SR and strain, were measured. Results: at baseline, median LV-EF was &gt; 55 %. There was no overall change in LV dimensions, EF and peak systolic velocity. In contrast, a significant reduction in longitudinal and radial SR and strain was found after 3 cycles (longitudinal strain -10.2% +/- 1.3 % vs baseline 22 +/- 4.1 %, P = .001; radial strain 26.1% +/-4,2% vs baseline 47.3% +/- 9.2 %, P &lt; .001). Changes in radial strain appeared earlier and were more pronounced than longitudinal strain. Conclusions: In this study we confirm the clinical use of TDI parameters for early detection of epirubicin mediated cardiac dysfunction. TDI detected subtle changes of LV function after 3 cycles of therapy. Use of Strain Rate Imaging detects subclinical LV dysfunction and can predict further changes in EF ,therefore can be used to monitor epirubicin-induced cardiotoxicity.

Perhexiline treatment improves toxic effects of β‐adrenergic receptor stimulation in experimental peripartum cardiomyopathy

AimsPeripartum cardiomyopathy (PPCM) is a pregnancy‐associated cardiomyopathy that occurs in previously heart‐healthy women towards the end of pregnancy or in the first months after delivery and is characterized by heart failure due to systolic dysfunction. The clinical course of PPCM differs between mild symptoms and severe forms with acute heart failure complicated by cardiogenic shock (CS). Treatment of CS complicating PPCM is challenging, as β‐adrenergic receptor (β‐AR) stimulation seems to be associated with progression of heart failure and adverse outcome. This experimental study aims to examine whether postpartum treatment with the glucose uptake‐promoting drug perhexiline alone or as co‐treatment with β‐AR stimulation prevents heart failure in the experimental PPCM mouse model.Methods and resultsPostpartum (PP) female PPCM‐prone mice with a cardiomyocyte‐restricted STAT3‐deficiency (αMHC‐Cretg/+;Stat3fl/fl; CKO) were treated with perhexiline over two to three pregnancies and nursing periods (2/3PP) or were co‐treated with perhexiline after one pregnancy (1PP) under chronic β‐AR stimulation using isoproterenol (Iso) infusion. Perhexiline was not able to prevent onset of PPCM in CKO mice (FS: CKO Pexsig‐2/3PP: 25 ± 12% vs. CKO Ctrl‐2/3PP: 24 ± 9%, n.s.) but attenuated worsening of left ventricular function in response to treatment with the β‐AR agonist Iso (FS: CKO Pexsig‐Iso‐1PP: 19 ± 4% vs. CKO Ctrl‐Iso‐1PP: 11 ± 5%, P < 0.05).ConclusionsTreatment of PPCM patients with β‐AR agonists should be avoided whenever possible. In cases with CS complicating PPCM, when treatment with β‐AR agonists cannot be prevented, co‐medication with perhexiline might help to reduce the cardiotoxic side effects of β‐AR stimulation. Clinical data are necessary to further validate this therapeutic approach.

Dopamine D1 receptor alleviates doxorubicin-induced cardiac injury by inhibiting NLRP3 inflammasome

Doxorubicin (DOX) is a broad-spectrum antineoplastic drug; however, its serious cardiotoxic side effects in inflammatory responses limit its use in clinical applications. Dopamine D1 receptor (DRD1), a G protein-coupled receptor, is crucial for the development and function of the nervous system; additionally, it also play a role in immune regulation. However, the specific role of DRD1 in DOX-induced cardiac inflammation has not yet been clarified. Here, we discovered that DRD1 expression was induced by DOX treatment in H9C2 cardiomyocytes. DRD1 activation by A-68930, a DRD1-specific agonist, decreased DOX-induced nucleotide-binding domain-like receptor protein 3 (NLRP3) expression, caspase-1 activation, and IL-1β maturation in H9C2 cells. Expression of the cytokines IL-1β and IL-18 in the supernatants was also inhibited by A-68930 treatment. DRD1 knockdown, using siRNA, abolished the effects of A-68930 on the DOX-induced NLRP3 inflammasome. Furthermore, we found that DRD1 signaling downregulated the NLRP3 inflammasome in H9C2 cells through cyclic adenosine monophosphate (cAMP). Moreover, application of A-68930 to activate DRD1 reduced cardiac injury and fibrosis in a DOX-treated mouse model by suppressing the NLRP3 inflammasome in the heart. These findings indicate that DRD1 signaling may protect against DOX-induced cardiac injury by inhibiting the NLRP3 inflammasome-mediated inflammation.

Effects of Cardiotoxins on Cardiac Stem and Progenitor Cell Populations.

As research and understanding of the cardiotoxic side-effects of anticancer therapy expands further and the affected patient population grows, notably the long-term survivors of childhood cancers, it is important to consider the full range of myocardial cell types affected. While the direct impacts of these toxins on cardiac myocytes constitute the most immediate damage, over the longer term, the myocardial ability to repair, or adapt to this damage becomes an ever greater component of the disease phenotype. One aspect is the potential for endogenous myocardial repair and renewal and how this may be limited by cardiotoxins depleting the cells that contribute to these processes. Clear evidence exists of new cardiomyocyte formation in adult human myocardium, along with the identification in the myocardium of endogenous stem/progenitor cell populations with pro-regenerative properties. Any effects of cardiotoxins on either of these processes will worsen long-term prognosis. While the role of cardiac stem/progenitor cells in cardiomyocyte renewal appears at best limited (although with stronger evidence of this process in response to diffuse cardiomyocyte loss), there are strong indications of a pro-regenerative function through the support of injured cell survival. A number of recent studies have identified detrimental impacts of anticancer therapies on cardiac stem/progenitor cells, with negative effects seen from both long-established chemotherapy agents such as, doxorubicin and from newer, less overtly cardiotoxic agents such as tyrosine kinase inhibitors. Damaging impacts are seen both directly, on cell numbers and viability, but also on these cells' ability to maintain the myocardium through generation of pro-survival secretome and differentiated cells. We here present a review of the identified impacts of cardiotoxins on cardiac stem and progenitor cells, considered in the context of the likely role played by these cells in the maintenance of myocardial tissue homeostasis.

Antioxidant Activity of &lt;i&gt;p&lt;/i&gt;-Hidroxy-&lt;i&gt;m&lt;/i&gt;-Methoxy Chalcone and its Combination with Doxorubicin: &lt;i&gt;In Vitro &lt;/i&gt;and &lt;i&gt;In Silico&lt;/i&gt; Study

Chalcone has a variety of interesting biological activities, including as an antioxidant and anticancer. Antioxidants are molecules that can retard or prevent the oxidation process or inhibit the formation of free radicals. p-Hydroxy-m-Methoxy Chalcone (pHmMC) is a chalcone derivative reported has anticancer activity both in used single and in combination treatment with Doxorubicin (DOX) in breast cancer cell lines. DOX is one of the chemotherapy agents widely used in cancer treatment but the medicine has side effects of cardiotoxicity. This effect is generally associated with free radical formation. This study aims to find out the activity of pHmMC as an antioxidant both in used single and in combination treatment with DOX by in vitro and to explore the potential of pHmMC as an antioxidant by in silico. Activity tests as antioxidants were measured by 1,1-diphenyl-2-picrylhydrazyl (DPPH) test. Ascorbic acid (Vitamin C) was used as a positive control. Antioxidant activity was calculated as the value of 50% Inhibition Concentration (IC50). In silico study was carried out by molecular docking using Protein Ligand ANT System (PLANTS) software with peroxiredoxin 5 [1HD2] as the target. The results showed that the IC50 values of pHmMC, DOX, and Vitamin C were 11.9; 21.6 and 3.3 μ/mL respectively. The combination of pHmMC-DOX has a higher antioxidant activity than single pHmMC or single DOX. The docking molecular showed that there were similarities amino acids involved in the interaction between PRDX5[1HD2]-pHmMC and PRDX5[1HD2]-DOX. This research indicated that pHmMC and pHmMC-DOX are potentially developed as an antioxidant.

Sulforaphane exposure impairs contractility and mitochondrial function in three-dimensional engineered heart tissue

Sulforaphane (SFN) is a phytochemical compound extracted from cruciferous plants, like broccoli or cauliflower. Its isothiocyanate group renders SFN reactive, thus allowing post-translational modification of cellular proteins to regulate their function with the potential for biological and therapeutic actions. SFN and stabilized variants recently received regulatory approval for clinical studies in humans for the treatment of neurological disorders and cancer. Potential unwanted side effects of SFN on heart function have not been investigated yet. The present study characterizes the impact of SFN on cardiomyocyte contractile function in cardiac preparations from neonatal rat, adult mouse and human induced-pluripotent stem cell-derived cardiomyocytes. This revealed a SFN-mediated negative inotropic effect, when administered either acutely or chronically, with an impairment of the Frank-Starling response to stretch activation. A direct effect of SFN on myofilament function was excluded in chemically permeabilized mouse trabeculae. However, SFN pretreatment increased lactate formation and enhanced the mitochondrial production of reactive oxygen species accompanied by a significant reduction in the mitochondrial membrane potential. Transmission electron microscopy revealed disturbed sarcomeric organization and inflated mitochondria with whorled membrane shape in response to SFN exposure. Interestingly, administration of the alternative energy source l-glutamine to the medium that bypasses the uptake route of pyruvate into the mitochondrial tricarboxylic acid cycle improved force development in SFN-treated EHTs, suggesting indeed mitochondrial dysfunction as a contributor of SFN-mediated contractile dysfunction. Taken together, the data from the present study suggest that SFN might impact negatively on cardiac contractility in patients with cardiovascular co-morbidities undergoing SFN supplementation therapy. Therefore, cardiac function should be monitored regularly to avoid the onset of cardiotoxic side effects.

Metabolomics Of Metformin's Cardioprotective Effect In Acute Doxorubicin Induced- Cardiotoxicity In Rats

Doxorubicin (DOX) is a powerful anticancer agent with sever cardiotoxic side effect which limits the clinical use. Metformin (MET) is antihyperglycemic drug with potential cardioprotective effect via AMP-activated protein kinase (AMPK) (increases fatty acid oxidation, decreases the production of ROS, maintaining energy homeostasis and apoptosis). Metabolomics technology deals with systematic study of chemical fingerprints of metabolite profiles. Different metabolic processes can be identified which will give information of any change in the metabolic profile of tissues as well as of biofluids after drug administration. This research designed to investigate MET cardioprotective effect against acute cardiotoxicity induced by DOX using metabolomics technology. Methods: Twenty four adult male wistar rats divided into four groups (6 animals each): control group (saline, i.p.); MET group (300mg/kg/day for 7dayes) by gavage; DOX group (20 mg/kg,i.p.) for acute induction of cardiotoxicity; Met + DOX group received DOX (20mg/kg i.p.) and Met (300 mg/kg/day, for 7 days, starting five days prior to DOX treatment) orally with gavage. Assessment of heart tissue metabolomics, serum MDA and GSH in addition to trichrome stain. Results: The results showed that pretreatment with MET (MET+DOX) significantly (p

Peptide-Based Hydrogels and Nanogels for Delivery of Doxorubicin.

IntroductionThe clinical use of the antitumoral drug doxorubicin (Dox) is reduced by its dose-limiting toxicity, related to cardiotoxic side effects and myelosuppression. In order to overcome these drawbacks, here we describe the synthesis, the structural characterization and the in vitro cytotoxicity assays of hydrogels (HGs) and nanogels (NGs) based on short peptide sequences loaded with Dox or with its liposomal formulation, Doxil.MethodsFmoc-FF alone or in combination with (FY)3 or PEG8-(FY)3 peptides, at two different ratios (1/1 and 2/1 v/v), were used for HGs and NGs formulations. HGs were prepared according to the “solvent-switch” method, whereas NGs were obtained through HG submicronition by the top-down methodology in presence of TWEEN®60 and SPAN®60 as stabilizing agents. HGs gelation kinetics were assessed by Circular Dichroism (CD). Stability and size of NGs were studied using Dynamic Light Scattering (DLS) measurements. Cell viability of empty and filled Dox HGs and NGs was evaluated on MDA-MB-231 breast cancer cells. Moreover, cell internalization of the drug was evaluated using immunofluorescence assays.ResultsDox filled hydrogels exhibit a high drug loading content (DLC=0.440), without syneresis after 10 days. Gelation kinetics (20–40 min) and the drug release (16–28%) over time of HGs were found dependent on relative peptide composition. Dox filled NGs exhibit a DLC of 0.137 and a low drug release (20–40%) after 72 h. Empty HGs and NGs show a high cell viability (>95%), whereas Dox loaded ones significantly reduce cell viability after 24 h (49–57%) and 72 h (7–25%) of incubation, respectively. Immunofluorescence assays evidenced a different cell localization for Dox delivered through HGs and NGs with respect to the free drug.DiscussionA modulation of the Dox release can be obtained by changing the ratios of the peptide components. The different cellular localization of the drug loaded into HGs and NGs suggests an alternative internalization mechanism. The high DLC, the low drug release and preliminary in vitro results suggest a potential employment of peptide-based HGs and NGs as drug delivery tools.

Docking of highly selective peptide ligands of 5HT2A/C receptors with antipsychotic activity

Search for new ligands selective to various 5HT2 receptor subtypes is an important scientific and practical problem for experimental psychopharmacology and clinical medicine. Most of existing antagonists of the 5HT2A- and 5HT2C- subtypes have necessary anti-anxiety and antipsychotic properties, but they are partially selective to 5HT2B receptors. The activation of the latter ones leads to cardiotoxic side effects, so it significantly limits clinical use of these drugs. For the search of new highly selective ligands of 5HT2A/C receptors an in silico screening algorithm was proposed using PScore.Max and Affinity.maxPScore indices, taking into account the affinity of low molecular weight compounds to each of 5HT2 receptor subtype. Cyclic physiologically active substances of peptide nature have been proposed as new promising drugs with antipsychotic activity. Based on the CXXC library, a number of cyclopeptides with a high selectivity of the structure to the target binding sites were selected for further in vitro studies by extending the peptide chain.It was also found that a promising direction for increasing the selectivity of peptide ligands to 5HT2A/C receptors is the introduction of non-proteinogenic amino acids during the formation of a starting docking library. Their choice will be stipulated by the nature of interactions between the reference ligands and amino acid residues of the binding site.

Loss of endothelial cell-specific autophagy-related protein 7 exacerbates doxorubicin-induced cardiotoxicity

Doxorubicin (DOX) is an effective, broad-spectrum antineoplastic agent with serious cardiotoxic side effects, which may lead to the development of heart failure. Current strategies to diagnose, prevent, and treat DOX-induced cardiotoxicity (DIC) are inadequate. Recent evidence has linked the dysregulation and destruction of the vascular endothelium to the development of DIC. Autophagy is a conserved pro-survival mechanism that recycles and removes damaged sub-cellular components. Autophagy-related protein 7 (ATG7) catalyzes autophagosome formation, a critical step in autophagy. In this study, we used endothelial cell-specific Atg7 knockout (EC-Atg7−/−) mice to characterize the role of endothelial cell-specific autophagy in DIC. DOX-treated EC-Atg7−/− mice showed reduced survival and a greater decline in cardiac function compared to wild-type controls. Histological assessments revealed increased cardiac fibrosis in DOX-treated EC-Atg7−/− mice. Furthermore, DOX-treated EC-Atg7−/− mice had elevated serum levels of creatine kinase-myocardial band, a biomarker for cardiac damage. Thus, the lack of EC-specific autophagy exacerbated DIC. Future studies on the relationship between EC-specific autophagy and DIC could establish the importance of endothelium protection in preventing DIC.

Aldose reductase regulates doxorubicin-induced immune and inflammatory responses by activating mitochondrial biogenesis

We have recently demonstrated that aldose reductase (AR) inhibitor; fidarestat prevents doxorubicin (Dox)-induced cardiotoxic side effects and inflammation in vitro and in vivo. However, the effect of fidarestat and its combination with Dox on immune cell activation and the immunomodulatory effects are not known. In this study, we examined the immunomodulatory effects of fidarestat in combination with Dox in vivo and in vitro. We observed that fidarestat decreased Dox-induced upregulation of CD11b in THP-1 monocytes. Fidarestat further attenuated Dox-induced upregulation of IL-6, IL-1β, and Nos2 in murine BMDM. Fidarestat also attenuated Dox-induced activation and infiltration of multiple subsets of inflammatory immune cells identified by expression of markers CD11b+, CD11b+F4/80+, Ly6C+CCR2high, and Ly6C+CD11b+ in the mouse spleen and liver. Furthermore, significant upregulation of markers of mitochondrial biogenesis PGC-1α, COX IV, TFAM, and phosphorylation of AMPKα1 (Ser485) was observed in THP-1 cells and livers of mice treated with Dox in combination with fidarestat. Our results suggest that fidarestat by up-regulating mitochondrial biogenesis exerts protection against Dox-induced immune and inflammatory responses in vitro and in vivo, providing further evidence for developing fidarestat as a combination agent with anthracycline drugs to prevent chemotherapy-induced inflammation and toxicity.

Application of Human Induced Pluripotent Stem Cell Technology for Cardiovascular Regenerative Pharmacology.

Cardiovascular diseases are one of the leading causes of mortality in the western world. Myocardial infarction is among the most prevalent and results in significant cell loss within the myocardium. Similarly, numerous drugs have been identified as having cardiotoxic side effects. The adult human heart is however unable to instigate an effective repair mechanism and regenerate the myocardium in response to such damage. This is in large part due to the withdrawal of cardiomyocytes (CMs) from the cell cycle. Thus, identifying, screening, and developing agents that could enhance the proliferative capacity of CMs holds great potential in cardiac regeneration. Human induced pluripotent stem cells (hiPSCs) and their cardiovascular derivatives are excellent tools in the search for such agents. This chapter outlines state-of-the art techniques for the two-dimensional differentiation and attainment of hiPSC-derived CMs and endothelial cells (ECs). Bioreactor systems and three-dimensional spheroids derived from hiPSC-cardiovascular derivatives are explored as platforms for drug discovery before focusing on relevant assays that can be employed to assess cell proliferation and viability.

Sunitinib-induced cardiac hypertrophy and the endothelin axis.

Anti-angiogenics drugs in clinical use for cancer treatment induce cardiotoxic side effects. The endothelin axis is involved in hypertension and cardiac remodelling, and addition of an endothelin receptor antagonist to the anti-angiogenic sunitinib was shown to reduce cardiotoxicity of sunitinib in mice. Here, we explored further the antidote effect of the endothelin receptor antagonist macitentan in sunitinib-treated animals on cardiac remodeling.Methods: Tumor-bearing mice treated per os daily by sunitinib or vehicle were imaged before and after 1, 3 and 6 weeks of treatment by positron emission tomography using [18F]fluorodeoxyglucose and by echocardiography. Non-tumor-bearing animals were randomly assigned to be treated per os daily by vehicle or sunitinib or macitentan or sunitinib+macitentan, and imaged by echocardiography after 5 weeks. Hearts were harvested for histology and molecular analysis at the end of in vivo exploration.Results: Sunitinib treatment increases left ventricular mass and ejection fraction and induces cardiac fibrosis. Sunitinib also induces an early increase in cardiac uptake of [18F]fluorodeoxyglucose, which is significantly correlated with increased left ventricular mass at the end of treatment. Co-administration of macitentan prevents sunitinib-induced hypertension, increase in ejection fraction and cardiac fibrosis, but fails to prevent increase of the left ventricular mass.Conclusion: Early metabolic changes predict sunitinib-induced cardiac remodeling. Endothelin blockade can prevent some but not all cardiotoxic side-effects of sunitinib, in particular left ventricle hypertrophy that appears to be induced by sunitinib through an endothelin-independent mechanism.

Testing a clinical risk score in the first Cardio-oncology unit in Morocco to assess Anthracyclines and Trastuzumab-induced cardiotoxicity in breast cancer patients

Breast cancer is becoming an increasingly urgent problem worldwide and in Morocco. Recent advances in the detection and treatment of cancer have improved cancer survival worldwide. However, despite major improvements in the outcome of these patients, long-term cardiotoxic side effects affect both patient survival and quality of life. Our study aimed to assess the utility of the Cardiotoxicity Risk Score (CRS) proposed by the American Society of Clinical Oncology (ASCO) to predict cardiotoxicty among Moroccan patients. We conducted a prospective observational study from June 2018 to December 2019 in the Casablanca cardio-oncology unit, Morocco. For each patient, before iniation of treatment, we calculated The CRS that takes both patient and treatment risk factors into consideration and the patients were classified into 2 groups (high and low risk). Finally, a sensitivity analysis was performed. Among the 413 patients included in our study, 42 patients (10,1%) experienced cardiotoxicity that was reversible with full recovery of LVEF in 31 patients (73,8%). According to the CRS, 136 of them (32,9%) were considered at high risk and 277 (67,1%) at low risk. The majority of patients who experienced cardiac events were in the high-risk group (83,4%, n = 35) against 7 patients (16,6%) in the low-risk group. The sensitivity analysis showed that the CRS had a sensitivity of 83% [95% CI: 0.78, 0.92], a specificity of 65% [95% CI: 0.54, 0.71], a positive predictive value of 21% [95% CI: 0.08, 0.39] and a negative predictive value of 97% [95% CI: 0.90, 0.99] The CRS tested in this breast cancer patients population showed good sensitivity and negative predictive value for the development of cardiotoxicity, which suggests the importance of early consultation in a cardio-oncology unit and close cardiac monitoring in high-risk patients unlike in low-risk patients who don’t really need such intensive cardiac monitoring.

Betulinic Acid Protects DOX-Triggered Cardiomyocyte Hypertrophy Response through the GATA-4/Calcineurin/NFAT Pathway.

Cardiac hypertrophy is a major risk factor for heart failure and leads to cardiovascular morbidity and mortality. Doxorubicin (DOX) is regarded as one of the most potent anthracycline antibiotic agents; however, its clinical usage has some limitations because it has serious cardiotoxic side effects such as dilated cardiomyopathy and congestive heart failure. Betulinic acid (BA) is a pentacyclic-cyclic lupane-type triterpene that has been reported to have anti-bacterial, anti-inflammatory, anti-vascular neogenesis, and anti-fibrotic effects. However, there is no study about its direct effect on DOX induced cardiac hypertrophy and apoptosis. The present study aims to investigate the effect of BA on DOX-induced cardiomyocyte hypertrophy and apoptosis in vitro in H9c2 cells. The H9c2 cells were stimulated with DOX (1 µM) in the presence or absence of BA (0.1–1 μM) and incubated for 24 h. The results of the present study indicated that DOX induces the increase cell surface area and the upregulation of hypertrophy markers including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), beta-myosin heavy chain (β-MHC), and Myosin Light Chain-2 (MLC2) in H9c2 cells. However, the pathological hypertrophic responses were downregulated after BA treatment. Moreover, phosphorylation of JNK, ERK, and p38 in DOX treated H9c2 cells was blocked by BA. As a result of measuring the change in ROS generation using DCF-DA, BA significantly inhibited DOX-induced the production of intracellular reactive oxygen species (ROS) when BA was treated at a concentration of over 0.1 µM. DOX-induced activation of GATA-4 and calcineurin/NFAT-3 signaling pathway were remarkably improved by pre-treating of BA to H9c2 cells. In addition, BA treatment significantly reduced DOX-induced cell apoptosis and protein expression levels of Bax and cleaved caspase-3/-9, while the expression of Bcl-2 was increased by BA. Therefore, BA can be a potential treatment for cardiomyocyte hypertrophy and apoptosis that lead to sudden heart failure.