The protective effect of a purified extract of <Emphasis Type="Italic">Withania somnifera</Emphasis> against doxorubicin-induced cardiac toxicity in rats

The therapeutic value of doxorubicin as an effective antineoplastic agent is limited by its cardiotoxic side-effects. The administration of doxorubicin (10 mg/kg) to male Wistar rats induced necrosis and apoptosis in heart tissues. It also caused oxidative stress damage as evidenced by the elevation of malondialdehyde and protein carbonyl levels and catalase activity, accompanied by the concurrent depletion of total antioxidant capacity and of superoxide dismutase level in cardiac tissues. The doxorubicin-induced cardiotoxicity and oxidative stress damage were also accompanied by increases of myeloperoxidase activity, total calcium content, and the expression of Bcl-2 protein in heart tissues. Most of these doxorubicin-induced biochemical and histological alterations were effectively attenuated by prior administration of purified standardized extract (1.5% withanolides; manufactured by Idea Sphere Inc., American Fork, UT, USA) of Withania somnifera (300 mg/kg). Thus, Withania may play a role in the protection against cardiotoxicity and thus might be a useful adjuvant therapy where doxorubicin is the cancer-treating drug.     

Resveratrol,a polyphenol phytoalexin,protects against doxorubicin‐induced cardiotoxicity

Doxorubicin is the mainstay of treatment for various haematological malignancies and solid tumours. However, its clinical application may be hampered by dose‐dependent cardiotoxicity. The mechanism of doxorubicin‐induced cardiotoxicity may involve various signalling pathways including free radical generation, peroxynitrite formation, calcium overloading, mitochondrial dysfunction and alteration in apoptosis and autophagy. Interestingly, the use of resveratrol in combination with doxorubicin has been reported to prevent cardiac toxicity as well as to exert a synergistic effect against tumour cells both in vivo and in vitro. Thus, the aim of this review is to summarize current knowledge and to elucidate the protective effect of resveratrol in doxorubicin‐induced cardiotoxicity.     

Baicalein protects against doxorubicin-induced cardiotoxicity by attenuation of mitochondrial oxidant injury and JNK activation

The cardiotoxicity of doxorubicin limits its clinical use in the treatment of a variety of malignancies. Previous studies suggest that doxorubicin-associated cardiotoxicity is mediated by reactive oxygen species (ROS)-induced apoptosis. We therefore investigated if baicalein, a natural antioxidant component of Scutellaria baicalensis, could attenuate ROS generation and cell death induced by doxorubicin. Using an established chick cardiomyocyte model, doxorubicin (10 μM) increased cell death in a concentration- and time-dependent manner. ROS generation was increased in a dose-response fashion and associated with loss of mitochondrial membrane potential. Doxorubicin also augmented DNA fragmentation and increased the phosphorylation of ROS-sensitive pro-apoptotic kinase c-Jun N-terminal kinase (JNK). Adjunct treatment of baicalein (25 μM) and doxorubicin for 24 h significantly reduced both ROS generation (587 ± 89 a.u. vs. 932 a.u. ± 121 a.u., P < 0.01) and cell death (30.6 ± 5.1% vs. 46.8 ± 8.3%, P < 0.01). The dissipated mitochondrial potential and increased DNA fragmentation were also ameliorated. Along with the reduction of ROS and apoptosis, baicalein attenuated phosphorylation of JNK induced by doxorubicin (1.7 ± 0.3 vs. 3.0 ± 0.4-fold, P < 0.05). Co-treatment of cardiomyocytes with doxorubicin and JNK inhibitor SP600125 (10 μM; 24 h) reduced JNK phosphorylation and enhanced cell survival, suggesting that the baicalein protection against doxorubicin cardiotoxicity was mediated by JNK activation. Importantly, concurrent baicalein treatment did not interfere with the anti-proliferative effects of doxorubicin in human breast cancer MCF-7 cells. In conclusion, baicalein adjunct treatment confers anti-apoptotic protection against doxorubicin-induced cardiotoxicity without compromising its anti-cancer efficacy.     

Flavonoids as protectors against doxorubicin cardiotoxicity: role of iron chelation, antioxidant activity and inhibition of carbonyl reductase

Anthracycline antibiotics (e.g. doxorubicin and daunorubicin) are among the most effective and widely used anticancer drugs. Unfortunately, their clinical use is limited by the dose-dependent cardiotoxicity. Flavonoids represent a potentially attractive class of compounds to mitigate the anthracycline cardiotoxicity due to their iron-chelating, antioxidant and carbonyl reductase-inhibitory effects. The relative contribution of various characteristics of the flavonoids to their cardioprotective activity is, however, not known. A series of ten flavonoids including quercetin, quercitrin, 7-monohydroxyethylrutoside (monoHER) and seven original synthetic compounds were employed to examine the relationships between their inhibitory effects on carbonyl reduction, iron-chelation and antioxidant properties with respect to their protective potential against doxorubicin-induced cardiotoxicity. Cardioprotection was investigated in the neonatal rat ventricular cardiomyocytes whereas the H9c2 cardiomyoblast cells were used for cytotoxicity testing. Iron chelation was examined via the calcein assay and antioxidant effects and site-specific scavenging were quantified by means of inhibition of lipid peroxidation and hydroxyl radical scavenging activity, respectively. Inhibition of carbonyl reductases was assessed in cytosol from human liver. None of the flavonoids tested had better cardioprotective action than the reference cardioprotector, monoHER. However, a newly synthesized quaternary ammonium analog with comparable cardioprotective effects has been identified. No direct correlation between the iron-chelating and/or antioxidant effect and cardioprotective potential has been found. A major role of carbonyl reductase inhibition seems unlikely, as the best two cardioprotectors of the series are only weak reductase inhibitors.     

Protective effect of resveratrol against doxorubicin-induced cardiac toxicity and fibrosis in male experimental rats

The possible effectiveness of resveratrol, a polyphenol present in different plants comprising berries, grapes and peanuts, on the prevention of doxorubicin-induced cardiac toxicity and fibrosis was investigated. Forty adult male Wistar albino rats were divided into four groups. Group I received normal saline, group II gavaged with resveratrol (20 mg/kg, daily for 4 weeks), group III received doxorubicin (2.5 mg/kg i.p. in six injections for 2 weeks; accumulative dose of 15 mg/kg), and group IV received doxorubicin?+?resveratrol (starting resveratrol intake 2 weeks before doxorubicin administration). Resveratrol significantly alleviated the increase in left ventricular lipid peroxidation, hydroxyproline, and tumor necrosis factor alpha levels as well as serum creatine kinase-myocardial band (CK-MB) activity and prevented the decrease in body and heart weights in doxorubicin-treated group. However, a marked protection against reduced glutathione content depletion and superoxide dismutase activity reduction was observed in the left ventricles of rats pretreated with resveratrol in combination with doxorubicin. Resveratrol also ameliorated the up-regulation of left ventricular caspase-3 and transforming growth factor-beta1 gene expression as well as left ventricular histopathological changes including necrosis and fibrosis induced by doxorubicin. Collectively, our results suggest that resveratrol provides a significant protection against doxorubicin-induced cardiotoxicity and fibrosis in rats. Therefore, it may be used as a promising cardioprotective agent in patients treated with doxorubicin due to malignant diseases. So, further clinical trials are required to confirm these findings.     

HSP25 down-regulation enhanced p53 acetylation by dissociation of SIRT1 from p53 in doxorubicin-induced H9c2 cell apoptosis

Heat shock proteins (HSPs) play important roles in cellular stress resistance. Previous reports had already suggested that HSP27 played multiple roles in preventing doxorubicin-induced cardiotoxicity. Although HSP25 might have biological functions similar to its human homolog HSP27, the mechanism of HSP25 is still unclear in doxorubicin-induced cardiomyocyte apoptosis. To investigate HSP25 biological function on doxorubicin-induced apoptosis, flow cytometry was employed to analyze cell apoptosis in over-expressing HSP25 H9c2 cells in presence of doxorubicin. Unexpectedly, the H9c2 cells of over-expressing HSP25 have no protective effect on doxorubicin-induced apoptosis. Moreover, no detectable interactions were detected by coimmunoprecipitation between HSP25 and cytochrome c, and HSP25 over-expression failed in preventing cytochrome c release induced by doxorubicin. However, down-regulation of endogenous HSP25 by a specific small hairpin RNA aggravates apoptosis in H9c2 cells. Subsequent studies found that HSP25, but not HSP90, HSP70, and HSP20, interacted with SIRT1. Knockdown of HSP25 decreased the interaction between SIRT1 and p53, leading to increased p53 acetylation on K379, up-regulated pro-apoptotic Bax protein expression, induced cytochrome c release, and triggered caspase-3 and caspase-9 activation. These findings indicated a novel mechanism by which HSP25 regulated p53 acetylation through dissociation of SIRT1 from p53 in doxorubicin-induced H9c2 cell apoptosis.     

Vincristine attenuates doxorubicin cardiotoxicity

Our aim was to test the hypothesis that the vinca alkaloid vincristine could prevent doxorubicin-induced cardiomyocyte death and to identify the mechanisms involved. Adult mouse cardiac myocytes were incubated for 24 h with doxorubicin, with and without concurrent vincristine. Trypan blue exclusion showed that 50–60% of myocytes treated with doxorubicin alone survived. Concurrent vincristine treatment increased survival to 85%. Treatment with doxorubicin + vincristine activated the prosurvival signal Akt and diminished cytochrome C release. The PI3K/Akt inhibitor LY294002 and the MEK/ERK inhibitor PD98059 augmented doxorubicin cardiotoxicity and attenuated salvage during concurrent vincristine treatment, indicating that the mechanism of vincristine cardioprotection involves activation of specific survival signals. Vincristine retarded the onset of apoptosis in association with a delay in poly(ADP) ribose polymerase activation. Vincristine also exhibited greater protection than the antioxidant MPG. These novel findings may have clinical implications for the prevention of doxorubicin cardiomyopathy.     

Effect of Glutathione and N-Acetylcysteine on in Vitro and in VIVO Cardiac Toxicity of Doxorubicin

The effects of two sulfhydryl compounds, glutathione (GSH) and N-acetylcysteine (NAC), on the cardiotoxicity of doxorubicin (DXR) were tested on in vitro and in vivo models. DXR was administered to rats as 4 weekly i.v. doses of 3mg/kg. GSH (1.5 mmoles/kg), given i.v. 10 min before and 1 hr after DXR, was found to prevent the development of the delayed cardiotoxic effects of DXR, as assessed by electrocardiographic and mechanical parameters, as well as by histological examination of left ventricular preparations. In contrast, equimolar oral doses of NAC (1 hr before and 2hrs after DXR) were found to be ineffective. Both GSH and NAC prevented the negative inotropic effect produced by DXR on isolated rat atria. A good correlation exists between the cardioprotective effects of the two agents and their ability to enhance the non-protein sulfhydryl group content of the myocardium. Differences observed in vivo between GSH and NAC might be accounted for by pharmacokinetic factors.     

Brain‐derived neurotrophic factor attenuates doxorubicin‐induced cardiac dysfunction through activating Akt signalling in rats

The clinical application of doxorubicin (Dox) is limited by its adverse effect of cardiotoxicity. Previous studies have suggested the cardioprotective effect of brain‐derived neurotrophic factor (BDNF). We hypothesize that BDNF could protect against Dox‐induced cardiotoxicity. Sprague Dawley rats were injected with Dox (2.5 mg/kg, 3 times/week, i.p.), in the presence or absence of recombinant BDNF (0.4 μg/kg, i.v.) for 2 weeks. H9c2 cells were treated with Dox (1 μM) and/or BDNF (400 ng/ml) for 24 hrs. Functional roles of BDNF against Dox‐induced cardiac injury were examined both in vivo and in vitro. Protein level of BDNF was reduced in Dox‐treated rat ventricles, whereas BDNF and its receptor tropomyosin‐related kinase B (TrkB) were markedly up‐regulated after BDNF administration. Brain‐derived neurotrophic factor significantly inhibited Dox‐induced cardiomyocyte apoptosis, oxidative stress and cardiac dysfunction in rats. Meanwhile, BDNF increased cell viability, inhibited apoptosis and DNA damage of Dox‐treated H9c2 cells. Investigations of the underlying mechanisms revealed that BDNF activated Akt and preserved phosphorylation of mammalian target of rapamycin and Bad without affecting p38 mitogen‐activated protein kinase and extracellular regulated protein kinase pathways. Furthermore, the beneficial effect of BDNF was abolished by BDNF scavenger TrkB‐Fc or Akt inhibitor. In conclusion, our findings reveal a potent protective role of BDNF against Dox‐induced cardiotoxicity by activating Akt signalling, which may facilitate the safe use of Dox in cancer treatment.     

An Efficient Approach for the Synthesis and Antitumor Evaluation of Novel Azo- and Anil-Linked with 3-Aminopyrazolo[3,4-b]pyridine

In this project, an effective procedure for constructing a new combination of pyrazolo[3,4-b]pyridine was depicted through the coupling of diazonium salt 2 of heterocyclic amine 1 with active methylene, enamine, and amidine moieties such as 3 , 5 , 7 , and 9 at 0–5 °C in pyridine to afford hydrazinylhydrazonoyl derivatives 4 , and diazenylheterocyclic derivatives 6 , 8 , and 10 , respectively. Also, aminopyrazolo[3,4-b]pyridine 1 condensed with different aryl or heteroaryl aldehydes in EtOH/AcOH gave the corresponding aldimine 14 , 15 , 16 . Compound 15 was cyclized via refluxing in DMF for 6 h to afford 18 , while the transformation of compound 16 with an alkyl halide afforded 19a , b . The synthesized compounds, explicated by spectral data and elemental analysis, were examined for their antitumor activities. The in vitro cytotoxic activity of new pyrazolo[3,4-b]pyridines against the A2780CP, MCF-7, and HepG-2 cell lines was evaluated using the reference doxorubicin. Compounds 15 and 19a exhibited high reactivity against the A2780CP cell lines, with IC₅₀ values of 35 and 17.9 μM, respectively. Also, compound 28 had the cytotoxic potential for A2780CP and MCF-7 cell lines, with IC₅₀ values of 14.5, and 27.8 μM, respectively.     

Melatonin as an effective protector against doxorubicin-induced cardiotoxicity

The present study was designed to explore the protective effects of melatonin and its analogs, 6-hydroxymelatonin and 8-methoxy-2-propionamidotetralin, on the survival of doxorubicin-treated mice and on doxorubicin-induced cardiac dysfunction, ultrastructural alterations, and apoptosis in mouse hearts. Whereas 60% of the mice treated with doxorubicin (25 mg/kg ip) died in 5 days, almost all the doxorubicin-treated mice survived when melatonin or 6-hydroxymelatonin (10 mg/l) was administered in their drinking water. Perfusion of mouse hearts with 5 microM doxorubicin for 60 min led to a 50% suppression of heart rate x left ventricular developed pressure and a 50% reduction of coronary flow. Exposure of hearts to 1 microM melatonin or 6-hydroxymelatonin reversed doxorubicin-induced cardiac dysfunction. 8-Methoxy-2-propionamidotetralin had no protective effects on animal survival and on in vitro cardiac function. Infusion of melatonin or 6-hydroxymelatonin (2.5 microg/h) significantly attenuated doxorubicin-induced cardiac dysfunction, ultrastructural alterations, and apoptosis in mouse hearts. Neither melatonin nor 6-hydroxymelatonin compromised the antitumor activity of doxorubicin in cultured PC-3 cells. These results suggest that melatonin protect against doxorubicin-induced cardiotoxicity without interfering with its antitumor effect.     

Amelioration of doxorubicin-induced cardiotoxicity by deferiprone in rats

The therapeutic usefulness of doxorubicin (Dox), an anthracycline antibiotic used as an anticancer agent, is limited by its cardiotoxicity. Dox-induced cardiotoxicity is mainly attributed to accumulation of reactive oxygen species and interaction of Dox with cellular iron metabolism. The present study investigated the effects of the iron chelator deferiprone (Def) against Dox-induced cardiotoxicity in rats. Dox (15?mg/kg) was injected intraperitoneally as a single dose, and Def (10?mg/kg) was administered orally for 10?days. Dox showed cardiotoxicity as evidenced by increased heart rate, elevated ST segment, prolonged QTc interval, and increased T wave amplitude. In addition, Dox enhanced aconitine cardiotoxicity by decreasing its dose, producing ventricular tachycardia. Administration of Def significantly attenuated Dox-induced electrocardiographic changes. Cardiotoxicity of Dox was confirmed biochemically by a significant elevation in serum creatine kinase-MB and lactate dehydrogenase activities as well as by myocardial malondialdehyde and reduced glutathione contents. Moreover, Dox caused a significant decrease in myocardial superoxide dismutase activity. Administration of Def significantly attenuated the biochemical changes. These results suggest that Def might be a potential cardioprotective agent against Dox-induced cardiotoxicity.     

Inhibition of Rac1 signaling by lovastatin protects against anthracycline-induced cardiac toxicity

Normal tissue damage limits the efficacy of anticancer therapy. For anthracyclines, the clinically most relevant adverse effect is cardiotoxicity. The mechanisms involved are poorly understood and putative cardioprotectants are controversially discussed. Here, we show that the lipid-lowering drug lovastatin protects rat H9c2 cardiomyoblasts from doxorubicin in vitro. Protection by lovastatin is related to inhibition of the Ras-homologous GTPase Rac1. It rests on a reduced formation of DNA double-strand breaks, resulting from the inhibition of topoisomerase II by doxorubicin. Doxorubicin transport and reactive oxygen species are not involved. Protection by lovastatin was confirmed in vivo. In mice, lovastatin mitigated acute doxorubicin-induced heart and liver damage as indicated by reduced mRNA levels of the pro-fibrotic cytokine connective tissue growth factor (CTGF) and pro-inflammatory cytokines, respectively. Lovastatin also protected from doxorubicin-provoked subacute cardiac damage as shown by lowered mRNA levels of CTGF and atrial natriuretic peptide. Increase in the serum concentration of troponin I and cardiac fibrosis following doxorubicin treatment were also reduced by lovastatin. Whereas protecting the heart from harmful doxorubicin effects, lovastatin augmented its anticancer efficacy in a mouse xenograft model with human sarcoma cells. These data show that statins lower the incidence of cardiac tissue injury after anthracycline treatment in a Rac1-dependent manner, without impairing the therapeutic efficacy.     

Intravenous rutin in rat exacerbates isoprenaline-induced cardiotoxicity likely due to intracellular oxidative stress

Objectives: Rutin, quercetin-3-O-rutinoside, a natural flavonol glycoside, has shown various in vitro benefits with potential use treating human diseases, especially cardiovascular system disorders. Antioxidant properties are assumed to underlie the majority of these benefits. Yet rutin pro-oxidant properties have been reported as well. Our research group has recently shown aggravating effects on isoprenaline (ISO)-induced cardiotoxicity in Wistar:Han rats after 24?hours.

Methods: This study was designed to examine in more detail the reasons for the negative effects of rutin (11.5 and 46?mg/kg, i.v.) after administration of ISO (100?mg/kg, s.c.) in rats within 2?hours of continuous experiment and in the H9c2 cardiomyoblast-derived cell line.

Results: Like our previous findings, rutin did not (11.5 or 46?mg/kg, i.v.) reduce the ISO-induced mortality within 2?hours although the lower dose significantly reduced cardiac troponin T (cTnT) and partly improved the histological findings. In contrast, the higher dose increased the mortality in comparison with solvent (1.26% w/v sodium bicarbonate). This was not caused by any specific haemodynamic disturbances. It appears to be associated with oxidative stress as rutin enhanced intracellular reactive oxygen species formation in vitro and had the tendency to increase it in vivo.

Conclusions: Rutin, likely due to its pro-oxidative effects, can exacerbate catecholamine cardiotoxicity depending on the dose used.     

Effects of MnDPDP and ICRF-187 on Doxorubicin-Induced Cardiotoxicity and Anticancer Activity

Oxidative stress participates in doxorubicin (Dx)-induced cardiotoxicity. The metal complex MnDPDP and its metabolite MnPLED possess SOD-mimetic activity, DPDP and PLED have, in addition, high affinity for iron. Mice were injected intravenously with MnDPDP, DPDP, or dexrazoxane (ICRF-187). Thirty minutes later, mice were killed, the left atria were hung in organ baths and electrically stimulated, saline or Dx was added, and the contractility was measured for 60 minutes. In parallel experiments, 10 μM MnDPDP or MnPLED was added directly into the organ bath. The effect of MnDPDP on antitumor activity of Dx against two human tumor xenografts (MX-1 and A2780) was investigated. The in vitro cytotoxic activity was studied by co-incubating A2780 cells with MnDPDP, DPDP, and/or Dx. Dx caused a marked reduction in contractile force. In vivo treatment with MnDPDP and ICRF-187 attenuated the negative effect of Dx. When added directly into the bath, MnDPDP did not protect, whereas MnPLED attenuated the Dx effect by approximately 50%. MnDPDP or ICRF-187 did not interfere negatively with the anti-tumor activity of Dx, either in vivo or in vitro. Micromolar concentrations of DPDP but not MnDPDP displayed an in vitro cytotoxic activity against A2780 cells. The present results show that MnDPDP, after being metabolized to MnPLED, protects against acute Dx cardiotoxicity. Both in vivo and in vitro experiments show that cardioprotection takes place without interfering negatively with the anticancer activity of Dx. Furthermore, the results suggest that the previously described cytotoxic in vivo activity of MnDPDP is an inherent property of DPDP.     

Gold(I) Complexes of 9-Deazahypoxanthine as Selective Antitumor and Anti-Inflammatory Agents

The gold(I) mixed-ligand complexes involving O-substituted derivatives of 9-deazahypoxanthine (HL_n) and triphenylphosphine (PPh₃) with the general formula [Au(L_n)(PPh₃)] (1–5) were prepared and thoroughly characterized by elemental analysis, FT-IR and multinuclear NMR spectroscopy, ESI+ mass spectrometry, single crystal X-ray (HL₅ and complex 2) and TG/DTA analyses. Complexes 1–5 were evaluated for their in vitro antitumor activity against nine human cancer lines, i.e. MCF7 (breast carcinoma), HOS (osteosarcoma), A549 (adenocarcinoma), G361 (melanoma), HeLa (cervical cancer), A2780 (ovarian carcinoma), A2780R (ovarian carcinoma resistant to cisplatin), 22Rv1 (prostate cancer) and THP-1 (monocytic leukaemia), for their in vitro anti-inflammatory activity using a model of LPS-activated macrophages, and for their in vivo antiedematous activity by λ-carrageenan-induced hind paw edema model on rats. The results showed that the complexes 1–5 exhibit selective in vitro cytotoxicity against MCF7, HOS, 22Rv1, A2780 and A2780R, with submicromolar IC₅₀ values for 2 against the MCF7 (0.6 µM) and HOS (0.9 µM). The results of in vitro cytotoxicity screening on primary culture of human hepatocytes (HEP220) revealed up to 30-times lower toxicity of compounds against healthy cells as compared with cancer cells. Additionally, the complexes 1–5 significantly influence the secretion and expression of pro-inflammatory cytokines TNF-α and IL-1β by a similar manner as a commercially used anti-arthritic drug Auranofin. The tested complexes also significantly influence the rate and overall volume of the edema, caused by the intraplantar application of λ-carrageenan polysaccharide to rats. Based on these promising results, the presented compounds could qualify to become feasible candidates for advanced testing as potential antitumor and anti-inflammatory drug-like compounds.     

FL3, a Synthetic Flavagline and Ligand of Prohibitins,Protects Cardiomyocytes via STAT3 from Doxorubicin Toxicity

Aims

The clinical use of doxorubicin for the treatment of cancer is limited by its cardiotoxicity. Flavaglines are natural products that have both potent anticancer and cardioprotective properties. A synthetic analog of flavaglines, FL3, efficiently protects mice from the cardiotoxicity of doxorubicin. The mechanism underlying this cardioprotective effect has yet to be elucidated.

Methods and Results

Here, we show that FL3 binds to the scaffold proteins prohibitins (PHBs) and thus promotes their translocation to mitochondria in the H9c2 cardiomyocytes. FL3 induces heterodimerization of PHB1 with STAT3, thereby ensuring cardioprotection from doxorubicin toxicity. This interaction is associated with phosphorylation of STAT3. A JAK2 inhibitor, WP1066, suppresses both the phosphorylation of STAT3 and the protective effect of FL3 in cardiomyocytes. The involvement of PHBs in the FL3-mediated cardioprotection was confirmed by means of small interfering RNAs (siRNAs) targeting PHB1 and PHB2. The siRNA knockdown of PHBs inhibits both phosphorylation of STAT3 and the cardioprotective effect of FL3.

Conclusion

Activation of mitochondrial STAT3/PHB1 complex by PHB ligands may be a new strategy against doxorubicin-induced cardiotoxicity and possibly other cardiac problems.     

Hydroxyl radical production by the iron complex of the hydrolysis product of the antioxidant cardioprotective agent ICRF-187 (dexrazoxane)

SUMMARY

Dexrazoxane (ICRF-187) is now in clinical use for the prevention of doxorubicin-induced cardiotoxicity. This cardiotoxicity is thought to be due to iron-mediated oxidative stress. Dexrazoxane may be acting through its strongly metal ion binding rings-opened hydrolysis product ADR-925 by complexing iron. Since iron-chelates are known to be able to produce hydroxyl radicals, an electron paramagnetic resonance spin trapping study was undertaken to compare the hydroxyl radical-producing ability of the ferrous-ADR-925 complex with that of the ferrous complexes of ethylenediaminetetraacetic acid (EDTA) and the tetraacid analog of ADR-925 (DAPTA). In spectrophotometric studies it was shown that the ferrous-ADR-925 complex underwent aerobic oxidation 87 and 44 times slower than the ferrous complexes of EDTA or 1,2-diaminopropane-N,N,N',N'-tetraacetic acid (DAPTA), respectively. In spite of the much slower oxidation of the ferrous-ADR-925 complex, it was, nonetheless, equally effective in producing hydrogen peroxide-dependent spin adducts. These spin adducts were produced from the reaction of the spin trap with free hydroxyl radical (HO^.), and with a transient iron oxidant with HO^.-like reactivity. Thus, it is concluded that ADR-925 acts by either complexing free iron or iron bound to doxorubicin, and forming a soluble iron complex that is less effective at producing site-specific oxygen radical damage.     

New synthetic flavonoids as potent protectors against doxorubicin-induced cardiotoxicity.

A series of 3,7-disubstituted-2(3',4'-dihydroxyphenyl) flavones has been studied as potential cardioprotective agents in doxorubicin antitumor therapy. The influence of substituents on the 3 and 7 position of the flavone nucleus on antioxidant activity cytotoxicity and cardioprotective properties was explored to improve the activity of our lead compound 7-monohydroxyethylrutoside. In the protection against Fe(2+)/vitamin C-induced microsomal lipid peroxidation (LPO assay), IC(50) values ranged from 0.2 to 37 microM. In general, the 3-substituted flavones were the most potent compounds in this assay. The cytotoxicity of the new compounds was tested (up to 250 microM) in hepatocytes. LDH leakage ranged from 2.6-29.2%, whereas the GSH concentrations decreased to 87.3-41.3%. Only four compounds out of this series protected the isolated mouse left atrium against doxorubicin-induced toxicity. Because of the positive inotropic effect of 8d (N-(3-(3',4'-dihydroxyflavon-7-yl)oxypropyl)-N,N,N-trimethylammonium chloride) and 10c (3-hydroxyethoxy-7,3',4'-trihydroxyflavone) on the atrium, compounds 9i (3',4'-dihydroxy-3-glucosylflavone) and 10d (N-(3-(7,3',4'-trihydroxyflavon-3-yl)oxypropyl)-N,N,N-trimethylammonium chloride) were selected to be evaluated as cardioprotective agents in vivo.