ВОЗМОЖНОСТИ МЕДИКАМЕНТОЗНОЙ ПРОФИЛАКТИКИ АНТРАЦИКЛИН-ИНДУЦИРОВАННОЙ КАРДИОТОКСИЧНОСТИ

Purpose. To estimate the possibility of trimethylhydrasine propionate using for prevention of acute doxorubicin-induced cariotoxicity in breast cancer patients. Material and methods. The study included 72 women (mean age – 51 ± 2.1 years) with breast cancer without significant pathology of the cardiovascular system. Main group consisted of 32 patients (mean age – 52 ± 2.2 years), which were injected intravenously trimethylhydrasine propionate 1000 mg 1 times/day for three days prior to chemotherapy. 40 patients of the control group (mean age – 50 ± 2.5 years) did not receive of cardioprotective therapy before chemotherapy. For the cancer treatment of these patients used doxorubicin in dose of 50 mg/m2  per course in combination with various drugs. All patients were studied by GATE SPECT before starting chemotherapy and at 1 hour after the first administration of doxorubicin. Results. Before the start of chemotherapy, none of the patients showed perfusion defects and contractility disorders. Baselines left ventricular contractility in control group and in main group was not different. After doxorubicin administration in the control group there was a decrease in left ventricular ejection fraction (LVEF) – from 65.5 ± 9.8 % to 61.8 ± 7.2 % (p<0.05), increase in left ventricular end-systolic volume – from 30.8 ± 16.7 ml to 34.2 ± 17.0 ml (p<0.05), reduction in the peak ejection rate – from 3.2 ± 0.8 EDV/s to 2.4 ± 0.5 EDV/s (p<0.05). In the main group after first course of chemotherapy statistically significant changes of left ventricular contractile function were not found. After administration of doxorubicin was found that 31 % patients of main group and 40 % patients of control group had a considerable (10% or more) reduction in LVEF.Цель. Изучение возможности применения триметилгидразиния пропионата для предупреждения развития острой кардиоток сичности цитостатической химиотерапии у больных злокачественными новообразованиями. Материал и методы. В исследование включены 72 женщины (средний возраст 51 ± 2,1 года) со злокачественными новооб разованиями молочной железы. Основную группу составили 32 пациентки, средний возраст – 52 ± 2,2 года, которым назначался триметилгидразиния пропионат в дозе 1000 мг 1 раз/день, в течение трех дней до начала химиотерапии (ХТ). В контрольную группу включены 40 женщин, средний возраст – 50 ± 2,5 года, которые получали ХТ доксорубицинсодержащими режимами. Всем обследуемым была выполнена ЭКГ-синхронизированная перфузионная однофотонная эмиссионная компьютерная томография миокарда (ЭКГ-ПСМ) до начала комбинированной химиотерапии и через 1 ч после первого введения доксорубицина (до введения других цитостатиков). Результаты и обсуждение. До начала ХТ не было выявлено нарушений перфузии и сократительной способности миокарда левого желудочка. После введения доксорубицина, помимо снижения фракции выброса с 65,5 ± 9,8 до 61,8 ± 7,2 (р<0,05), в контроль ной группе наблюдалось значимое увеличение конечно-систолического объема левого желудочка – с 30,8 ± 16,7 до 34,2 ± 17,0 мл и снижение максимальной скорости изгнания – с 3,2 ± 0,8 КДО/c до 2,4 ± 0,5 КДО/с. При этом оказалось, что у 40 % пациентов контрольной группы происходит значительное (на 10 % и более) снижение ФВЛЖ. В группе с профилактическим применением пропионата триметилгидразиния после введения доксрубицина не отмечалось статистически значимого снижения фракции вы броса левого желудочка и увеличения его конечно-систолического объема. У 31 % больных в ответ на введение доксорубицина в дозе 50 мг/м2  после профилактического применения пропионата триметилгидразиния отмечалось значимое (на 10 % и более от начального) снижение фракции выброса левого желудочка

Mice lacking mitochondrial ferritin are more sensitive to doxorubicin-mediated cardiotoxicity

15noMitochondrial ferritin is a functional ferritin that localizes in themitochondria.Itisexpressedinthetestis, heart,brain,and cells with active respiratory activity. Its overexpression in culturedcellsprotectedagainstoxidativedamageandreduced cytosolic iron availability. However, no overt phenotype was describedinmicewithinactivationoftheFtMtgene.Here,we usedthe doxorubicin model ofcardiac injuryina novel strain of FtMt-null mice to investigate the antioxidant role of FtMt. These mice did not show any evident phenotype, but after acute treatment to doxorubicin, they showed enhanced mortalityandaltered heartmorphologywithfibrildisorganization and severe mitochondrial damage. Signs of mitochondrial damage were present also in mock-treated FtMt−/− mice. The hearts of saline- and doxorubicin-treated FtMt−/− mice had higher thiobarbituric acid reactive substance levels, heme oxygenase 1 expression, and protein oxidation, but did not differ from FtMt+/+ in the cardiac damage marker B-type natriureticpeptide(BNP),ATP levels, and apoptosis.However,the autophagy marker LC3 was activated. The results show that the absence of FtMt, which is highly expressed in the heart, increases the sensitivity of heart mitochondria to the toxicity of doxorubicin. This study represents the first in vivo evidence of the antioxidant role of FtMt.openopenMaccarinelli, Federica; Gammella, Elena; Asperti, Michela; Mariaregon, ; Donetti, Elena; Recalcati, Stefania; Poli, Maura; Finazzi, Dario; Arosio, Paolo; Biasiotto, Giorgio; Emiliaturco, ; Altruda, Fiorella; Lonardi, Silvia; Cornaghi, Laura; Cairo, GaetanoMaccarinelli, Federica; Gammella, Elena; Asperti, Michela; Mariaregon, ; Donetti, Elena; Recalcati, Stefania; Poli, Maura; Finazzi, Dario; Arosio, Paolo; Biasiotto, Giorgio; Emiliaturco, ; Altruda, Fiorella; Lonardi, Silvia; Cornaghi, Laura; Cairo, Gaetan

Doxorubicin paradoxically protects cardiomyocytes against iron-mediated toxicity: role of reactive oxygen species and ferritin.

The cardiotoxicity induced by the anticancer anthracycline doxorubicin (DOX) is attributed to reactions between iron and reactive oxygen species (ROS) that lead to oxidative damage. We found that DOX forms ROS in H9c2 cardiomyocytes, as shown by dichlorodihydrofluorescein oxidation and the expression of stress-responsive genes such as catalase or aldose reductase. DOX also increased ferritin levels in these cells, particularly the H subunit. A considerable increase in ferritin mRNA levels showed that DOX acted at transcriptional level, but an additional potential mechanism was identified as the down-regulation of iron regulatory protein-2, post-transcriptional inhibitor of ferritin synthesis. Pretreatment with DOX protected H9c2 cells against the damage induced by subsequent exposure to ferric ammonium citrate, and experiments with 55Fe revealed that the protection was due to the deposition of iron in ferritin. Cytoprotection was also observed when DOX was replaced by glucose/glucose oxidase, a source of H2O2, thus suggesting that DOX increases ferritin synthesis through the action of ROS. This concept was supported by three more lines of evidence. (i) DOX-induced ferritin synthesis was blocked by N-acetylcysteine, a scavenger of ROS. (ii) Mitoxantrone, a ROS-forming analogue, similarly induced ferritin expression and protected the cells against iron toxicity. (iii) 5-Iminodaunorubicin, an analogue lacking ROS-forming activity, did not induce ferritin synthesis or protect the cells against iron toxicity. These results characterize a paradoxically beneficial link between anthracycline-derived ROS, increased ferritin synthesis, and resistance to iron-mediated damage. The role of iron and ROS in anthracycline-induced cardiotoxicity may, therefore, be more complex than previously believed

Theoretical ground for adsorptive therapy of anthracyclines cardiotoxicity

Anthracyclines play an important role in treatment of variety types of cancer due to their high effectiveness and broad spectrum of activity. However, a major limitation of their use is the dose-limiting cardiotoxicity. The inability to predict and prevent anthracycline cardiotoxicity is in part due to the fact that the molecular and cellular mechanisms remain controversial and incompletely understood. This review focuses on the biochemical basis of the anthracyclines toxic cardiac effects and pharmacological measures to their treatment and preventing. We describe the theoretical substantiation of the enterosorption abilities for diminishing of cardiac damage

New perspectives on the molecular basis of the interaction between oxygen homeostasis and iron metabolism

Oxygen and iron are two elements closely related from a (bio)chemical point of view. Moreover, they share the characteristic of being indispensable for life, while also being potentially toxic. Therefore, their level is strictly monitored, and sophisticated pathways have evolved to face variations in either element. In addition, the expression of proteins involved in iron and oxygen metabolism is mainly controlled by a complex interplay of proteins that sense both iron levels and oxygen availability (ie, prolyl hydroxylases, hypoxia inducible factors, and iron regulatory proteins), and in turn activate feedback mechanisms to re-establish homeostasis. In this review, we describe how cells and organisms utilize these intricate networks to regulate responses to changes in oxygen and iron levels. We also explore the role of these pathways in some pathophysiological settings

Effects of cellular iron deficiency on the formation of vascular endothelial growth factor and angiogenesis. Iron deficiency and angiogenesis

<p>Abstract</p> <p>Background</p> <p>Young women diagnosed with breast cancer are known to have a higher mortality rate from the disease than older patients. Specific risk factors leading to this poorer outcome have not been identified. In the present study, we hypothesized that iron deficiency, a common ailment in young women, contributes to the poor outcome by promoting the hypoxia inducible factor-1α (HIF-1α and vascular endothelial growth factor (VEGF) formation. This hypothesis was tested in an <it>in vitro </it>cell culture model system.</p> <p>Results</p> <p>Human breast cancer MDA-MB-231 cells were transfected with transferrin receptor-1 (TfR1) shRNA to constitutively impair iron uptake. Cellular iron status was determined by a set of iron proteins and angiogenesis was evaluated by levels of VEGF in cells as well as by a mouse xenograft model. Significant decreases in ferritin with concomitant increases in VEGF were observed in TfR1 knockdown MDA-MB-231 cells when compared to the parental cells. TfR1 shRNA transfectants also evoked a stronger angiogenic response after the cells were injected subcutaneously into nude mice. The molecular mechanism appears that cellular iron deficiency elevates VEGF formation by stabilizing HIF-1α. This mechanism is also true in human breast cancer MCF-7 and liver cancer HepG2 cells.</p> <p>Conclusions</p> <p>Cellular iron deficiency increased HIF-1α, VEGF, and angiogenesis, suggesting that systemic iron deficiency might play an important part in the tumor angiogenesis and recurrence in this young age group of breast cancer patients.</p

Iron-regulatory proteins: molecular biology and pathophysiological implications

Iron is required for key cellular functions, and there is a strong link between iron metabolism and important metabolic processes, such as cell growth, apoptosis and inflammation. Diseases that are directly or indirectly related to iron metabolism represent major health problems. Iron-regulatory proteins (IRPs) 1 and 2 are key controllers of vertebrate iron metabolism and post-transcriptionally regulate expression of the major iron homeostasis genes. Here we discuss how dysregulation of the IRP system can result from both iron-related and unrelated effectors and explain how this can have important pathological consequences in several human disorders

ROLE OF HIF ACTIVATION IN THE PROTECTION OF CARDIOMYOCYTES FROM DOXORUBICIN TOXICITY

Anthracyclines are important and effective anticancer drugs used in the treatment of many adult and children malignancies. Doxorubicin (DOX) is the anthracycline most commonly used in cancer patients but its cardiotoxicity limits its clinical use. The precise molecular basis of anthracyclines cardiotoxicity remains elusive, but a number of theories have been proposed, one of which is the formation of reactive oxygen species (ROS). Iron aggravates the cardiotoxicity of DOX; indeed, dexrazoxane (DRZ) is the only agent able to protect the myocardium from anthracycline-induced toxicity both in experimental and clinical settings. Iron has been proposed to catalyse ROS formation in reactions primed by DOX. However, the oxidative nature of the role of iron in cardiotoxicity is challenged by results showing that antioxidants do not always protect against cardiotoxicity. Therefore, the mechanisms of DOX-mediated cardiotoxicity, and the protective role of DRZ, remain to be established. The hypoxia inducible factors (HIF, HIF-1a and HIF-2a) are transcription factors which regulate the expression of several genes mediating adaptive responses to lack of oxygen. Iron is required for HIF degradation and therefore decreased iron availability activates HIF in normoxic cells. In consideration of the antiapoptotic and protective role of some HIFinduced genes, we tested the hypothesis that DRZ-dependent HIF activation may mediate the cardioprotective effect of DRZ. Treatment with DRZ induced HIF protein levels and transactivation capacity in the H9c2 cardiomyocytes cell line. DRZ also prevented the induction of cell death and apoptosis caused by the exposure of H9c2 cells to clinically-relevant concentrations of DOX. Experiments involving suppression of HIF-1a activity or HIF-1a overexpression showed that the protective effect of DRZ was dependent on HIF-1 activity. By examining the expression of HIF target genes with a possible role in cell survival in DRZ-treated H9c2 cells we found that a strong increase in protein levels of antiapoptotic genes and haem oxygenase (HO-1) plays a role in the HIF-mediated cardioprotection offered by DRZ. We also explored two possible alternative pharmacological strategies to prevent DOXinduced toxicity. 4 The first one was based on a small molecular mimic of hypoxia that could be exploited in an attempt to limit anthracycline cardiotoxicity. We examined HIF-1a levels and activity, as well as protection from DOX damage, in H9c2 cardiomyocytes pre-exposed to DMOG, an antagonist of \u3b1-ketoglutarate which activates HIF under normoxic conditions. However, we did not find any kind of protection from damage induced by DOX in H9c2 cells pre-treated with DMOG. The second one was based on the activation of the sodium-dependent glucose transporter- 1 (SGLT-1), which has been shown to protect different types of cells from various injuries. We found that pre-treatment with D-glucose protected H9c2 cells from DOXinduced toxicity, but the non-metabolizable glucose analog 3-O-methylglucose, and the SLGT-1 agonist BLF50 were ineffective, thus indicating that the protection was not mediated by the activation of SGLT-1