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Cardiotoxicity - Top 30 Publications

Concerns about cardiotoxicity in the HERA trial - Authors' reply.

Concerns about cardiotoxicity in the HERA trial.

Early detection of the cardiotoxicity induced by chemotherapy drug through two-dimensional speckle tracking echocardiography combined with high-sensitive cardiac troponin T.

Objective: To investigate the clinical value of two-dimensional speckle tracking echocardiography(2D-STE) combined with high-sensitive cardiac troponin T (hs-cTnT) in early detection of the cardiotoxicity induced by chemotherapy drug. Methods: Seventy-five non-Hodgkin's lymphoma patients who received the CHOP regimen were recruited in this study. Conventional echocardiography and 2D-STE were performed on these patients before chemotherapy, the second day after the third course of chemotherapy (during chemotherapy) and the second day after the last course of chemotherapy (after chemotherapy). The parameters included left ventricular ejection fraction (LVEF), global longitudinal strain (LS), global circumferential strain (CS) and global radial strain (RS). The serum hs-cTNT levels were tested simultaneously. Results: Three cycles of CHOP were completed in 30 patients and 6-8 cycles of CHOP were completed in 45 patients. The LVEF of 75 patients before, during and after chemotherapy was (63.8±2.6)%, (63.8±2.8)% and (64.0±3.3)%, respectively, without significant difference (P=0.91). However, the LS of 75 patients before, during and after chemotherapy was (-18.5±1.7)%, (-16.5±1.9)% and (-16.0±1.6)%, respectively. The CS was (-20.9±2.9)%, (-19.3±3.5)% and (-19.2±3.2)%, respectively. The RS was (39.2±6.4)%, (35.3±5.2)% and (35.0±6.2)%, respectively. The hs-cTnT was (0.001 0±0.002 0)ng/ml, (0.006 3±0.008 9)ng/ml and (0.007 3±0.003 8)ng/ml, respectively. The LS, CS and RS were significantly decreased while hs-cTnT was significantly increased during chemotherapy when compared to those before chemotherapy (all of P<0.01). Alternatively, the LS, CS, RS and hs-cTnT after chemotherapy were marginally different from those during chemotherapy (all of P>0.05). Moreover, T(LS-SD), T(CS-SD) and T(RS-SD) showed no significant difference before, during and after chemotherapy (all of P>0.05). The reduction of LS was positively associated with the enhancement of hs-cTnT after chemotherapy (r=0.60, P<0.01). Conclusion: 2D-STE combined with hs-cTnT can effectively and precisely detect the occult cardiotoxicity induced by anthracycline.

Assessing for Cardiotoxicity from Metal-on-Metal Hip Implants with Advanced Multimodality Imaging Techniques.

High failure rates of metal-on-metal (MoM) hip implants prompted regulatory authorities to issue worldwide safety alerts. Circulating cobalt from these implants causes rare but fatal autopsy-diagnosed cardiotoxicity. There is concern that milder cardiotoxicity may be common and underrecognized. Although blood metal ion levels are easily measured and can be used to track local toxicity, there are no noninvasive tests for organ deposition. We sought to detect correlation between blood metal ions and a comprehensive panel of established markers of early cardiotoxicity.

Oxymatrine Ameliorates Doxorubicin-Induced Cardiotoxicity in Rats.

Doxorubicin-induced cardiac toxicity has been a major concern of oncologists and is considered the main restriction on its clinical application. Oxymatrine has shown potent anti-cancer, anti-fibrosis, and anti-oxidative effects. Recently, it has been reported that oxymatrine is protective against some cardiovascular diseases. In this study, we aimed to investigate the effects of oxymatrine on doxorubicin-induced cardiotoxicity in rat hearts and H9c2 cells.

Cardiac safety profile of patients receiving high cumulative doses of pegylated-liposomal doxorubicin: use of left ventricular ejection fraction is of unproven value.

One of the great conundrums for both oncologists and cardiologists is how to best monitor the potential and actual cardiotoxicity of doxorubicin. Pegylated-liposomal doxorubicin (PLD) has a safer cardiotoxicity profile than bolus administration of doxorubicin. Although ejection fraction (EF) is commonly performed to monitor doxorubicin-induced cardiotoxicity, evidence for its predictive utility is limited. We examined the incidence of doxorubicin-induced heart failure (HF) in patients who received a large cumulative dose of doxorubicin as PLD and its relation to EF and HF.

Incidence and risk of cardiotoxicity in cancer patients treated with targeted therapies.

Cardiotoxicityis a serious side effect of molecularly targeted agents. The purpose of this study was to evaluate the incidence and Relative Risk (RR) of developing all-grade and high-grade cardiotoxicity in patients with solid tumors receiving targeted agents through a revised meta-analysis of available clinical trials.

Absence of cardiotoxicity with prolonged treatment and large accumulating doses of pegylated liposomal doxorubicin.

Pegylated liposomal doxorubicin (PLD) is used as a second-line therapy for gynecologic cancers, with a better short-term toxicity profile compared to doxorubicin or other anthracyclines.

Allicin ameliorates doxorubicin-induced cardiotoxicity in rats via suppression of oxidative stress, inflammation and apoptosis.

Doxorubicin (DOX) is a highly active antineoplastic agent; however, its clinical use is limited due to associated cardiotoxicity. This study was performed to evaluate the beneficial effects of allicin, a dietary garlic active constituent against DOX-induced cardiotoxicity.

Cardiotoxic effects of anthracycline-based therapy: what is the evidence and what are the potential harms?

Despite the known cardiotoxic effects of doxorubicin and other anthracyclines, no evidence-based guidelines exist for the surveillance and prevention of chemotherapy-induced cardiotoxicity in adult survivors of breast cancer who have had limited previous doses of anthracyclines (ie, total cumulative dose 240 mg/m2), or limited-dose anthracyclines followed by trastuzumab-based regimens. Nonetheless, some national and international cardio-oncology and cardiac-imaging organisations recommend increased cardiac surveillance during or after treatment, measurement of cardiac biomarkers and other surrogate endpoints, and in some cases initiation of cardioprotective drug therapy in asymptomatic women. However, two unintended potential harms of such approaches are medicalisation (definition and treatment of subclinical heart problems without high-level evidence for a consequent reduction in the incidence of subsequent heart failure or cardiac deaths) and increased health-care costs when the value of providing that care is unknown. Whether existing cardio-oncology or imaging guideline recommendations will provide increased value or cause increased distress and lower health-related quality of life is unknown. Further research is needed to assess the long-term benefits, harms, and value of expanded cardiac surveillance, use of surrogate cardiac biomarkers, and prophylactic cardioprotective therapy in asymptomatic women with limited exposure to anthracyclines.

Comment on Asghari et al. 2017: On the mechanisms of melatonin in protection of aluminum phosphide cardiotoxicity. Arch Toxicol Epub ahead of print. doi:10.1007/s00204-017-1998-6.

In response to the comments on our recently published paper entitled "on the mechanisms of melatonin in protection of aluminum phosphide cardiotoxicity".

Cardiac autonomic modulation induced by doxorubicin in a rodent model of colorectal cancer and the influence of fullerenol pretreatment.

The very effective anticancer drug doxorubicin (DOX) is known to have cardiotoxic side effects, which could be accompanied by autonomic modulation. Autonomic disbalance might even be an initiating mechanism underlying DOX-induced cardiotoxicity and can be studied noninvasively by the analysis of heart rate variability (HRV). A number of strategies have been assessed to predict chemotherapy-induced cardiac dysfunction while HRV, a potential detecting tool, has not yet been tested. Thus, we aimed to determine the effect of DOX treatment on HRV in a rat model of colorectal cancer. While pretreatment with fullerenol (Frl) acts protectively on DOX-induced cardiotoxicity, we aimed to test the effect of Frl pretreatment on DOX-induced HRV alterations. After the induction of colorectal cancer, adult male Wistar rats were treated with saline (n = 7), DOX (1.5 mg/kg per week, n = 7) or DOX after pretreatment with Frl (25 mg/kg per week, n = 7) for three weeks (cumulative DOX dose 4.5 mg/kg). One week after treatment rats were anaesthetized, standard ECG was measured and HRV was analyzed in time and frequency domain. During autopsy the intestines and hearts were gathered for biochemical analysis and histopathological examination. DOX treatment significantly decreased parasympathetically mediated high-frequency component (p<0.05) and increased the low-frequency component of HRV (p<0.05), resulting in an increased LF/HF ratio (p<0.05) in cancerous rats. When pretreated with Frl, DOX-induced HRV alterations were prevented: the high-frequency component of HRV increased (p<0.01), the low-frequency decreased (p<0.01), LF/HF ratio decreased consequently (p<0.01) compared to DOX only treatment. In all DOX-treated animals, disbalance of oxidative status in heart tissue and early myocardial lesions were found and were significantly reduced in rats receiving Frl pretreatment. Autonomic modulation accompanied the development of DOX-induced cardiotoxicity in rat model of colorectal cancer and was prevented by Frl pretreatment. Our results demonstrated the positive prognostic power of HRV for the early detection of DOX-induced cardiotoxicity.

Breast cancer treatment-induced cardiotoxicity.

Breast cancer is the most frequent cancer affecting women worldwide. In every setting, the majority of women are treated with an evergrowing arsenal of therapeutic agents that have greatly improved their outcomes. However, these therapies can also be associated with significant adverse events. Areas covered: This review aims to thoroughly describe the current state of the evidence regarding the potential cardiotoxicity of agents commonly used in the treatment of breast cancer. These include chemotherapeutic agents, anti-HER2 therapies and CDK4/6 and mTOR inhibitors. Furthermore, issues related to the risk stratification and monitoring tools are explored. Expert opinion: Anthracycline- and trastuzumab-related cardiac toxicities have been extensively studied. Substantial evidence is now available concerning additional anti-HER2 agents such as pertuzumab, T-DM1 and tyrosine kinase inhibitors; overall, the cardiotoxicity profile is reassuring. Cardiac events due to endocrine therapy are mostly ischemic and, in the context of prolonged therapy, need specific attention. Novel agents implicated in the treatment of hormone receptor-positive disease are potentially arrhythmogenic and the exact risk will need to be further refined. As for today, assessment of baseline risk factors prior to treatment initiation and cardiac imaging before and during treatment remains the optimal way to prevent cardiac dysfunction. Cardioprotective therapy in primary prevention is still a matter of debate.

Chemotherapy-induced cardiotoxicity in children.

With advances in clinical oncology, the burden of morbidity and mortality for cancer survivors due to the cardiac side effects of the chemotherapy is steadily increasing. Treatment-related cardiac damage is progressive and often irreversible. Primary prevention of cardiotoxicity during treatment is possible with strategies like limiting the cumulative anthracycline dose, the use of anthracycline structural analogs, and especially cardioprotective agents. Areas covered: This review covers the various cardiotoxic chemotherapeutic agents, the pathophysiology of cardiotoxicity due to anthracyclines, and the clinical and subclinical presentations and progression of childhood anthracycline cardiotoxicity. We also discuss preventive measures and strategies, especially the cardioprotectant agent dexrazoxane where there is strong evidence-based support for its use with anthracycline chemotherapy. However, there is a paucity of evidence-based recommendations for diagnosing and treating cancer therapy-induced cardiovascular complications. Finally, we discuss the potential of cardio-oncology. Expert opinion: There is no 'safe' anthracycline dose if the goal is normal long-term cardiovascular status but higher lifetime cumulative doses of anthracyclines, higher dose rates, female sex, longer follow-up, younger age at anthracycline treatment, pre-existing cardiovascular disease, and cardiac irradiation are associated with more severe cardiotoxicity. With deeper understanding of the mechanisms of the adverse cardiac effects and identification of driver mutations causing these effects, personalized cancer therapy to limit cardiotoxic effects can be achieved, such as with the cardioprotectant dexrazoxane.

Doxorubicin Effect on Myocardial Metabolism as a Prerequisite for Subsequent Development of Cardiac Toxicity: A Translational 18F-FDG PET/CT Observation.

The present translational study aimed to verify whether serial 18F-FDG PET/CT predicts doxorubicin cardiotoxicity. Methods: Fifteen athymic mice were treated intravenously with saline (n = 5) or with 5 or 7.5 mg of doxorubicin per kilogram (n = 5 each) and underwent dynamic small-animal PET beforehand and afterward to estimate left ventricular (LV) metabolic rate of glucose (MRGlu). Thereafter, we retrospectively identified 69 patients who had been successfully treated with a regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine for Hodgkin disease (HD) and had undergone 4 consecutive 18F-FDG PET/CT scans. Volumes of interest were drawn on LV myocardium to quantify mean SUV. All patients were subsequently interviewed by telephone (median follow-up, 30 mo); 36 of them agreed to undergo electrocardiography and transthoracic echocardiography. Results: In mice, LV MRGlu was 17.9 ± 4.4 nmol × min-1 × g-1 at baseline. Doxorubicin selectively and dose-dependently increased this value in the standard-dose (27.9 ± 9 nmol × min-1 × g-1, P < 0.05 vs. controls) and high-dose subgroups (37.2 ± 7.8 nmol × min-1 × g-1, P < 0.01 vs. controls, P < 0.05 vs. standard-dose). In HD patients, LV SUV showed a progressive increase during doxorubicin treatment that persisted at follow-up. New-onset cardiac abnormalities appeared in 11 of 36 patients (31%). In these subjects, pretherapy LV SUV was markedly lower with respect to the remaining patients (1.53 ± 0.9 vs. 3.34 ± 2.54, respectively, P < 0.01). Multivariate analysis confirmed the predictive value of baseline LV SUV for subsequent cardiac abnormalities. Conclusion: Doxorubicin dose-dependently increases LV MRGlu, particularly in the presence of low baseline 18F-FDG uptake. These results imply that low myocardial 18F-FDG uptake before the initiation of doxorubicin chemotherapy in HD patients may predict the development of chemotherapy-induced cardiotoxicity, suggesting that prospective clinical trials are warranted to test this hypothesis.

Severe Pneumococcal Pneumonia Causes Acute Cardiac Toxicity and Subsequent Cardiac Remodeling.

Up to one-third of patients hospitalized with pneumococcal pneumonia experience major adverse cardiac events (MACE) during or after pneumonia. In mice, Streptococcus pneumoniae can invade the myocardium, induce cardiomyocyte death, and disrupt cardiac function following bacteremia, but it is unknown whether the same occurs in humans with severe pneumonia.

JS-K, a GST-activated nitric oxide donor prodrug, enhances chemo-sensitivity in renal carcinoma cells and prevents cardiac myocytes toxicity induced by Doxorubicin.

Doxorubicin, a highly effective and widely used anthracycline antibiotic in multiple chemotherapy regimens, has been limited by its cardiotoxicity. The aim of this study is to investigate the effect of nitric oxide donor prodrug JS-K on proliferation and apoptosis in renal carcinoma cells and cardiac myocytes toxicity induced by Doxorubicin and to explore possible p53-related mechanism in renal carcinoma cells.

Fibroblast Activation Protein α Activated Tripeptide Bufadienolide Antitumor Prodrug with Reduced Cardiotoxicity.

Bufadienolides are the major pharmacologic constituents of traditional Chinese medicine Chan'su, which is frequently used clinically for cancer treatment in China. Motivated by reducing or avoiding the cardiac toxicity of bufadienolides, we have designed, synthesized, and evaluated the fibroblast activation protein α (FAPα) activated tripeptide arenobufagin prodrugs with the purpose of improving the safety of arenobufagin (a representative bufadienolide). Among these FAPα-activated prodrugs, 3f exhibited the best hydrolytic efficiency by recombinant human FAPα (rhFAPα) and was activated in tumors. The LD50 of 3f was 6.5-fold higher than that of arenobufagin. We also observed that there are nonapparent changes in echocardiography, pathological section of cardiac muscle, and the lactate dehydrogenase activities (LDH) in 3f-treatment tumor-bearing mice, even when the dose reached 3 times the amount of parent drug arenobufagin that was used. Compound 3f also exhibits significant antitumor activity in vitro and in vivo. The improved safety profile and favorable anticancer properties of 3f warrant further studies of the potential clinical implications. Our study suggests that FAPα prodrug strategy is an effective approach for successful increasing the therapeutic window of bufadienolides.

Cardiotoxicity of ErbB2-targeted therapies and its impact on drug development, a spotlight on trastuzumab.

Trastuzumab, a therapeutic monoclonal antibody directed against ErbB2, is often noted as a successful example of targeted therapy. Trastuzumab improved outcomes for many patients with ErbB2-positive breast and gastric cancers, however, cardiac side effects [e.g., left ventricular dysfunction and congestive heart failure (CHF)] were reported in the early phase clinical studies. This finding, subsequently corroborated by multiple clinical studies, raised concerns that the observed cardiotoxicity induced by trastuzumab might adversely impact the clinical development of other therapeutics targeting ErbB family members. Areas covered: In this review we summarize both basic research and clinical findings regarding trastuzumab-induced cardiotoxicity and assess if there has been an impact of trastuzumab-induced cardiotoxicity on the development of other agents targeting ErbB family members. Expert opinion: There are a number of scientific gaps that are critically important to address for the continued success of HER2-targeted agents. These include: 1) elucidating the molecular mechanisms contributing to cardiotoxicity; 2) developing relevant preclinical testing systems for predicting cardiotoxicity; 3) developing clinical strategies to identify patients at risk of cardiotoxicity; and 4) enhancing management of clinical symptoms of cardiotoxicity.

Fertility, Cardiac, and Orthopedic Challenges in Survivors of Adult and Childhood Sarcoma.

The combination of cisplatin, doxorubicin, and methotrexate was established as the standard backbone of contemporary osteosarcoma therapy in 1986. Since then, however, further improving the survival of patients with osteosarcoma has been challenging-30% to 40% of patients with osteosarcoma still die of this disease. In addition, these patients often experience loss of fertility at a young age, short- and long-term treatment-related cardiotoxicity, and adverse orthopedic effects from surgical resection of the tumor or endoprosthetic reconstructions. Cancer treatment often markedly increases the risk of infertility later in life, causing many patients substantial distress and regret. Sperm banking and oocyte cryopreservation are standard of care and should be available to all at-risk patients. Newer techniques, such as autologous gonadal tissue transplant for prepubertal children, are being developed, and newer systemic agents have infertility risk profiles that remain undefined and warrant further study. Cost and access remain barriers to these options. The late effects of anthracycline-induced cardiotoxicity are also increasingly a problem for these patients. These effects are often progressive and can be disabling. Adding dexrazoxane to doxorubicin therapy significantly reduces the risk for most adverse cardiac outcomes without compromising the efficacy of induction chemotherapy. Limb salvage surgery remains the standard of care for treatment in the majority of patients with extremity sarcomas. Modular metal prostheses and allograft reconstructions comprised the majority of surgical procedures for limb salvage surgery. The most common mechanism of failure of these implants is infection and mechanical failure of the implant.

Functional and Structural Assessment of the Effect of Human Umbilical Cord Blood Mesenchymal Stem Cells in Doxorubicin-Induced Cardiotoxicity.

Cardiomyopathy induced by doxorubicin (DOX) was recognized at an early stage and also several years after drug administration. Mesenchymal stem cells (MSCs) have many properties that make them suitable for preventive and/or regenerative therapies. In this study, we evaluated the effect of MSCs in the functional and the structural improvement of DOX-induced cardiomyopathy in rats. Ninety adult male albino rats were randomly divided into three equal groups of thirty rats each: Group I (control): rats received normal saline. Group II (DOX- group): rats received DOX. Group III (DOX-MSCs group): rats received DOX for 2 weeks then human umbilical cord blood mesenchymal stem cells (hUCB-MSCs). Rats in all groups were evaluated for: physical condition, electrocardiography (ECG), and hemodynamic parameters. Serum cardiac troponin I (cTnI), malondialdehyde (MDA), total antioxidant capacity (TAC), and DNA fragmentation on heart tissue isolated DNA were estimated for evaluation of the mechanism and the extent of the damage. Hearts were examined histopathologically for detection of MSCs homing, structural evaluation, with counting of the collagen fibers for evaluation of fibrosis. DOX-administered rats showed significant functional and structural deterioration. DOX-MSCs treated rats (group III) showed improved functional and structural criteria with restoration of all biochemical indicators of cardiac damage and reactive oxygen species (ROS) to normal, as well. In Conclusion, hUCB-MSCs significantly ameliorated the cardiotoxic manifestations as shown by biochemical, functional, and structural cardiac improvement. J. Cell. Biochem. 118: 3119-3129, 2017. © 2017 Wiley Periodicals, Inc.

Computer-aided estimation of the hERG-mediated cardiotoxicity risk of potential drug components.

The hERG potassium channel is one of the most important anti-targets determining cardiotoxicity of potential drugs. Using fragmental descriptors and artificial neural networks, the predictive models of the relationship between the structure of organic compounds and their activity with respect to hERG were built, and the structural factors affecting it were analyzed. By their predictive ability and applicability domain, these models (N = 1000, Q 2 = 0.77, RMSE cv = 0.45 for affinity and N = 2886, Q 2 = 0.60, RMSE cv = 0.55 for channel inhibition) are superior to the previously published models and can be used to minimize the risk of cardiotoxicity during drug development.

Cardio-oncology: a multidisciplinary approach for detection, prevention and management of cardiac dysfunction in cancer patients.

Cardiac dysfunction that develops during or after completion of cancer therapy is a growing health concern that should be addressed in a multidisciplinary setting. Cardio-oncology is a new discipline that focuses on screening, monitoring and treating cardiovascular disease during and after cancer treatment. A baseline cardiovascular risk assessment is essential. For high-risk patients, a tailored and detailed plan for cardiovascular management throughout treatment and beyond should also be established. Anthracycline and/or trastuzumab-containing chemotherapy and chest-directed radiation therapy are well known cardiotoxic cancer therapies. Monitoring for the development of subclinical cardiotoxicity is crucial for the prevention of clinical heart failure. Detecting a decreased left ventricular ejection fraction after cancer therapy might be a late finding; therefore, earlier markers of cardiac injury are being actively explored. Abnormal myocardial strain and increased serum cardiac biomarkers (e.g. troponins and natriuretic peptides) are possible candidates for this purpose. An important method for preventing heart failure is the avoidance or minimization of the use of cardiotoxic therapies. Decisions must balance the anti-tumor efficacy of the treatment with its potential cardiotoxicity. If patients develop cardiac dysfunction or heart failure, they should be treated in accordance with established guidelines for heart failure. Cancer survivors who have been exposed to cardiotoxic cancer therapies are at high risk of developing heart failure. The management of cardiovascular risk factors and periodic screening with cardiac imaging and biomarkers should be considered in high-risk survivors.

Polyphenols, autophagy and doxorubicin-induced cardiotoxicity.

Doxorubicin is a highly effective, first line chemotherapeutic agent used in the management of hematological and solid tumors. The effective use of doxorubicin in cancer therapy has been severely limited owing to its well-documented cardiotoxic side effect. Oxidative stress, lipid peroxidation, apoptosis as well as dysregulation of autophagy, has been implicated as a major contributor associated with doxorubicin-induced cardiotoxicity. Increased oxidative stress and lipid peroxidation are known to enhance the production of reactive oxygen species, while autophagy has been reported to protect the cell from stress stimuli or, alternatively, contribute to cell death. Nonetheless, to date, no single chemical synthesized drug is available to prevent the harmful action of doxorubicin without reducing its anti-cancer efficacy. Therefore, the search for an effective and safe antagonist of doxorubicin-induced cardiotoxicity remains a challenge. In recent years, there has been much interest in the role plant-derived polyphenols play in the regulation of oxidative stress and autophagy. Therefore, the present review renders a concise overview of the mechanism associated with doxorubicin-induced cardiotoxicity as well as giving insight into the role plant-derived phytochemical play as a possible adjunctive therapy against the development of doxorubicin-induced cardiotoxicity.

Cardiac Imaging Methods for Chemotherapy-related Cardiotoxicity Screening and Related Radiation Exposure: Current Practice and Trends.

Radiation exposure is a serious concern with usage of serial multigated acquisition (MUGA) scans (7.8mSv/study) for chemotherapy-related cardiotoxicity (CRC) screening. The current practice with respect to the imaging modalities chosen for cardiotoxicity screening and related radiation exposure has not been studied.

Cardioprotective effect of curcumin and piperine combination against cyclophosphamide-induced cardiotoxicity.

Curcumin is a well-established cardioprotective phytoconstituent, but the poor bioavailability associated with it is always a matter of therapeutic challenge. The present study was undertaken to increase the therapeutic efficacy of curcumin by combining with bio-enhancer like piperine against cyclophosphamide (CP)-induced cardiotoxicity in rats.

Content decline of SERCA inhibitors saikosaponin a and d attenuates cardiotoxicity and hepatotoxicity of vinegar-baked Radix bupleuri.

Improper usage of unprocessed Radix bupleuri root (chaihu) may cause cardiotoxicity and liver injury. Baking herb with vinegar is believed to attenuate the adverse responses. However, the chemical and molecular basis involved remained unclear. To this end, we investigated the in vitro toxicity of saikosaponin a, c, d, and their hydrolysates saikosaponin b1 and b2. Results showed that SSa and SSd possessed higher affinity with sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) by molecular docking, and exhibited stronger toxic responses on cardiomyocytes and hepatocytes than the other three saikosaponins in equivalent concentrations. Further, SSa and SSd induced LC3 puncta formation in U2OS-mCherry-EGFP-LC3 cells. Blockage of autophagy by 3-methyladenine did not abrogate the cytotoxicities induced by SSa and SSd. In parallel, none of SSc, SSb1, or SSb2 caused cell injury. Our study reveals how changes in chemical ingredients are connected to the toxicity of Chaihu during vinegar baking process and also provides a guidance for structure optimization to reduce drug induced toxicity.

Cardiotoxicity in oncology and coronary microcirculation: future challenges in theranostics.

Many of the patients undergoing chemotherapy or radiotherapy for cancer are at increased risk of developing cardiovascular diseases. Recent evidence suggests that cardiac dysfunction and subsequent heart failure are mainly due to vascular toxicity rather than only to due to myocyte toxicity. However, not all of the vascular toxicity of cancer therapies can be explained by epicardial coronary artery disease. In fact, in the last decades, it has been found that myocardial ischemia may occur as a consequence of structural or functional dysfunction of the complex network of vessels, which cannot be seen by a coronary angiography: the coronary microcirculation. Nowadays many diagnostic and therapeutic options are available both in coronary microvascular dysfunction and cardio-oncology. Aim of this review is to suggest future theranostic implications of the relationship between cardiotoxicity in oncology and coronary microvascular dysfunction, showing common pathophysiologic mechanisms, proposing new diagnostic approaches and therapeutic options for cardioprotection.

The importance of drug metabolites synthesis: the case-study of cardiotoxic anticancer drugs.

Anticancer drugs are presently guarantying more survivors as a result of more powerful drugs or combinations of drugs used in therapy. Thus, it has become more crucial to study and overcome the side effects of these therapies. Cardiotoxicity is one of the most relevant side effects on the long-term cancer survivors, because of its high social and economic impact. Drug metabolism can result in active metabolites or toxic metabolites that can lead to important side effects. The metabolites of anticancer drugs are possible culprits of cardiotoxicity; however, the cardiotoxicity of many of the metabolites in several drug classes was not yet suitably studied so far. On the other hand, the use of prodrugs that are bioactivated through metabolism can be a good alternative to obtain more cardio safe drugs. In this review, the methods to obtain and study metabolites are summarized and their application to the study of a group of anticancer drugs with acknowledged cardiotoxicity is highlighted. In this group of drugs, doxorubicin (DOX, 1), mitoxantrone (MTX, 2), cyclophosphamide (CTX, 3) and 5-fluorouracil (5-FU, 4) are included, as well as the tyrosine kinase inhibitors, such as imatinib (5), sunitinib (6) and sorafenib (7). Only with the synthesis and purification of considerable amounts of the metabolites can reliable studies be performed, either in vitro or in vivo that allow accurate conclusions regarding the cardiotoxicity of anticancer drug metabolites and then pharmacological prevention or treatment of the cardiac side effects can be done.