stilbenes and 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.

Topics: Animals; Cardiotonic Agents; Cardiotoxicity; Doxorubicin; Humans; Myocytes, Cardiac; Phytoalexins; Resveratrol; Sesquiterpenes; Stilbenes

Vascular co-option is a resistance mechanism to anti-angiogenic agents, but combinations of anti-vascular agents may overcome this resistance. We report a phase 1b and randomised phase 2 trial to determine the safety and efficacy of pazopanib with fosbretabulin.. Eligible patients had recurrent, epithelial ovarian cancer with a platinum-free interval (PFI) of 3 to 12 months. Patients were stratified according to PFI (>6 versus ≤6 months) and prior bevacizumab use.. It remains unclear whether pazopanib with with fosbretabulin is an efficacious regimen to treat epithelial ovarian cancer. Effective cardiac risk mitigation is needed to increase the tolerability and maximize patient safety in future trials.

Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Ovarian Epithelial; Cardiotoxicity; Dose-Response Relationship, Drug; Female; Humans; Indazoles; Neoplasm Recurrence, Local; Neovascularization, Pathologic; Ovarian Neoplasms; Progression-Free Survival; Pyrimidines; Stilbenes; Sulfonamides; Survival Rate

Combretastatin A4 (CA4) inhibits microtubule polymerization, and clinical trials of the prodrug, CA4 disodium phosphate (CA4DP), as an anti-cancer agent have been conducted. However, CA4DP has not been marketed to date because the margin between the effective dose and the cardiotoxic dose is insufficient. Meanwhile, bromodomain-containing protein 4 (BRD4) has been reported to be required for recovery from mitotic arrests induced by anti-microtubule drugs. BRD4 has also been reported to be involved in the progression of heart failure. Therefore, we hypothesized that the combined use of CA4DP with BRD4 inhibitors can enhance the antitumor effect and attenuate CA4DP-induced cardiotoxicity. In this study, the antitumor effect and cardiotoxicity caused by the co-administration of CA4DP with JQ1, a BRD4 inhibitor, were evaluated. CA4 or JQ1 alone reduced the viability of cultured canine mammary tumor cells (CHMp-13a). Viability was further reduced by co-administration, through the suppression of c-Myc. BRD4 positivity in CHMp-13a cytoplasm showed a significant increase when treated with CA4 alone, while the increase was not significant following co-administration. In CHMp-13a xenograft-transplanted mice, co-administration of CA4DP and JQ1 suppressed tumor growth significantly. In CA4DP-induced cardiac injury model rats, echocardiography showed a CA4DP-induced decrease in cardiac function and histopathology showed cardiomyocyte necrosis. Meanwhile, these cardiac changes tended to be milder following the co-administration of CA4DP and JQ1. These results suggest that CA4DP-JQ1 co-administration enhances the antitumor effect of CA4DP while attenuating its cardiotoxicity and therefore potentially open the doors to the development of a novel cancer chemotherapy with reduced cardiotoxicity risks.

Topics: Animals; Azepines; Cardiotoxicity; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Dogs; Humans; Mice; Nuclear Proteins; Rats; Stilbenes; Transcription Factors; Tubulin Modulators; Xenograft Model Antitumor Assays

Resveratrol (RSV), a polyphenolic compound and naturally occurring phytoalexin, has been reported to exert cardio-protective effects in several animal studies. However, the outcome of initial clinical trials with RSV was less effective compared to pre-clinical studies. Therefore, RSV treatment protocols need to be optimized. In this study we evaluated prophylactic versus therapeutic effect of resveratrol (RSV) in mitigating doxorubicin (Dox)-induced cardiac toxicity in rats. To investigate prophylactic effects, RSV was supplemented for 2 weeks along with Dox administration. After 2 weeks, Dox treatment was stopped and RSV was continued for another 4 weeks. To study therapeutic effects, RSV treatment was initiated after 2 weeks of Dox administration and continued for 4 weeks. Both prophylactic and therapeutic use of RSV mitigated Dox induced deterioration of cardiac function as assessed by echocardiography. Also RSV treatment (prophylactic and therapeutic) prevented Dox induced myocardial damage as measured by cardiac enzymes (LDH and CK-MB) in serum. Which was associated with decrease in Dox induced myocardial apoptosis and fibrosis. Interestingly our study also reveals that prophylactic use of RSV was more effective than its therapeutic use in mitigating Dox induced apoptosis and fibrosis in the myocardium. Therefore, prophylactic use of resveratrol may be projected as a possible future adjuvant therapy to minimize cardiotoxic side effects of doxorubicin in cancer patients.

Topics: Animals; Apoptosis; Biomarkers; Cardiotoxicity; Creatine Kinase, MB Form; Doxorubicin; Drug Administration Schedule; Drug Evaluation, Preclinical; Echocardiography; Heart; Immunohistochemistry; L-Lactate Dehydrogenase; Male; Myocardium; NFATC Transcription Factors; Protective Agents; Random Allocation; Rats, Wistar; Resveratrol; Stilbenes

Topics: AMP-Activated Protein Kinases; Animals; Antioxidants; Arterial Pressure; Ascorbic Acid; Cardiotoxicity; Doxorubicin; Drug Synergism; Glucosides; Glutathione; Glutathione Peroxidase; Heart Rate; Male; Malondialdehyde; Myocardium; Oxidative Stress; PPAR gamma; Rats; Rats, Sprague-Dawley; Stilbenes; Superoxide Dismutase

Clinical application of triptolide (TP), a main active ingredient of the traditional Chinese herb Tripterygium wilfordii Hook f. (TWHF), is limited by a series of severe toxicities, including cardiotoxicity. In previous studies, we found the activation of sirtuin 3 (SIRT3) attenuated TP-induced toxicity in cardiomyocytes. Resveratrol (RSV), a polyphenol from the skins of grapes and red wine, is an activator of SIRT3. The current study aimed to investigate the protective effect of RSV against TP-induced cardiotoxicity and the underlying mechanisms. Mice were treated with a single dose of TP (2.5 mg/kg) via the intragastric (i.g.) route. After 24 h, TP induced abnormal changes of serum biochemistry, activity decrease of antioxidant enzymes and damage of heart tissue such as myocardial fiber rupture, cell swelling and interstitial congestion. In contrast, administration with RSV (50 mg/kg i.g. 12 h before and 2 h after the administration of TP) attenuated the detrimental effects induced by TP in BALB/c mice. Moreover, the cardiomyocyte protective effects of RSV on TP-induced heart injury were associated with the activation of SIRT3 and its downstream targets. In vitro study also indicated that RSV counteracted TP-induced cardiotoxicity through SIRT3-FOXO3 signaling pathway in H9c2 cells. Collectively, these findings suggest the potential of RSV as a promising agent in protecting heart from TP-induced damage.

Topics: Animals; Antioxidants; Apoptosis; Cardiotonic Agents; Cardiotoxicity; Cell Line; Diterpenes; Epoxy Compounds; Female; Forkhead Box Protein O3; Heart Diseases; Humans; Male; Mice; Mice, Inbred BALB C; Myocardium; Myocytes, Cardiac; Phenanthrenes; Resveratrol; Signal Transduction; Sirtuin 3; Stilbenes

Study of the exacerbating effects of chemotherapeutics, such as doxorubicin, on the impairment of insulin metabolic signaling in aged skeletal muscle is very limited. Here, we tested the hypothesis that activation of sirtuin 1 deacetylase activity by resveratrol would prevent the disruption of insulin signaling and augmentation of catabolic markers induced by doxorubicin in aged skeletal muscle. Two- and 10-month-old senescence-accelerated mice (prone 8) were randomized to receive saline, doxorubicin, doxorubicin and resveratrol, or a combination of doxorubicin, resveratrol, and sirtinol or EX527. Doxorubicin reduced the sirtuin 1 activity without affecting the phosphorylation levels of IRS1(Ser307), mTOR(Ser2481), Akt(Thr308/Ser473), membranous glucose transporter 4, protein abundance of PDK4, and enzymatic activity of pyruvate dehydrogenase in aged muscles. Intriguingly, resveratrol attenuated the doxorubicin-induced elevations of apoptotic and catabolic markers measured as Bax, caspase 3 activity, apoptotic DNA fragmentation, MuRF-1, ubiquitinated proteins, and proteasomal activity in aged muscles, whereas these beneficial effects were abolished on inhibition of sirtuin 1 by sirtinol or EX527. Markers of insulin signaling were not affected by doxorubicin or resveratrol in the senescent skeletal muscle. Nevertheless, the antiapoptotic and anticatabolic effects of resveratrol in aged skeletal muscle treated with doxorubicin were mediated in a sirtuin 1-dependent signaling manner.

Topics: Age Factors; Animals; Apoptosis; Cardiotoxicity; Caspase 3; Doxorubicin; Enzyme-Linked Immunosorbent Assay; Male; Mice; Muscle, Skeletal; Oxidative Stress; Proteasome Endopeptidase Complex; Pyruvate Dehydrogenase Complex; Random Allocation; Resveratrol; Signal Transduction; Sirtuin 1; Staining and Labeling; Stilbenes

Doxorubicin (DOX) has been reported to be a very potent and effective anticancer agent. However, clinical treatment with DOX has been greatly limited due to its cardiotoxicity. Furthermore, several studies have suggested a role for cytochrome P450 1B1 (CYP1B1) and mid-chain hydroxyeicosatetraenoic acids (mid-chain HETEs) in DOX-induced cardiac toxicity. Therefore, we hypothesized that DOX induced cardiotoxicity is mediated through the induction of CYP1B1 and its associated mid-chain HETEs metabolite. To test our hypothesis, Sprague-Dawley rats and RL-14 cells were treated with DOX in the presence and absence of 2,3',4,5'-tetramethoxystilbene (TMS), a selective CYP1B1 inhibitor. Thereafter, cardiotoxicity parameters were determined using echocardiography, histopathology, and gene expression. Further, the level of mid-chain HETEs was quantified using liquid chromatography-electron spray ionization-mass spectrometry. Our results showed that DOX induced cardiotoxicity in vivo and in vitro as evidenced by deleterious changes in echocardiography, histopathology, and hypertrophic markers. Importantly, the TMS significantly reversed these changes. Moreover, the DOX-induced cardiotoxicity was associated with a proportional increase in the formation of cardiac mid-chain HETEs both in vivo and in our cell culture model. Interestingly, the inhibition of cardiotoxicity by TMS was associated with a dramatic decrease in the formation of cardiac mid-chain HETEs suggesting a mid-chain HETEs-dependent mechanism. Mechanistically, the protective effect of TMS against DOX-induced cardiotoxicity was mediated through the inhibition of mitogen activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB). In conclusion, our study provides the first evidence that the inhibition of CYP1B1 and mid-chain HETE formation attenuate DOX-induced cardiotoxicity.

Topics: Animals; Antibiotics, Antineoplastic; Cardiotoxicity; Cell Line; Cytochrome P-450 CYP1B1; Doxorubicin; Enzyme Inhibitors; Humans; Hydroxyeicosatetraenoic Acids; Male; Myocardium; Rats, Sprague-Dawley; Stilbenes

Resveratrol (RSV) has many biological effects, including antitumor and antiviral activities, and vascular protection. Recent studies have suggested that RSV exerts its antitumor effects through induction of autophagy by an unknown mechanism. Doxorubicin (DOX) is a wide spectrum antitumor drug, but its clinical application is limited by its cardiotoxicity. This study evaluated whether the manipulation of autophagy could attenuate the cardiotoxic effects of DOX in vitro as well as in a rat model of DOX-induced cardiotoxicity. We found that DOX induced H9C2 cell apoptosis by inhibiting AMPK activation and promoting pro-apoptotic protein expression through p38MAPK/p53 signaling. RSV-treated H9C2 cells showed increased autophagy through the AMPK/mTOR/Ulk1 pathway. When DOX and RSV were combined, apoptosis was decreased, despite a slight increase in the autophagy ratio. The same result was observed in the rat model of DOX-induced cardiotoxicity. Injection with DOX or RSV alone, or in combination, for a week, resulted in a reduced apoptotic ratio in the combination group compared with the DOX alone group. Our results strongly indicate that this co-treatment strategy with RSV can attenuate the cardiotoxic effects of DOX. Our findings may have important clinical implications.

Topics: AMP-Activated Protein Kinases; Animals; Antibiotics, Antineoplastic; Autophagy; Cardiotoxicity; Cell Line; Cell Survival; Doxorubicin; Rats, Sprague-Dawley; Resveratrol; Stilbenes

Carbon monoxide (CO) poisoning leads to tissue hypoxia resulting in cardiovascular disturbances. Resveratrol (RES) is considered a natural cardioprotective agent especially in the setting of ischemia/reperfusion injury. In the present study, the cardioprotective potential of RES against CO-induced cardiotoxicity was evaluated. 45 male Wistar rats, animals were randomly assigned to 5 experimental groups. The first group served as negative control and was not exposed to CO. All remaining rats were exposed to CO 3000ppm for 60min. The second group received normal saline following CO exposure, while groups 3, 4 and 5 were injected intraperitoneally with different doses of RES (1, 5 and 10mg/kg, respectively). Histopathological examination showed that RES administration reduced myocardial lesions compared to control groups. Myocardial Akt expression was significantly increased in rats treated with the highest dose of RES (p<0.05) compared to CO-exposed non-treated animals. Caspase-3 activity in rat cardiomyocytes of RES-treated animals was significantly decreased in a dose-dependent manner. ECG findings did not differ significantly among CO-exposed groups. In conclusion, the present study offers evidence of a protective effect of RES administration on CO-induced cardiotoxicity via Akt up-regulation and attenuation of caspase-3 activity in rat hearts.

Topics: Animals; Carbon Monoxide; Carbon Monoxide Poisoning; Carboxyhemoglobin; Cardiotonic Agents; Cardiotoxicity; Caspase 3; Dose-Response Relationship, Drug; Electrocardiography; Heart; Male; Myocardium; Proto-Oncogene Proteins c-akt; Rats, Wistar; Resveratrol; Stilbenes

Doxorubicin induced functional deteriorations and elevations of USP7-related apoptotic/catabolic signalling in the senescent heart Resveratrol protects against doxorubicin-induced alterations through the restoration of SIRT1 deacetylase activity. A compromised cardiac function is often seen in elderly cancer patients receiving doxorubicin therapy. The present study tested the hypothesis that acute intervention with resveratrol, a natural anti-oxidant found in grapes and red wine, reduces the cardiotoxicity of doxorubicin through restoration of sirtuin 1 (SIRT1) deacetylase activity, and attenuation of the catabolic/apoptotic pathways orchestrated by USP7, a p53 deubiquitinating protein, using young (aged 2 months) and old (aged 10 months) senescence-accelerated mice prone 8 (SAMP8). Animals were randomised to receive saline, doxorubicin, and doxorubicin in combination with resveratrol, in the presence or absence of SIRT1 inhibitors, sirtinol or EX527. Resveratrol alone, but not in combination with either of the SIRT1 inhibitors, suppressed the doxorubicin-induced impairment of cardiac systolic function in aged animals. Doxorubicin reduced SIRT1 deacetylase activity, and elevated proteasomal activity and USP7; it also increased the protein level of p300 and ubiquitinated proteins in hearts from aged SAMP8. These doxorubicin-induced alterations were prevented by resveratrol, whereas the protective action of resveratrol was antagonised by sirtinol and EX527. In young SAMP8 hearts, resveratrol attenuated the doxorubicin-induced increases in acetylation of Foxo1 and transactivation of MuRF-1, whereas these mitigations were not found after treatment with SIRT1 inhibitors. However, the protein contents of acetylated Foxo1 and MuRF-1 were not affected by any of the drugs studied in aged SAMP8 hearts. Resveratrol also ameliorated the augmentation of pro-apoptotic markers including p53, Bax, caspase 3 activity and apoptotic DNA fragmentation induced by doxorubicin in hearts from aged animals, whereas these reductions were diminished by combined treatment with SIRT1 inhibitors. These data demonstrate that resveratrol ameliorates doxorubicin-induced cardiotoxicity in aged hearts through the restoration of SIRT1 activity to attenuate USP7-related catabolic/pro-apoptotic signalling.

Topics: Animals; Antioxidants; Apoptosis; Cardiotoxicity; Doxorubicin; Heart; Mice; Myocytes, Cardiac; Oxidative Stress; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes; Ubiquitin-Specific Peptidase 7; Ubiquitin-Specific Proteases

Doxorubicin hydrochloride (ADR) is an anthracycline antibiotic used to treat various cancers. However, due to its extensive cardiotoxic side effects a lifetime cumulative dose limit of 450-550 mg/m2 exists. The postulated mechanism of the cardiotoxicity is generation of reactive oxygen and nitrogen species. Natural products like resveratrol (RES), and quercetin (QUE) are known free radical scavengers and have shown cardioprotective effects. However, concurrent dosing of these natural products with ADR is limited due to their low solubility, and low oral bioavailability. We hypothesize that the combination of RES and QUE in Pluronic® F127 micelles (mRQ) when co-administered with ADR, will be cardioprotective in vitro and in vivo, while maintaining or increasing the efficacy of ADR against cancer cell lines in vitro. We prepared mRQ micelles capable of retaining 1.1mg/mL and 1.42 mg/mL of RES and QUE respectively. The in vitro release of RES and QUE from the micelles followed first order kinetics over 48h. In vitro cell viability and combination index analysis studies in human ovarian cancer cells (SKOV-3) and rat cardiomyocytes (H9C2) showed that RES:QUE: ADR at 10:10:1 ratio was synergistic in SKOV-3 cells and antagonistic in H9C2 cells. Caspase 3/7 activity studies indicated that mRQ did not interfere with ADR caspase activity in SKOV-3 cells but significantly decreased it in H9C2 cells. The generation of reactive oxygen species (ROS) in SKOV-3 and H9C2 cells in the presence of mRQ also indicated no changes in ROS activity in SKOV-3 cells but significant scavenging in H9C2 cells. Healthy mice were exposed to acute doses of ADR and ADR with mRQ. Based on biochemical estimations the presence of mRQ with ADR conferred full cardioprotection in these mice. Concurrent administration of mRQ with ADR at 10:10:1 ratio provides a viable strategy to mitigate acute ADR induced cardiotoxicity.

Topics: Animals; Antibiotics, Antineoplastic; Antioxidants; Cardiotonic Agents; Cardiotoxicity; Cell Line; Cell Line, Tumor; Doxorubicin; Drug Carriers; Female; Heart; Humans; Male; Micelles; Myocytes, Cardiac; Poloxamer; Quercetin; Rats; Reactive Oxygen Species; Resveratrol; Stilbenes

Treatment with doxorubicin (DOX) is one of the major causes of chemotherapy-induced cardiotoxicity and is therefore, the principal limiting factor in the effectiveness of chemotherapy for cancer patients. DOX‑induced heart failure is thought to result from endoplasmic reticulum (ER) stress and cardiomyocyte apoptosis. Resveratrol (RV), a polyphenol antioxidant found in red wine, has been shown to play a cardioprotective role. The aim of the present study was to examine the effects of RV on DOX‑induced cardiotoxicity in H9c2 cells. We hypothesized that RV would protect H9c2 cells against DOX‑induced ER stress and subsequent cell death through the activation of the Sirt1 pathway. Our results demonstrated that the decrease observed in the viability of the H9c2 cells following exposure to DOX was accompanied by a significant increase in the expression of the ER stress‑related proteins, glucose‑regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP). However, we found that RV downregulated the expression of ER stress marker protein in the presence of DOX and restored the viability of the H9c2 cells. Exposure to RV or DOX alone only slightly increased the protein expression of Sirt1, whereas a significant increase in Sirt1 protein levels was observed in the cells treated with both RV and DOX. The Sirt1 inhibitor, nicotinamide (NIC), partially neutralized the effects of RV on the expression of Sirt1 in the DOX‑treated cells and completely abolished the effects of RV on the expression of GRP78 and CHOP. The findings of our study suggest that RV protects H9c2 cells against DOX‑induced ER stress through ER stabilization, and more specifically through the activation of the Sirt1 pathway, thereby leading to cardiac cell survival.

Topics: Animals; Antibiotics, Antineoplastic; Antioxidants; Cardiotoxicity; Cell Line; Cell Survival; Doxorubicin; Endoplasmic Reticulum Stress; Myoblasts; Rats; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes

Resveratrol (RES) and curcumin (CUR) have free radical scavenging ability and potential chemosensitizing effects. Doxorubicin hydrochloride (DH) is a potent chemotherapeutic with severe cardiotoxicity. We hypothesize that RES and CUR co-loaded in Pluronic(®) micelles and co-administered with DH will result in cardioprotective effects while maintaining/improving DH anti-proliferative effect in vitro. RES-CUR at a molar ratio of 5:1 in F127 micelles (mRC) were prepared and characterized for size, drug loading, and release. In vitro cell viability and apoptosis assays in ovarian cancer cells (SKOV-3) and cardiomyocytes (H9C2) with either individual drugs or RES-CUR or mRC in combination with DH were conducted. Combination index (CI) analysis was performed to determine combination effects. Reactive oxygen species (ROS) were quantified in H9C2 for DH, and combinations. The mRC solubilized 2.96 and 0.97 mg/mL of RES and CUR, respectively. Cell viability and CI studies indicated that the combinations were synergistic in SKOV-3 and antagonistic in H9C2 cells. Caspase 3/7 activity in combination treatments was lower than with DH alone in both cell lines. ROS activity was restored to baseline in H9C2 cells in the micelle combination groups. Co-administration of mRC with DH in vitro mitigates DH-induced cardiotoxicity through reduction in apoptosis and ROS while improving DH potency in ovarian cancer cells.

Topics: Antineoplastic Agents; Apoptosis; Cardiotoxicity; Cell Line; Cell Line, Tumor; Cell Survival; Curcumin; Doxorubicin; Drug Carriers; Drug Combinations; Female; Humans; Micelles; Myocytes, Cardiac; Ovarian Neoplasms; Poloxamer; Resveratrol; Stilbenes

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.

Topics: Animals; Antioxidants; Cardiotonic Agents; Cardiotoxicity; Caspase 3; Doxorubicin; Fibrosis; Gene Expression; Glutathione; Heart; Heart Ventricles; Male; Rats; Rats, Wistar; Resveratrol; RNA, Messenger; Stilbenes; Superoxide Dismutase; Transforming Growth Factor beta1; Ventricular Remodeling

Doxorubicin (DOX), is a highly active anticancer agent, but its clinical use is limited by its severe cardiotoxic side‑effects associated with increased oxidative stress and apoptosis. Resveratrol (RSVL) is a naturally occurring polyphenolic compound (trans-3,5,4'-trihydroxystilbene) found primarily in root extracts of the oriental plant Polygonum cuspidatum and of numerous additional plant species. It has recently been shown that RSVL has a number of beneficial effects in different biological systems, which include anti-oxidant, antineoplastic, anticarcinogenic, cardioprotective and antiviral effects. In this study, we examined whether RSVL has protective effects against DOX‑induced free radical production and cardiotoxicity in male rats. The tested dose of DOX (20 mg/kg) caused a significant increase in the serum activities of the cardiac enzymes lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) and the level of malondialdehyde (MDA) in the heart tissue. However, there was a significant decrease in the glutathione level in the heart tissue. Simultaneous treatment of rats with RSVL [10 mg/kg, intraperitoneal (i.p.) injection] reduced the activity of LDH and CPK and significantly reduced MDA production in the heart. The total antioxidant capacity was increased following RSVL administration. Electron microscopy examination of the heart tissue showed that DOX treatment results in massive fragmentation and lysis of the myofibrils, and that mitochondria show either vacuolization or complete loss of the cristae. Simultaneous treatment with RSVL ameliorated the effect of DOX administration on cardiac tissue, with cardiomyocytes appearing normal compared to the control samples, and mitochondria retaining their normal structure.

Topics: Animals; Antioxidants; Cardiotoxicity; Creatine Kinase; Doxorubicin; Glutathione; Heart; L-Lactate Dehydrogenase; Male; Malondialdehyde; Myocytes, Cardiac; Oxidative Stress; Plant Extracts; Polyphenols; Rats; Rats, Wistar; Resveratrol; Stilbenes

Arsenic trioxide (As2O3) is used to treat acute promyelocytic leukemia. However, the cardiotoxicity of long QT syndrome restricts its clinical application. Previous studies showed that As2O3 can damage the human ether-a-go-go-related gene (hERG) current via disturbing its trafficking to cellular membrane. This study aimed to investigate whether the As2O3-insulted hERG channel can be rescued by resveratrol, a recognized cardioprotective agent. The whole-cell patch clamp technique was used to record the hERG current and action potential duration. Co-immunoprecipitation and Western blot assay were applied to determine the function of hERG-Hsp70/Hsp90 chaperone complexes and the expression alteration of protein-folding-related proteins, respectively. Compared with treatment of As2O3 alone, co-treatment with resveratrol successfully restored the current and surface expression of hERG and obviously shortened action potential duration in guinea pig ventricular myocytes. Further experiments demonstrate that resveratrol relieved As2O3-caused endoplasmic reticulum (ER) stress by restoring the function of hERG-Hsp70/Hsp90 chaperone complexes and downregulating the protein expression of ER chaperone proteins (calnexin and calreticulin) and activating transcription factor 6. In conclusion, resveratrol was able to rescue the trafficking deficiency and relieve the ER stress (ERS). Our findings suggest that resveratrol has a potential effect to alleviate the adverse effect of As2O3 on cardiotoxicity.

Topics: Action Potentials; Animals; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Blotting, Western; Cardiotonic Agents; Cardiotoxicity; Down-Regulation; Endoplasmic Reticulum Stress; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Guinea Pigs; Heart Ventricles; HEK293 Cells; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Myocytes, Cardiac; Oxides; Patch-Clamp Techniques; Resveratrol; Stilbenes