DOX-treated Group Research Articles

Date Palm Pollen Extract Avert Doxorubicin-Induced Cardiomyopathy Fibrosis and Associated Oxidative/Nitrosative Stress, Inflammatory Cascade, and Apoptosis-Targeting Bax/Bcl-2 and Caspase-3 Signaling Pathways.

Simple SummaryThe use of date palm pollen ethanolic extract (DPPE) is a conventional approach in improving the side-effects induced by Doxorubicin (DOX).DPPE mitigated DOX-induced body and heart weight changes and ameliorated DOX-induced elevated cardiac injury markers. In addition, serum cardiac troponin I concentrations (cTnI), troponin T (cTnT), and N-terminal NBP and cytosolic (Ca+2) were amplified by alleviating the inflammatory and oxidative injury markers and decreasing histopathological lesions severity. DPPE decreased DOX-induced heart injuries by mitigating inflammation, fibrosis, and apoptosis through its antioxidant effect. To reduce DOX-induced oxidative stress injuries and other detrimental effects, a combined treatment of DPPE is advocated.Doxorubicin (DOX) has a potent antineoplastic efficacy and is considered a cornerstone of chemotherapy. However, it causes several dose-dependent cardiotoxic results, which has substantially restricted its clinical application. This study was intended to explore the potential ameliorative effect of date palm pollen ethanolic extract (DPPE) against DOX-induced cardiotoxicity and the mechanisms underlying it. Forty male Wistar albino rats were equally allocated into Control (CTR), DPPE (500 mg/kg bw for 4 weeks), DOX (2.5 mg/kg bw, intraperitoneally six times over 2 weeks), and DPPE + DOX-treated groups. Pre-coadministration of DPPE with DOX partially ameliorated DOX-induced cardiotoxicity as DPPE improved DOX-induced body and heart weight changes and mitigated the elevated cardiac injury markers activities of serum aminotransferases, lactate dehydrogenase, creatine kinase, and creatine kinase-cardiac type isoenzyme. Additionally, the concentration of serum cardiac troponin I (cTnI), troponin T (cTnT), N-terminal pro-brain natriuretic peptide (NT-pro BNP), and cytosolic calcium (Ca+2) were amplified. DPPE also alleviated nitrosative status (nitric oxide) in DOX-treated animals, lipid peroxidation and antioxidant molecules as glutathione content, and glutathione peroxidase, catalase, and superoxide dismutase activities and inflammatory markers levels; NF-κB p65, TNF-α, IL-1β, and IL-6. As well, it ameliorated the severity of histopathological lesions, histomorphometric alteration and improved the immune-staining of the pro-fibrotic (TGF-β1), pro-apoptotic (caspase-3 and Bax), and anti-apoptotic (Bcl-2) proteins in cardiac tissues. Collectively, pre-coadministration of DPPE partially mitigated DOX-induced cardiac injuries via its antioxidant, anti-inflammatory, anti-fibrotic, and anti-apoptotic potential.

Memantine improves memory and hippocampal proliferation in adult male rats.

Neurogenesis occurs during the embryological development of the brain. However, it is universally accepted that in all adult mammalian brains, there are two sites of high-density cell division: the subventricular zone of the lateral ventricles (SVZ) and the subgranular zone (SGZ) of the dentate gyrus of the hippocampal formation. Doxorubicin (DOX) is an anthracycline agent which results in cognitive deterioration and memory impairment, whereas memantine (MEM) is an NMDA receptor antagonist which is approved for the treatment of Alzheimer's dementia. Many studies have revealed MEM's positive impact on memory and demonstrated that it stimulates neuronal division in the hippocampus. This study aimed to assess the effect of MEM on spatial memory and neural proliferation in the hippocampus in adult male rats treated with DOX. For this purpose, forty male Sprague-Dawley rats were divided into four groups of ten rats each according to the agent: control, MEM (2.5 mg/kg), DOX (2 mg/kg), and DOX with MEM. The rats were given seven intraperitoneal injections every other day. We tracked the rat's weights to assess the weight-reducing effects of the drugs. In order to test spatial memory, the rats were subjected to the novel location recognition (NLR) task 30 minutes after the last injection. Additionally, Ki67 immunohistochemistry was performed to examine hippocampal proliferation. The results showed a significant reduction in discrimination index (DI) in the DOX-treated group compared to MEM- (p < 0.001) and MEM with DOX-treated groups (p < 0.001). There was a significant increase in Ki67-positive cells in the MEM-treated group compared to the saline-treated group. Treatment with DOX impaired hippocampal proliferation compared to treatment with MEM or saline. The co-administration of MEM with DOX ameliorated the decline in hippocampal proliferation compared to treatment with DOX alone. There was a significant weight reduction in the DOX group in comparison to the control group, but MEM attenuated DOX-induced weight loss. Rats treated with DOX displayed a drop in memory, hippocampal proliferation, and weight compared to the MEM-treated group, whereas the co-administration of MEM with DOX protected memory, hippocampal proliferation, and doxorubicin-induced weight loss.

Use of Creatine and Creatinine to Minimize Doxorubicin-Induced Cytotoxicity in Cardiac and Skeletal Muscle Myoblasts

Doxorubicin (DOX), an effective anticancer agent, can damage cardiac and skeletal muscle tissue via excessive generation of reactive oxygen species (ROS). Supplemental creatine (Cr) has been shown to have a therapeutic role in disease states characterized by increased oxidative stress. To investigate the effects of Cr and creatinine (CrN) on DOX-induced cytotoxicity. Cultured L6 and H9C2 myoblasts were exposed to 25 μM DOX, 10 mM Cr, 10 mM CrN, 25 μM DOX + 10 mM Cr, 25 μM DOX + 10 mM CrN, or control media for 12 h. Viability was assessed using Confocal and Widefield imaging. Immunoblotting was used to determine protein expression. Viability was lowest in the DOX-treated group regardless of cell type; however, when DOX was combined with Cr or CrN, viability was improved. Levels of oxidative stress, as measured by 4-hydroxynonenal (4HNE), were significantly (p < 0.05) higher in the DOX treated cells vs. controls; however, Cr + DOX and CrN + DOX significantly lowered 4HNE levels compared to DOX-treated cells. Creatine kinase (CK), a key marker of cellular damage, was significantly higher in DOX-treated H9c2 cells vs. controls. However, Cr or CrN in combination with DOX, resulted in no significant differences in CK vs. controls. Supplementation with Cr or CrN may preserve cell viability during DOX treatment.

GFP Plasmid and Chemoreagent Conjugated with Graphene Quantum Dots as a Novel Gene Delivery Platform for Colon Cancer Inhibition In Vitro and In Vivo.

Scientists have studied intensively the gene delivery carriers for treating genetic diseases. However, there are challenges that impede the application of naked gene-based therapy at the clinical level, such as quick elimination of the circulation, lack of membrane penetrability, and poor endosome trapping. Herein, we develop graphene quantum dots (GQDs)-derivative nanocarriers and introduce polyethylenimine (PEI) to equip the system with enhanced biocompatibility and abundant functional groups for modification. In addition to carrying green fluorescent protein (GFP) as an example of gene delivery, this system covalently binds colon cancer cells targeted antibody and epidermal growth factor receptor (EGFR) to enhance cell membrane penetrability and cell uptake of nanocarriers. To achieve multistrategy cancer therapy, the anticancer drug doxorubicin (Dox) is noncovalently encapsulated to achieve pH-induced drug release at tumor sites and leaves space for further functional gene modification. This nanoparticle serves as a multifunctional gene delivery system, which facilitates improved cytotoxicity and longer-sustained inhibition capacity compared to free Dox treatments in colon cancer cells. Moreover, our GQD composites display compatible tumor suppression ability compared with the free Dox treatment group in xenograft mice experiment with significantly less toxicity. This GQD nanoplatform was demonstrated as a multifunctional gene delivery system that could contribute to treating other genetic diseases in the future.

Importance of the fatty acid chain length on in vitro and in vivo anticancer activity of fattigation-platform albumin nanoparticles in human colorectal cancer xenograft mice model

The aims of this study were to design different chain length fatty acid-conjugated albumin nanoparticles (ANPs) and evaluate their anticancer activity in the HCT116 human colorectal cancer xenograft mouse model. Doxorubicin hydrochloride (DOX·HCl) was chosen as a model drug. The different chain lengths of fatty acids (butyric acid; C4, and stearic acid; C18) in albumin conjugates exhibited different physicochemical properties and anticancer activity. Fatty acid-conjugated albumin aided the formation of self-assembled structures with an average size of approximately 200 nm and a negative charge when incubated with excess DOX in an aqueous solution. DOX-loaded long-chain C18-conjugated ANPs allowed efficient encapsulation of hydrophobic DOX into the core of the self-assembled structure, enabling higher drug loading, enhanced colloidal stability and controlled release behavior in PBS pH 7.4 medium as compared with free DOX·HCl or non-fatty acid conjugated ANPs. Furthermore, DOX-loaded fatty acid-conjugated ANPs showed an increased cellular uptake intensity and cytotoxic effects in vitro. In vivo, HCT116 xenograft model experiments confirmed that DOX-loaded C18-conjugated ANPs showed improved anticancer activity and reduced side effects compared with the DOX-treated groups. The long-chain fatty acid-conjugated ANPs synergistically activated the interaction with the free-fatty acid receptor (FFAR) on HCT116 colorectal cancer cells as compared with short-chain C4 or other non-conjugated ANPs. Specifically, DOX-loaded C18-conjugated NPs exhibited significant performance to overexpressed FFAR4 on HCT116 colorectal cancer cells. The fatty acid chain length in the fattigation-platform system could be a promising molecular moiety to improve targeting efficiency and drug accumulation in various cancer therapy.

Early Moderate Intensity Aerobic Exercise Intervention Prevents Doxorubicin-Caused Cardiac Dysfunction Through Inhibition of Cardiac Fibrosis and Inflammation.

Doxorubicin (DOX) is known as an effective drug in the fight against various cancers. However, one of the greatest impediments is DOX-induced cardiomyopathy, which may potentially lead to heart failure. Accumulating evidence has shed light on the pathological mechanism of DOX-induced cardiotoxicity, but treatments to mitigate the cardiac damage are still required. In an attempt to address this issue, we evaluated whether exercise provides cardioprotective effects on the DOX-induced cardiotoxicity. We showed that treadmill exercise (3 times/week; 1-week of exercise acclimatization and 4-weeks of endurance exercise) during the DOX treatment successfully prevented the cardiac dysfunction. The DOX-stimulated expression of IκBα, NF-κB, COX-2, and IL-8 were all downregulated by exercise as well as the fibrosis factors (TGF-β1, phosphorylated ERK, Sp1, and CTGF). Moreover, we showed that treadmill exercise diminished the expression of several cardiac remodeling-associated factors, such as FGF2, uPA, MMP2, and MMP9. These results were in line with the finding that exercise intervention reduced cardiac fibrosis and restored cardiac function, with higher values of ejection fraction and fractional shortening compared to the DOX-treated group. Two commonly used indicators of cardiac injury, lactate dehydrogenase, and creatine kinase-MB, were also decreased in the exercise group. Collectively, our results suggested that it may be beneficial to prescribe treadmill exercise as an adjunct therapy to limit cardiac damage caused by DOX.

Ultrastructural and Echocardiographic Assessment of Chronic Doxorubicin-Induced Cardiotoxicity in Rats.

Doxorubicin (DOX) is one of the secondary metabolites of Streptomyces peucetius var. caesius. It is a common and effective chemotherapeutic agent used for the treatment of different diseases, including lymphoma, leukemia, breast cancer, and solid tumors. However, this medicine causes cardiotoxic side effects, which limit its clinical application. The present study examined the cardiomyopathy induced by DOX via echocardiography and transmission electron microscopy (TEM). The main objective was to evaluate the capacity of echocardiography and TEM as diagnostic tools for DOX-induced cardiotoxicity. Moreover, the correlation between intracellular and functional changes due to cardiotoxicity was assessed in a rat model. Cardiomyopathy was induced in rats by two cumulative doses of DOX. Group I received DOX 12 [i.e., 12 mg/kg, intraperitoneal (IP)] and group II received DOX 15 (i.e., 15 mg/kg, IP) in six equal doses over two weeks. Group III as the control (Ctrl) group received normal saline as a vehicle. Mortality during the study was only observed in the DOX 15 group. The echocardiographic assessments revealed significant changes in ejection fraction, fractional shortening, and heart rate in the groups which received DOX. In addition, severe cardiac arrhythmia was evident in DOX-treated groups. Remarkable adverse effects, such as moderately degenerated cells and inflated mitochondria were observed in the TEM analysis of rat hearts in the DOX groups. The present study indicated that rat models are suitable for investigating DOX-induced cardiomyopathy, especially at the dose of 12 mg/kg. Furthermore, echocardiography and TEM examinations were found to be valuable methods for the determination of cardiotoxicity in rats due to DOX.

Doxorubicin-induces NFAT/Fas/FasL cardiac apoptosis in rats through activation of calcineurin and P38 MAPK and inhibition of mTOR signalling pathways.

This study investigated the role of NFAT/Fas/FasL axis in cardiomyocyte apoptosis following doxorubicin (DOX) treatment in rats and evaluated the involvement and regulation of all NFAT members in cardiac apoptosis. Forty adult male Wistar rats were divided equally into control or DOX-treated groups (15mg/kg over 2weeks). Cardiomyocytes were cultured and pre-incubated with various inhibitors and activators (10μmol/L) prior to DOX exposure (1μmol/L). In the left ventricles and cultured cells, DOX increased cytoplasmic protein levels of cytochrome C, Bax and increased the activities of caspase-8, caspase3, ERK1/2, JNK, and P38 mitogen-activated protein kinases (MAPKs), reducing levels of Bcl-2 and the activity of mTOR, and inducing cell death. In addition, DOX enhanced mRNA and protein levels of Fas and FasL. Furthermore, the nuclear and cytoplasmic levels of NFAT1 and nuclear accumulation of NFAT2-4were increased with DOX treatment. The inhibition of calcineurin with FK506 significantly inhibited the nuclear levels of NFAT2 and NFAT4 and the inhibition of P38 MAPK with SB203580 inhibited the nuclear and cytoplasmic accumulation of NFAT1. However, the activation of mTOR by IGF-1 significantly lowered NFAT3. In conclusion, NFAT/Fas/FasL-induced cell death in cardiac myocytes of DOX-treated rats is regulated, at least, by the activation of calcineurin and P38 MAPK and inhibition of mTOR.

Basic fibroblast growth factor promotes doxorubicin resistance in chondrosarcoma cells by affecting XRCC5 expression.

Chondrosarcoma is the second most common form of bone cancer and is characterized by its ability to produce an extracellular matrix of the cartilage. High-grade chondrosarcoma is highly aggressive and can metastasize to other parts of the body. Chondrosarcoma is resistant to both conventional chemotherapy and radiotherapy; hence, the current main treatment is still surgical resection. Doxorubicin (Dox) has been shown to significantly improve patient survival compared with untreated chondrosarcoma. However, for patients with metastasis, surgical resection alone can hardly treat them. In addition, drug resistance is one of the leading causes of death in patients with chondrosarcoma. Secreted proteins can mediate cell-cell interactions in the cancer microenvironment, which may be associated with the development of drug resistance. In the present study, chondrosarcoma cells were treated with Dox, the conditioned medium was then collected and changes in secreted proteins were analyzed using the antibody array. Results showed that the Dox-treated group had the highest secretion of basic fibroblast growth factor (bFGF), indicating the effect of bFGF on Dox sensitivity in chondrosarcoma. Furthermore, lentiviral-mediated knockdown and treatment of exogenous recombinant protein were employed to further investigate the effect of bFGF on Dox resistance. Results demonstrated that bFGF can promote the expression of X-ray repair cross-complementing protein 5 (XRCC5), leading to Dox resistance. Secreted bFGF is likely to be detected in serum, in addition to being a biomarker for predicting Dox resistance, the combination of Dox and bFGF/XRCC5 blockers may be a new therapeutic strategy to improve the efficacy of Dox in future.

Synergistic Effect of Quercetin in Combination with Sulfamethoxazole as New Antibacterial Agent: In Vitro and In Vivo Study

The present study was aimed at creating a combination between lower dose of sulfamethoxazole (S) as a broad-spectrum synthetic antibiotic and quercetin (Q), a natural polyphenol to decrease the antibiotic side effects and increase its antioxidant activity. Staphylococcus aureus infected animal model was studied both in vitro and in vivo in comparison to doxycycline (Dox) as standard antibiotic. The in vitro test results indicated that Q exhibited activity alone and in combination with S against tested bacterial strains, while S in low concentration was inactive. The in vivo results revealed that the S+Q combination in mice showed significant improvements in the liver and kidney functions as compared to those in the infected group or S- and Dox-treated groups. Moreover, malondialdehyde level was significantly decreased, while superoxide dismutase and catalase activities were significantly increased in the sera of (S+Q)-treated group in comparison to other treated groups. The spleen recovery in the (S+Q)-treated group was observed with the disappearance of S. aureus colonies as compared to the infected mice. In conclusion, the in vivo treatment of S. aureus infection with S+Q combination decreased the sulfamethoxazole side effects while increasing its antibacterial activity, which supported the therapeutic use of this combination in humans.

Metformin administration increases the survival rate of doxorubicin-treated mice.

Background: The chemotherapeutic agent doxorubicin (DOX), an anthracycline broadly used to treat different types of cancers, induces several side effects, including cardiotoxicity, hepatotoxicity, and nephrotoxicity, in a time- and dose-dependent manner. Metformin (MET) is an antidiabetic drug used as a first-line treatment for type-2 diabetes, and is reported to work against various various drug-induced toxicities. This study aimed to investigate whether the administration of MET prophylactically suppresses DOX-induced toxicity, and prolongs the survival following DOX treatment. Methods: Fifty mice were divided into four groups, and each group received different treatments. The animals in the control group received a single injection of saline. The animals in the DOX group received a single dose of DOX (25 mg/kg). The animals in the MET group received MET on a daily basis. The animals in the DOX+MET group received only a single dose of DOX and daily doses of MET. The animals were observed on a daily basis for determining their body weight and evaluating the survival rate of the four study groups. Results: DOX accelerated the mortality rate of the animals in the DOX-treated group. Co-administration of MET and DOX increased the survival rate of the mice. Conclusion: The results of this study demonstrated that the administration of MET can reduce DOX-induced toxicity and increase the survival rate among chemotherapy-treated mice.

Edaravone and benidipine protect myocardial damage by regulating mitochondrial stress, apoptosis signalling and cardiac biomarkers against doxorubicin-induced cardiotoxicity

ABSTRACTBackground: Doxorubicin (DOX) is a potential chemotherapeutic agent but its use is restricted due to cardiotoxicity. Edaravone is a potent-free radical scavenging agent used in cerebral ischaemia. Benidipine is a triple calcium channel blocker.Objective: We investigated the potential cardioprotective effects of edaravone and benidipine alone and their combination against DOX-induced cardiotoxicity. Cardiotoxicity was induced by administering six equal injections of DOX (2.5 mg/kg) on alternative days for 2 weeks.Result: DOX-treated group showed significant increase level of lipid peroxide and decrease in antioxidant status along with mitochondrial enzymatic activity. Cardiotoxity effect of DOX illustrated by significantly increased the cardiac biomarkers such as Cardiac troponin-I, Brain natriuretic peptide, Creatine kinase-MB in serum. Significant increased activation of TNF-α, Caspase-3 activity and myocardial infarct size in DOX-treated group. Histopathological evaluation also confirmed the DOX-induced cardiotoxicity. Pretreated with edaravone and benidipine was significantly attenuated level of thiobarbituric acid reactive substance, endogenous enzymes, mitochondrial enzyme activities and cardiac biomarkers. Furthermore, pretreated group showed decreased activation of TNF-α, Caspase-3 activity along with reduction in the myocardial infarct size. Histopathological evaluation also strengthened the above results.Conclusion: Taken together these results suggest that the pretreated with edaravone and benidipine have potential protective effect against DOX-induced cardiotoxicity.

&lt;p&gt;Effects of quercetin, sitagliptin alone or in combination in testicular toxicity induced by doxorubicin in rats&lt;/p&gt;

ObjectiveThis study aimed to evaluate the effect of quercetin and/or sitagliptin on testicular damage induced by doxorubicin (DOX).MethodologyTwenty-five male Wistar rats, weighing 240±20 g, were randomly divided into five groups as follows: a negative control group; that was treated with 1 mL of 0.9% sodium chloride; a DOX-treated group received Intraperitoneal (I.P.) DOX injection (3 mg/kg); a group treated with quercetin 80 mg/kg + sitagliptin 10 mg/kg + DOX; a group treated with quercetin 80 mg/kg + DOX; and a group treated with sitagliptin 10 mg/kg+ DOX. All treatment were given orally daily for 21 days with I.P. DOX 3 mg/kg injection for the treatment groups at days 8, 10, 12, 15, 17, and 19. On day 22, blood was collected for analysis of testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), glutathione peroxidase (GPx), and total antioxidant capacity (TAOC). The testes were also removed and sent for histopathological examination.ResultsThe study revealed that the combination of quercetin with sitagliptin produced a significant increase in testosterone and FSH levels with a non-significant increase in LH level. This combination also non-significantly decreased the level of ALP and LDH and restored the GPx level with enhancing TAOC.ConclusionThe results suggest quercetin/sitagliptin combination as a promising therapeutic modality for attenuation of DOX-induced testicular toxicity in rats, and the main mechanism involved in such effect could be due to the antioxidant and anti-inflammatory properties of both agents.

Protective properties of glycogen synthase kinase-3 inhibition against doxorubicin-induced oxidative damage to mouse ovarian reserve

Chemotherapy induces ovarian failure in female children and young female cancer survivors. It has been shown that doxorubicin (DOX), an antitumor drug of the anthracycline group, causes gonadotoxicity via the stimulation of oxidative stress. The inhibition of glycogen synthase kinase-3 (GSK-3) was reported to be able to regulate oxidative stress. The present study assessed whether GSK-3 inhibition confers protection to the ovary against DOX-induced oxidative stress damage. An intraperitoneal injection of DOX was used to induce oxidative damage in the mouse ovary, while the inhibition of GSK-3 was achieved by the administration of SB216763, a small and potent GSK-3 inhibitor. DOX increased the mRNA expression levels of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and the antioxidant genes heme-oxygenase-1 (HO-1) and catalase (CAT), while reducing the levels of glutathione peroxidase (GSH-Px) and superoxide dismutase-1 (SOD-1) compared with those of the control. When the GSK-3 inhibitor was combined with DOX increased more expression levels of Nrf2 mRNA and restored levels of GSH-Px and SOD-1 mRNA similar to those in the control group. DOX remarkably decreased the Nrf2 protein expression compared to that in the control, which was significantly associated with increased MDA levels. Interestingly, the SB216763 and DOX coadministration restored the Nrf2 protein expression and MDA levels to levels that were similar to those in the control. DOX significantly decreased the number of primordial, primary, preantral and antral follicles while increasing the number of atretic follicles compared to those in the control. SB216763 caused the drastic recovery of these follicles from the DOX effects. SB216763 and DOX coadministration significantly reduced the apoptotic index compared with that with DOX treatment. DOX decreased the serum AMH and E2 levels and increased the FSH levels compared to those in the controls. However, SB216763 and DOX coadministration restored AMH and E2 while decreasing the FSH levels compared to those in the DOX-treated group. In addition, SB216763 and DOX coadministration reduced the mature oocyte abnormalities that resulted from DOX-induced ovarian damage. Given these results, we suggest that GSK-3/Nrf2 is a promising protective pathway against doxorubicin-induced oxidative damage to the ovaries of females at reproductive ages. Thus, GSK-3 could be an attractive target for the research and development of new drugs for preserving ovarian function during chemotherapy.

Dkk1 exacerbates doxorubicin-induced cardiotoxicity by inhibiting the Wnt/β-catenin signaling pathway.

The cancer clinical therapy of doxorubicin (Dox) treatment is limited by its life-threatening cardiotoxic effects. Dickkopf-1 (Dkk1), the founding and best-studied member of the Dkk family, functions as an antagonist of canonical Wnt/β-catenin. Dkk1 is considered to play a broad role in a variety of biological processes, but its effects on Dox-induced cardiomyopathy are poorly understood. Here, we found that the level of Dkk1 was significantly increased in Dox-treated groups, and this increase exacerbated Dox-induced cardiomyocyte apoptosis and mitochondrial dysfunction. Overexpressing Dkk1 aggravated Dox-induced cardiotoxicity in H9C2 cells. Similar results were detected when adding active Dkk1 protein extracellularly. Conversely, adding specific antibody blocking extracellular Dkk1 attenuated the cardiotoxic response to Dox. Adenovirus encoding Dkk1 was transduced through intramyocardial injection and exacerbated Dox-induced cardiomyocyte apoptosis, mitochondrial damage and heart injury in vivo Furthermore, Wnt/β-catenin signaling was inhibited during Dox-induced cardiotoxicity, and the re-activation of β-catenin prevented the effect of overexpressed Dkk1 and Dox-induced cardiotoxicity. In conclusion, these results reveal the crucial role of the Dkk1-Wnt/β-catenin signaling axis in the process of Dox-induced cardiotoxicity and provide novel insights into the potential mechanism of cardiomyopathy caused by clinical application of Dox.

Mesenchymal stem cells pretreated with platelet-rich plasma modulate doxorubicin-induced cardiotoxicity.

The cardiotoxic adverse effect of doxorubicin (DOX) is the major factor limiting its use. Recently, mesenchymal stem cells (MSCs) have been implicated in the preclinical studies of treatment of DOX-induced cardiotoxicity. The question is MSCs pretreated with platelet-rich plasma (PRP) have a better influence on DOX-induced cardiotoxicity compared to the influence of MSCs alone. Twenty-four Wistar rats were categorized into control, DOX-treated, MSC-treated, and PRP/MSC-treated groups. DOX was injected for two consecutive weeks. Light microscopic, biochemical markers (interleukin 10 (IL-10), tumor necrosis factor alpha (TNF-α), and creatine kinase-MB (CK-MB)), immunohistochemical (Bax, Bcl2, vascular endothelial growth factor (VEGF), and cardiac troponin-I (CT-I)), and oxidative/antioxidative markers (malondialdehyde (MDA)/superoxide dismutase (SOD)) were measured. Degenerative cardiac changes were detected in the DOX-treated group with complete loss of the architecture and coagulative necrosis. These changes were accompanied with the elevation of the serum level of CK-MB and loss of CT-I immunoreactivity. The major factors in the DOX-induced cardiotoxicity were the oxidative stress (elevated MDA/decreased SOD), inflammation (elevated TNF-α/decreased IL-10), and cardiac apoptosis (lower Bcl2, higher Bax, and lower Bcl2/Bax ratio). MSCs and PRP/MSCs attenuate DOX-induced cardiotoxicity. Better attenuation was observed in the PRP/MSC-treated group. PRP/MSC combination reduced greatly the MDA and TNF-α and increased IL-10, Bcl2/Bax ratio, and VEGF. PRP had no significant influence over the Bcl2, Bax, and SOD. In conclusion, DOX in its toxic dose induced myocardial injury. This destructive effect is related to oxidative stress, inflammation, and cardiac apoptosis. PRP/MSC possesses a better attenuation over the DOX-induced toxicity compared to MSC alone.

Atorvastatin Improves Doxorubicin-Induced Cardiac Dysfunction by Modulating Hsp70, Akt, and MAPK Signaling Pathways.

Atorvastatin is a lipid-regulating drug that is commonly used in clinical practice and can stabilize plaques. Increasing evidence shows that statins have anti-heart failure (HF) effects, but their specific mechanism is not clear. The purpose of this study was to investigate the cardioprotective effects of atorvastatin on HF in rats and its mechanism. Continuous intraperitoneal injection of 2.5 mg/kg/w doxorubicin for 6 weeks, with a cumulative dose of 15 mg/kg, was used to induce a rat model of HF. Then, the rats were treated with low-dose atorvastatin, high-dose atorvastatin, or saline for 4 weeks. In the DOX-treated groups, echocardiography showed decreases in left ventricular ejection fraction and fractional shortening and increases in left ventricular end-diastolic diameter and left ventricular posterior wall thickness compared with those in the control group, and increased levels of brain natriuretic peptide and Hsp70 were also found in the doxorubicin-treated groups. Compared with saline intervention, atorvastatin ameliorated left ventricular ejection fraction, fractional shortening, left ventricular end-diastolic diameter, and left ventricular posterior wall thickness (a significant difference was observed only in the high-dose group) and reduced serum brain natriuretic peptide. Hematoxylin and eosin staining showed that atorvastatin ameliorated myocardial injury. The improvement in cardiac function induced by atorvastatin was accompanied by increased Hsp70 expression, decreased p-ERK and p-JNK expression, and a reduction in myocardial fibrosis shown by Masson staining. In addition, atorvastatin had a protective effect on the myocardial apoptosis signaling pathway, with increased p-Akt expression and downregulated cleaved caspase-3 expression, and the reduction in myocardial apoptosis was confirmed by a TUNEL assay. Therefore, our experiments demonstrated that atorvastatin may protect cardiac function by modulating Hsp70, p-Akt, p-ERK, and p-JNK signaling to reduce myocardial fibrosis and myocardial apoptosis.

Cardio-protective Effect of Vitamin E on Doxorubicin-Induced Cardiotoxicity in Adult Male Albino Rats: A Histological and Biochemical Study

Background: Doxorubicin (Dox) is a powerful and greatly effective drug in cancer. However, its clinical usefulness is still restricted due to its specific toxicity to the cardiac tissue. Vitamin E is a well-known antioxidant used as a dietary supplement.Aim of the work: To evaluate the possible protective effects of vitamin E against Dox-induced cardiotoxicity.Material and Methods: Forty 3-months adult male albino rats weighing 200-250 gm were divided into four equal groups: Group (I): served as a negative control and received no treatment. Group (II): served as a positive control and treated with an intraperitoneal injection of 0.9% sodium chloride saline once daily for one week. Group (III): treated with 4mg Dox/kg b.w./day intraperitoneally for one week. Group (IV): was pretreated with 100mg vitamin E/kg body weight/day orally for 2 weeks followed by a combination of an intraperitoneal injection of Dox and oral vitamin E for one week in the same previous doses. Then, the animals were anaesthetized and blood samples were utilized for measurement of lactate dehydrogenase (LDH), creatine kinase (CK), triglyceride, total cholesterol and high-density lipoprotein (HDL-C). Animals were sacrificed, and a portion of each heart was taken from all groups for determination of the levels of total cardiac antioxidant capacity (TAC). The remaining portions of the heart muscle were prepared for light and electron microscopic studies.Results: Administration of Dox resulted in histological alterations in the form of vacuolated disorganized cardiac muscle fibers, degenerated mitochondria and congested dilated blood vessels. Also, significant decreases of cardiac TAC and serum HDL-C and increases of serum levels of LDH, CK, triglyceride and total cholesterol of Dox-treated group were noticed in comparison with the control ones. Pre and concomitant administration of vitamin E with Dox improved these alterations.Conclusion: Vitamin E ameliorates the cardiac damage induced by Dox.

Time course of cardiomyopathy induced by doxorubicin in rats

Doxorubicin (DOX)-related cardiotoxicity may expose cancer survivors to increased risk of cardiovascular morbidity and mortality. Here, we characterized the time course of DOX-induced cardiomyopathy in rats. Sprague-Dawley male rats (12 wk old) received doxorubicin hydrochloride (1 mg/kg/d, ip) during 10 consecutive days and they were euthanized one (DOX1), two (DOX2) or four (DOX4) weeks after the last drug injection. Control group received NaCl 0.9% (ip). Hearts were mounted on a Langendorff perfusion system, left ventricle fragments were processed for microscopy and oxidative stress-related assays, and blood was collected for cardiac troponin I assay. All DOX-treated groups showed swollen and vacuolated cardiomyocytes with myofilaments disarray and mitochondrial damage. These changes were already evident after one week and became more pronounced after four weeks. Cardiac troponin I plasma levels were significantly increased in DOX1 and further increased in DOX4 compared to control group. Increased oxidative damage to lipids was observed in DOX1, and to proteins in DOX4. Glutathione peroxidase activity increased in DOX4. The morphological changes resulted in cardiac remodeling, including interstitial fibrosis, apoptosis and significant impairment of both contractile and relaxation function in DOX 4 compared to control group. Hearts from all animals displayed an early reduction in the responsiveness to norepinephrine. These findings support the view that DOX cardiotoxicity occurs in a "continuum", and as the hypothesis of an irreversible cardiac injury is being challenged, understanding the progression of morphological and functional changes caused by DOX may allow proper timing of initiation of prophylactic treatment.

Prophylactic and Ameliorative Effect of N-Acetylcysteine on Doxorubicin-Induced Neurotoxicity in Wister Rats

Doxorubicin (DOX) is an anthracycline antibiotic and a quinone-containing chemotherapeutic drug used for various types of cancers. However, as with most anticancer drugs, it causes many toxic effects, one of them is cognitive impairment. The present study investigated the prophylactic and ameliorative effect of n-acetylcysteine (NAC) against DOX-induced neurotoxicity in rats. Rats were divided into four groups. Control group: rats received saline. NAC treated group: rats received NAC (100 mg/kg, p.o.) daily for 35 days. DOX-treated group: rats received DOX (4 mg/kg, i.p.) for four weeks on day 7, 14, 21 and 28. DOX+NAC treated group 1: rats received NAC (100 mg/kg, p.o.) daily for 35 days and DOX (4 mg/kg, i.p.) for four weeks on day 7, 14, 21 and 28). DOX+NAC treated group 2: rats received NAC (100 mg/kg, p.o.) daily started at the 7th day of the experiment till the end of the experiment and DOX (4 mg/kg, i.p.) for four weeks on day 7, 14, 21 and 28. The present results showed a significant reduction in the body weight, which was associated with a significant increase in brain to body weight ratio in DOX-treated rats. Tumor necrosis factor (TNF-α) level, malondialdehyde (MDA) and total protein levels were significantly elevated. Whilst, reduced glutathione (GSH) and glutathione peroxidase (GPx) levels were significantly decreased. Moreover, there were histopathological abnormalities in the brain tissue of DOX-treated rats, as most of the neurons degenerated and the blood vessels surrounded with wide perivascular spaces. In addition, the neuropil was vacuolated. The present study demonstrated that NAC has a neuroprotective effect on the brain damage induced by DOX, through inhibition of inflammation and oxidative stress. This neuroprotective effect was more pronounced in DOX+NAC treated group 1, as it produced a significant increase in brain GSH and GPx levels and more improvement in the histopathological abnormality compared to DOX+NAC treated group 2.