Adriamycin Toxicity Research Articles

#5649 HEPARANASE OVEREXPRESSION MODIFIES PODOCYTE MOTILITY

Abstract Background and Aims Heparanase is an endo-β-d-glucuronidase that degrades heparan sulfate side chains, which are essential components of extracellular matrices and cell surfaces, including in the kidney filtration apparatus, the glomerulus. Upregulation of heparanase in glomerular diseases (GDs) was demonstrated in experimental models of GDs and in humans. Using transgenic mice overexpressing the human heparanase gene, we recently showed that heparanase reduced proteinuria and preserved the glomerular filtration barrier (GFB) after Adriamycin-induced injury. Furthermore, heparanase improved survival of key GFB cells, the podocytes and enhanced their autophagic flux both in vitro and in vivo. Here, we aimed to study the potential role of heparanase on podocyte locomotion and adhesion. Methods We utilized immortalized human podocyte cell line AB8/13 (a kind gift of Prof. Moin Saleem, Bristol, UK) as an experimental platform. Cells were infected with pLenti6/V5-DEST carrying the heparanase gene construct (H) or control empty vector (V) and were allowed to differentiate for 14 days. To induce injury, differentiated podocytes were treated with Adriamycin (0.5 μg/mL), mimicking Adriamycin nephropathy, an established experimental model for progressive proteinuric GDs. For readouts, we used scratch assay, RT-qPCR, Western blot (WB) and immunofluorescence (IF) analyses. Results The in vitro scratch assay showed that differentiated (H) podocytes migrated at a slower rate compared with control (V) podocytes, both at baseline and after a 12-hour treatment with Adriamycin. Hence, we hypothesized that heparanase may alter podocyte adhesion properties. Indeed, IF staining of differentiated (H) podocytes exhibited an increase in focal contacts containing vinculin compared with control (V) cells treated with Adriamycin. Of note, we observed no differences in vinculin abundance by WB, suggesting that heparanase mediates the active form of vinculin. Moreover, among the integrins, we noticed temporal upregulation of ITGB1 transcription, as early as two hours after Adriamycin treatment, in (H) compared with control (V) podocytes (P = 0.032). Conclusions Collectively, our results suggest that in response to Adriamycin injury, constitutive heparanase overexpression could stabilize podocyte focal adhesions and control motility. Although further research is needed, improving the anchoring of podocytes over the basement membrane may provide an additional cellular mechanism by which heparanase conferred protection against Adriamycin toxicity.

In vivo and molecular docking studies of the pathological mechanism underlying adriamycin cardiotoxicity

Adriamycin (ADR), one of the most effective broad-spectrum antitumor chemotherapeutic agents in clinical practice, is used to treat solid tumors as well as hematological malignancies in adults and children. However, long-term ADR use causes several adverse reactions, including time- and dose-dependent cardiotoxicity, which limit its clinical application. In addition, the mechanism by which ADR induces cardiotoxicity remains unclear. Therefore, we used zebrafish as animal models to evaluate ADR toxicity during embryonic heart development owing to the similarity of this process in zebrafish to that in humans. Exposure of zebrafish embryos to 1.25, 2.5, and 5 mg/L ADR induced abnormal embryonic development, with the occurrence of cardiac malformations, pericardial edema, decreased movement speed and activity, and increased distance between the venous sinus and the arterial bulb (SV-BA). ADR exposure induced dysregulated cardiogenesis during the precardiac mesoderm formation period. We also observed irregular expression of cardiac-related genes, an upregulation of apoptotic gene expression, and a dose-dependent increase in oxidative stress levels. Furthermore, oxidative stress-induced apoptosis exerted deleterious effects on cardiac development in zebrafish embryos, and treatment with astaxanthin (ATX) alleviated these heart defects. ADR- and Wnt pathway-related genes exhibited good energy and spatial matching, and ADR upregulated the Wnt signaling pathway in zebrafish. Moreover, IWR-1 effectively alleviated ADR-induced heart defects. In conclusion, we demonstrated that the toxic effects of ADR on cardiac development in zebrafish embryos could provide a theoretical basis for explaining the pathogenesis of ADR-induced cardiotoxicity, which occurs through the upregulation of oxidative stress and Wnt signaling pathway, as well as its prevention and treatment in humans. These findings will help develop effective treatment strategies to combat ADR-induced cardiotoxicity and broaden the application of ADR for clinical practice.

Delivery of Adriamycin Loaded Niosomes for Liver Cancer Treatment

The delivery efficiency of Adriamycin is crucial for the therapy of hepatocellular carcinoma. Niosome is a promising carrier that can be used for targeted drug delivery. However, the therapeutic effect of Adriamycin loaded niosome is still unclear. In this study, Adriamycin loaded niosomes were constructed as a promising drug carrier system. The morphological determination of niosomes was conducted by transmission electron microscopy. Cell fluorescence was used for cellular uptake analysis. Western blotting was used to estimate the apoptosis-related protein expression in HepG2 cells. 3-(4,5)-di-methylthiahiazo(-z-y1)-3,5-di-phenytetrazolium bromide assay was used for estimating the apoptosis of cancer cells. The in vivo anti-cancer effect and safety of Adriamycin loaded niosomes were analyzed in tumor-bearing mice. Adriamycin loaded niosomes improved the cellular uptake of Adriamycin. The anti-cancer effect of Adriamycin in vivo was enhanced. The responsive release of Adriamycin loaded niosomes under acidic conditions reduced the toxicity of Adriamycin to normal cells and the mortality of tumor-bearing mice. Together, Adriamycin loaded niosomes improved its anti-cancer effect and safety for liver cancer treatment.

P-Coumaric acid alleviates adriamycin-induced hepatotoxicity in rats

Objective: To evaluate the effect of p-coumaric acid against adriamycin-induced hepatotoxicity in rats. Methods: The rats were divided into 4 groups. The control group received solvent; the p-coumaric acid group was treated with 100 mg/kg of p-coumaric acid orally for five consecutive days; the adriamycin group was administered with a single dose of adriamycin (15 mg/kg, i.p.), and the p-coumaric acid + adriamycin group was given p-coumaric acid five days before adriamycin administration. Twenty-four hours after the last administration, blood samples were collected for biochemical analysis, and liver tissues were removed for histopathological and immunohistochemistrical studies. Moreover, the levels of tissue lipid peroxidation and enzyme activities of glutathione peroxidase, superoxide dismutase, and catalase in liver tissue were measured. Results: Treatment with p-coumaric acid protected the liver from the toxicity of adriamycin by attenuating the increase in alkaline phosphatase, alanine transaminase, aspartate transaminase, total bilirubin, total cholesterol, triglyceride, and low-density lipoprotein cholesterol and lessening the decrease in high-density lipoprotein cholesterol and albumin. p-Coumaric acid also raised the levels of glutathione peroxidase, superoxide dismutase, and catalase, as well as decreased lipid peroxidation in liver tissue and hepatic IL- 1β expression. Additionally, histopathological study confirmed the protective effect of p-coumaric acid against liver damage. Conclusions: p-Coumaric acid can alleviate adriamycin-induced hepatotoxicity.

The Synergistic Antitumor Effect of Tanshinone IIA Plus Adriamycin on Human Hepatocellular Carcinoma Xenograft in BALB/C Nude Mice and Their Influences on Cytochrome P450 CYP3A4 In Vivo.

Objective Hepatocellular carcinoma is one of the most common diseases that seriously threaten human life and health. In this study, we evaluated the inhibitory effect of tanshinone IIA (Tan IIA) combined with adriamycin (ADM) on human hepatocellular carcinoma and developed a platform to assess the function if Chinese herbal ingredients combined with chemotherapy drugs have synergistic antitumor effects in vivo. Methods Established animal model of human hepatocarcinoma HepG2 cell in nude mice. Mice were divided into model control group, Tan IIA group, ADM group, and Tan IIA + ADM group. The changes from general condition, weight, tumor volume, and inhibition rate were observed. The data were gathered from serum AST level and histopathological changes. The content and activity of cytochrome P450 were determined by spectrophotometric analysis. CYP3A4 protein expression was analyzed by western blotting. The binding model crystal structure of Tan IIA and ADM with pregnane X receptor (PXR) was evaluated by Discovery Studio 2.1. Results A combination of Tan IIA with ADM could improve life quality by relieving ADM toxicity, decreasing tumor volume, declining serum AST level, and improving liner pathological section in tumor-bearing mice. The inhibitory rates of Tan IIA, ADM, and cotreatment were 32.77%, 60.96%, and 73.18%, respectively. The Tan IIA group significantly enhanced the content of cytochrome b5, P450, and erythromycin-N-demethylase activity. CYP3A4 protein expression was enhanced obviously by the Tan IIA + ADM group. Virtual molecular docking showed that both Tan IIA and ADM could be stably docked with the same binding site of PXR but different interactions. Conclusions Tan IIA in combination with ADM could improve the life quality in tumor-bearing mice and enhance the antitumor effect. The Tan IIA group increased the concentration of cytochrome P450 enzymes and activity. Combined Tan IIA with ADM could upregulate the CYP3A4 protein expression and make relevant interaction with protein PXR by virtual docking.

Kaempferol in reversing drug resistance of chronic myelogenous leukemia K562/ADM cells and its related mechanism

Objective To investigate the drug resistance of kaempferol reversed adriamycin (ADM)-resistant K562/ADM cells in chronic myelogenous leukemia (CML) and its related mechanism. Methods Methyl thiazolyl tetrazolium (MTT) method was used to detect the toxicity of ADM on K562 and K562/ADM cells for 24 h. The half inhibitory concentration (IC50) of ADM and the drug resistance multiple for 24 h were calculated. MTT method was used to detect the toxicity of kaempferol on K562/ADM cells for 24 h. The 5% inhibitory concentration (IC5) and 10% inhibitory concentration (IC10) of kaempferol for 24 h were calculated to determine the concentration of kaempferol in the subsequent experiments. And the cells untreated by the kaempferol were selected as the control group. The cell inhibition after the treatment of ADM for 24 h of the blank control group and kaempferol intervention group was detected by using MTT method. And then the cell inhibition for 24 h and ADM IC50 for 24 h in the above groups were calculated. The ratio of IC50 in the blank control group and kaempferol group was the reversal drug resistance multiple of kaempferol. The fluorescence intensity of ADM in K562/ADM cells treated by kaempferol was detected by using flow cytometry. Western blotting was used to detect the expressions of P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), phosphorylated p38 (p-p38), and total p38 (t-p38) protein in K562/ADM cells after the treatment of kaempferol, the specific inhibitor of p38-MAPK signaling pathway SB202190, and the combination of kaempferol and SB202190. Results After the treatment of ADM for 24 h, the IC50 value of K562 and K562/ADM cells was (0.9±0.6), (28.1 ±3.5) μg/ml, respectively. The drug resistance multiple of K562/ADM cells on the treatment of ADM for 24 h was 31.16 compared with the K562 cells. MTT method showed that kaempferol inhibited the proliferation of K562/ADM cells in a dose-dependent manner. According to the IC5 and IC10, 0.5 μmol/L and 1.0 μmol/L kaempferol were determined to do the subsequent experiments. After the combined interaction of kaempferol and ADM for 24 h, the ADM IC50 of K562/ADM cells in the blank control group, 0.5 μmol/L kaempferol group and 1.0 μmol/L kaempferol group was (33.7±5.7), (21.4±0.6), (15.9±1.8) μg/ml, respectively (F = 30.85, P 0.05); SB202190 could reduce the relative expressions of P-gp, MRP1 and p-p38 protein (all P 0.05). Conclusions Kaempferol can decrease the relative expressions of P-gp and MRP1 in K562/ADM cells by inhibiting p38-MAPK pathway, so as to increase the concentrations of ADM and to reverse the drug resistance of K562/ADM cells. Key words: Leukemia, myelogenous, chronic; Drug resistance, neoplasm; Kaempferol; Doxorubicin; P-glycoprotein; Multidrug resistance-associated protein 1; p38; MAP kinase; K562/ADM cells

Shenmai injection suppresses multidrug resistance in MCF-7/ADR cells through the MAPK/NF-κB signalling pathway

Context Shenmai Injection (SMI) is usually used to treat atherosclerotic coronary heart disease and viral myocarditis in China. However, the effect of SMI on multidrug resistance has not been reported. Objective To investigate the reversal effect of SMI in adriamycin (ADR) resistant breast cancer cell line (MCF-7/ADR) and explore the related molecular mechanisms. Materials and methods The effect of SMI (0.25, 0.5, 1 mg/mL) to reverse chemoresistance in MCF-7/ADR cells was elucidated by MTT, HPLC-FLD, DAPI staining, flow cytometric analysis, western blotting. At the same time, in vivo test was conducted to probe into the effect of SMI on reversing ADR resistance, and verapamil (10 μM) was used as a positive control. Results The results showed that the toxicity of ADR to MCF-7/ADR cells was strengthened significantly after treated with SMI (0.25, 0.5, 1 mg/mL), the IC50 of ADR was decreased 54.4-fold. The intracellular concentrations of ADR were increased 2.2-fold (p < 0.05) and ADR accumulation was enhanced in the nuclei (p < 0.05). SMI could strongly enhance the ADR-induced apoptosis and increase intracellular rhodamine 123 accumulation in MCF-7/ADR cells. Additionally, a combination of ADR and SMI (5 mg/kg) could dramatically reduce the weight and volume of tumour (p < 0.05). Furthermore, the results revealed that SMI might reverse MDR via inhibiting ADR-induced activation of the mitogen-activated protein kinase/nuclear factor (NF)-κB pathway to down-regulated the expression of P-glycoprotein (P-gp). Discussion and conclusions SMI could potentially be used to treat ADR-resistance. This suggests possibilities for future clinical research.

The Role of CHK1 Varies with the Status of Oestrogen-receptor and Progesterone-receptor in the Targeted Therapy for Breast Cancer.

Objective: The therapeutic effects of the checkpoint kinase 1 (CHK1)-targeted inhibition in tumor therapy have been confirmed, but how to choose an effective application method in breast cancer with heterogeneous molecular characteristics has remained unclear.Methods: We evaluated the status of CHK1 in breast cancer using the cancer genome atlas database. Chemosensitivity and single-agent antitumor activity of CHK1 inhibition were measured by drug sensitivity assay, cell proliferation assay, cell cycle and apoptosis analysis in breast cancer with different ER/PR status. And based on the conjoint transcriptome atlas analyses, the corresponding mechanism were explored.Results: In ER-/PR-/HER2- breast cancer, CHK1 inhibition enhanced adriamycin (ADR) chemosensitivity which was mediated by the mitotic checkpoint complex (MCC)-anaphase-promoting complex/cyclosome (APC/C)-cyclin B1 axis, Msh homeobox 2 (MSX2) and Bcl-2-like protein 11 (BIM). However, in ER+/PR+/HER2- breast cancer, because of the significant suppression for centromere protein F (CENPF)-mediated transcriptional activation of CHK1 induced by ADR itself, CHK1 inhibition fails to sensitize ADR toxicity. Interestingly, CHK1 inhibition showed the single-agent antitumor activity in ER+/PR+/HER2- breast cancer which was mediated by the cyclin dependent kinase inhibitor 1A (p21), kinesin family member 11 (Eg5) and cell surface death receptor (Fas).Conclusions: CHK1's variable role determines the application of CHK1 inhibition in breast cancer with ER/PR heterogeneity.

Hypoxic Isolated Abdominal Perfusion (HAP) chemotherapy for non-operable advanced staged ovarian cancer with peritoneal carcinosis: an experience in 45 platinum-refractory ovarian cancer patients

In order to break through drug resistance in platinum-refractory ovarian cancer, augmented drug exposure was administered to the abdomen by means of an isolated perfusion system. Four cycles of isolated hypoxic abdominal perfusion with cisplatin, adriamycin, and mitomycin were conducted in 4-week intervals. Cisplatin and adriamycin were chosen because of their increased cytotoxicity under hypoxic conditions. Chemofiltration was performed for prophylaxis of cumulative toxicity of adriamycin and mitomycin. The study included 45 patients with recurrent epithelial ovarian cancer who had prior platinum containing therapies (3, stage Federation of Gynecology and Obstetrics (FIGO) IIIB; 20, stage FIGO IIIC; 22; stage FIGO IV). The median survival rate in stage FIGO IIIBC was 12 months, and in stage IV was 10 months. The tumor marker decreased to complete response or partial response at 17.8% and 55.6% of the patients. CT or MRI visualization showed complete response in 4.1%, and partial response was in 54.1%. Complete resolution of ascites was noted in 30% of cases and substantial reduction in another 43%. Toxicity was generally low. Quality of life was improved in the majority of cases. Bone-marrow suppression ranged between WHO grade 1 and 2, and in patients with previous third- or fourth-line chemotherapy, it was WHO grade 3. Isolated hypoxic abdominal perfusion with chemofiltration for patients with progressive and platinum-refractory stage III and IV ovarian cancer is an effective therapy, breaking through chemoresistance and offering comparably long survival at good quality of life.

Alteronol Enhances the Anti-tumor Activity and Reduces the Toxicity of High-Dose Adriamycin in Breast Cancer.

The first-line chemotherapy drug adriamycin (ADM) is widely used for the treatment of breast cancer, but the acquired drug resistance and the normal tissue toxicity remain clinical challenges. Alteronol has been reported to exert wide-ranging anti-tumor activity. In this study, we firstly examined the synergistic anti-tumor effects and the underlying mechanisms of alteronol combined with ADM in breast cancer. We have found that the combination of alteronol and ADM significantly suppressed the expression levels of the cell cycle-related proteins (CDC2 and Cyclin B1) and induced cell cycle arrest at the G2/M phase, leading to cell proliferation inhibition in breast cancer 4T1 cells. Moreover, co-treatment of alteronol and ADM (i) remarkably activated p38 and JNK kinases, (ii) elevated ROS levels, (iii) triggered mitochondrial dysfunction, (iv) released cytochrome c into the cytoplasm, (v) upregulated apoptosis-related proteins, e.g., cleaved PARP, Bax, and cleaved caspase-3/9, and (vi) downregulated the expression of Bcl-2, followed by apoptosis. Furthermore, our in vivo studies showed that the low-dose combination of alteronol (2 mg/kg) and ADM (1 mg/kg) significantly inhibited tumor growth in tumor bearing mice, and the anti-tumor effect of the combination was the same as that of high-dose ADM (8 mg/kg). In addition, the low-dose combination group showed lower toxicities to major organs than the high-dose ADM group. Taken together, these data demonstrate that the low-dose combination of alteronol and ADM could notably improve the anti-tumor activity and have lower toxicities to major organs than those in high-dose ADM group.

Protective effect of Shengxian decoction and each single herb component against adriamycin-induced cardiomyocyte injury

Objective To study the protective effect of Shengxian decoction (SXT) and its each single herb component against doxorubicin induced cardiomyocyte injury. Methods Myocardial cells isolated from the neonatal rats with hypoxia/reoxygenation injury of cardiomyocytes were divided into eight groups,control group (Con group),doxorubicin-induced injury group (M group),and treatment groups with Shengxian decoction and its each single herb decoction (SXT,A-E groups) following doxorubicin-induced injury.The indicators tested included cell viability,cell ROS,Ca2+ and LDH levels. Results Compared with the control group,doxorubicin induced obvious myocardial injury in model group.Compared with the model group,all tested drug groups increased the cell viability,reduced the levels of cell Ca2+ and LDH.Besides,SXT and the single herb decoction reduced the concentration of ROS except the decoction of Platycodon grandiflorum and Cimicifuage Rhizoma.The experimental results suggested that the application of SXT in the early episode could reduce the cardiac toxicity of adriamycin to a certain extent. Conclusion SXT and its each single herb decoction showed protective effect against doxorubicin-induced cardiomyocyte injury.

A 20(S)-protopanaxadiol derivative PPD12 reverses ABCB1-mediated multidrug resistance with oral bioavailability and low toxicity.

The ATP-binding cassette subfamily B member 1 (ABCB1) is a transporter that mediates multidrug resistance (MDR) against chemotherapy, which leads to decreased patient survival. To inhibit ABCB1 activity in MDR cancer cells, the authors previously designed and synthesized a derivative from 20(S)-protopanaxadiol (PPD) PPD12 and verified its efficacy in ABCB1-overexpressing cancer cells. In the present study, the reversal effect of PPD12 on MDR was further evaluated and its pharmacokinetics and toxicity in vitro and in vivo were investigated. Incubation with PPD12 may significantly ameliorate the drug resistance of KB/VCR cells in a short time and maintain its reversed MDR ability for increasing time periods. In assays on a series of CYP450 activities, PPD12 demonstrated slight inhibition effects on the majority of enzymes. The bioavailability of PPD12 was nearly 100% by oral administration in a mouse model. Single PPD12 oral gavage at either high doses or subchronic low doses, was well tolerated by the mice. In addition, PPD12 at the therapeutic dosage did not significantly increase the toxicity of the chemotherapeutic agent Adriamycin when mice received a combination of the two compounds. In conclusion, PPD12 represents a novel type of ABCB1 inhibitor that has significant bioactivity in terms of MDR, high oral bioavailability and low toxicity.

Pituitary adenylate cyclase-activating polypeptide (PACAP) in zebrafish models of nephrotic syndrome.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is an inhibitor of megakaryopoiesis and platelet function. Recently, PACAP deficiency was observed in children with nephrotic syndrome (NS), associated with increased platelet count and aggregability and increased risk of thrombosis. To further study PACAP deficiency in NS, we used transgenic Tg(cd41:EGFP) zebrafish with GFP-labeled thrombocytes. We generated two models for congenital NS, a morpholino injected model targeting nphs1 (nephrin), which is mutated in the Finnish-type congenital NS. The second model was induced by exposure to the nephrotoxic compound adriamycin. Nephrin RNA expression was quantified and zebrafish embryos were live-screened for proteinuria and pericardial edema as evidence of renal impairment. Protein levels of PACAP and its binding-protein ceruloplasmin were measured and GFP-labeled thrombocytes were quantified. We also evaluated the effects of PACAP morpholino injection and the rescue effects of PACAP-38 peptide in both congenital NS models. Nephrin downregulation and pericardial edema were observed in both nephrin morpholino injected and adriamycin exposed congenital NS models. However, PACAP deficiency was demonstrated only in the adriamycin exposed condition. Ceruloplasmin levels and the number of GFP-labeled thrombocytes remained unchanged in both models. PACAP morpholino injections worsened survival rates and the edema phenotype in both congenital NS models while injection with human PACAP-38 could only rescue the adriamycin exposed model. We hereby report, for the first time, PACAP deficiency in a NS zebrafish model as a consequence of adriamycin exposure. However, distinct from the human congenital NS, both zebrafish models retained normal levels of ceruloplasmin and thrombocytes. We further extend the renoprotective effects of the PACAP-38 peptide against adriamycin toxicity in zebrafish.

Afatinib Decreases P-Glycoprotein Expression to Promote Adriamycin Toxicity of A549T Cells.

We investigated the reversal effect of afatinib (AFT) on activity of adriamycin (ADR) in A549T cells and clarified the related molecular mechanisms. A549T cells overexpressing P-glycoprotein (P-gp) were resistant to anticancer drug ADR. AFT significantly increased the antitumor activity of ADR in A549T cells. AFT increased the intracellular concentration of ADR by inhibiting the function and expression of P-gp at mRNA and protein levels in A549T cells. Additionally, the reversal effect of AFT on P-gp mediated multidrug resistance (MDR) might be related to the inhibition of PI3K/Akt pathway. Cotreatment with AFT and ADR could enhance ADR-induced apoptosis and autophagy in A549T cells. Meanwhile, the co-treatment significantly induced cell apoptosis and autophagy accompanied by increased expression of cleaved caspase-3, PARP, LC3B-II, and beclin 1. Apoptosis inhibitors had no significant effect on cell activity, while autophagy inhibitors decreased cell viability, suggesting that autophagy may be a self protective mechanism of cell survival in the absence of chemotherapy drugs. Interestingly, when combined with AFT and ADR, inhibition of apoptosis and/or autophagy could enhance cell viability. These results indicated that in addition to inhibit P-gp, ADR-induced apoptosis, and autophagy promoted by AFT contributed to the antiproliferation effect of combined AFT and ADR on A549T cells. These findings provide evidence that AFT combined ADR may achieve a better therapeutic effect to lung cancer in clinic. J. Cell. Biochem. 119: 414-423, 2018. © 2017 Wiley Periodicals, Inc.

The reversal effect of abnormal savda munziq total flavonoids on leukemia cell lines

Objective To investigate the reversal effect of abnormal savda munziq total flavonoids on leukemic cell lines. Methods CCK-8 method was used to detect the cytotoxicity of abnormal savda munziq total flavonoids on leukemia cells, by multivariate analysis of variance in the chemotherapy drug intervention, further calculated the reversal fold. Results CCK-8 results showed that with the increase of concentration of ASMq800(μg/mL) compared with 200(μg/mL) and 400(μg/mL), the A value of K562/ADR cells gradually decreased, the growth curve suggested that with the increase of ASMq concentration in K562/ADR cell, survival time was shortened, the inhibition of the cells was significantly increased.Different concentrations of ASMq on the adriamycin toxicity with increase of concentration of adriamycin, the inhibition of ASMq on multidrug resistance cell line was significantly higher.The reversal multiples calculated that with the increase of ASMq concentration 600 μg/mL and 900 μg/mL, the reversal index increased significantly 2.485 times and 3.651 times. Conclusion ASMq on human leukemia multidrug resistance cell line K562/ADR could reverse the drug resistance, the reversal mechanism needs further study. Key words: Abnormal savda munziq total flavonoids; Leukemia; Multidrug resistance cell; Reversal

Cardioprotective effect of creatine phosphate sodium combined with compound coenzyme on myocardial injury induced by Adriamycin of children with tumor

Objective To explore the protective effect of creatine phosphate sodium and compound coenzyme on tumor children with Adriamycin(ADM)-induced myocardial injury. Methods From Feb.2012 to Feb.2014, there were 153 tumor children administered in Shijitan Hospital, the Capital Medical University, among which there were 112 male and 41 female, aged from 10 months to 5 years, and the median age was 2.3 years.All the cases were randomly divided into 3 groups, with the dose of ADM at 20-30 mg/(m2·d) for 3 days, and for 3 to 6 courses of treatment.All cases were rolled in the ADM chemotherapy: group A, intravenous infusion of creatine phosphate sodium(1.0 g/d) and compound coenzyme(1 injection/d), at a total of 7 days; group B with only intravenous infusion of creatine phosphate sodium(1.0 g/d) for a total of 7 days; group C with only intravenous infusion compound coenzyme(1 injection/d) for a total of 7 days.Two days before ADM chemotherapy, creatine phosphate sodium and / or compound coenzyme were administrated to protect the musculus cardiacus.One day before chemotherapy and two days after chemotherapy, the peripheral blood was taken to determine levels of malondialdehyde(MDA), creatine kinase(CK), creatine kinase MB(CK-MB), cardiac troponin(cTnT), N terminal pro-brain natriuretic peptide(NT-proBNP), high-sensitivity C-reactive protein(hsCRP), electrocardiogram, echocardiogram and so on.Then the changes of all those indicators before and after the chemotherapy between the groups were compared. Results The morbidity of myocardial damage induced by ADM was increased significantly with its dose accumulation(χ2=18.462, P<0.05). Creatine phosphate sodium combined with compound coenzyme could decrease the morbidity of myocardial damage induced by ADM(χ2=4.883, 5.971, all P<0.05). Compared with those before chemotherapy, the cTnT(t=2.561, P<0.05), NT-proBNP(t=6.654, P<0.01) and hsCRP(t=3.149, P<0.01) levels of group A decreased markedly.Serum levels of MDA(t=2.170, P<0.05), CK-MB(t=2.596, P<0.05) and hsCRP(t=2.604, P<0.05) of group B increased obviously.Serum levels of MDA(t=2.151, P<0.05) and CK-MB(t=4.109, P<0.05) of group C also increased obviously.After chemotherapy, the detection of serum indexes of all groups showed as below.Contracted with those of group A, the serum MDA(t=4.461, P<0.01), CK-MB(t=3.273, P<0.01), cTnT(t=3.476, P<0.01), NT-proBNP(t=7.081, P<0.01) and hsCRP(t=5.941, P<0.01) levels of group B increased distinctly.Meanwhile, the MDA(t=4.064, P<0.01), CK-MB(t=5.452, P<0.01), cTnT(t=2.768, P<0.05), NT-proBNP(t=4.806, P<0.01) and hsCRP(t=3.436, P<0.05) levels of group C also increased significantly. Conclusions Both creatine phosphate and compound coenzyme could reduce the myocardial damage induced by ADM.Combination of them has important clinical value for better prevention of cardiac toxicity of ADM, enhancement of the prognosis of childhood tumor, and improvement of the long-term quality life of those children. Key words: Creatine phosphate sodium; Compound coenzyme; Doxorubicin; Myocardial injury; Tumor; Child

Melatonin increased vitamin C and antioxidant enzyme values in the plasma,heart, liver, and kidney of Adriamycin-treated rats

Adriamycin, an anticarcinogenic agent, causes excessive production of reactive oxygen species (ROS). These radicals may affect antioxidant defense systems. The present study was designed to investigate the effects of melatonin on antioxidant enzyme activities and vitamin C in Adriamycin-treated rats. In the current study, rats were divided into three groups: control, Adriamycin, and melatonin+Adriamycin groups. The control group was intraperitoneally injected physiological saline (0.9%) as a placebo. The Adriamycin and melatonin+Adriamycin groups were administered Adriamycin (25 mg/kg body weight). The melatonin+Adriamycin group was pretreated with melatonin (0.5 mg/kg body weight). Vitamin C concentration and catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), glutathione reductase (GR), and myeloperoxidase (MPO) activities were determined in the plasma, heart, liver, and kidneys in the Adriamycin-treated rats. The activities of CAT, SOD, GSH-Px, GR, and MPO decreased generally (between P < 0.045 and P < 0.006) with Adriamycin treatment, but these enzymes were near to the control values with melatonin treatment. In conclusion, melatonin inhibited Adriamycin-induced ROS production through supporting antioxidant enzyme systems in the plasma, heart, liver, and kidneys of rats, and thus may play an important role against Adriamycin toxicity.

A retrospective study on combination therapy with ifosfamide, adriamycin and cisplatin for progressive or recurrent uterine sarcoma.

There is currently insufficient evidence to recommend a specific chemotherapeutic regimen as standard treatment for uterine sarcomas. In this study, we investigated the toxicity and effectiveness of ifosfamide, adriamycin and cisplatin (IAP therapy) in patients with progressive and recurrent uterine sarcoma. A total of 11 patients with progressive or recurrent uterine sarcoma containing leiomyosarcoma (LMS), undifferentiated endometrial sarcoma (UES) or adenosarcoma, who were diagnosed at our institution, were retrospectively investigated. We recorded the adverse events, response rate and progression-free survival in these cases. The histological types included LMS (54.5%), adenosarcoma (27.3%) and UES (18.2%). Grade ≥3 leukopenia or neutropenia were observed in all the cases, febrile neutropenia developed in 45.5% of the patients and grade 4 thrombocytopenia developed in 3 cases (27.3%). With IAP therapy, the response rate was 36.4% and the disease control rate was 90.9%. Therefore, IAP therapy may be a viable option as chemotherapy for uterine sarcoma.

Camel Thorn Has Hepatoprotective Activity against Carbon Tetrachloride or Acetaminophen Induced Hepatotoxicity, but Enhances the Cardiac Toxicity of Adriamycin in Rodents

Abstract — In this study the administration of 660 mg/kg of the ethanolic extract of the Alhagigraecorum (Camel Thorn)to mice, showed a significant decrease in the level of transaminases in animals treated with a combination of CTE plus carbon tetrachloride (CCl 4 ) or acetaminophen as compared to animals receiving CCl 4 or acetaminophen alone. Histopatological investigation also confirmed that, camel thorn extract protects liver against damage-induced either by carbon tetrachloride or acetaminophen. On the other hand the cardiac toxicity produced by adriamycine was significantly increased in the presence of the ethanolic extract of camel thorn. Our study suggested that camel thorn can protect the liver against the injury produced by carbon tetrachloride or acetaminophen, with unexpected increase in the cardiac toxicity –induced by adriamycin in rodents. Keywords — Acetaminophen, Adriamycin, Alhagi graecorum , Carbon tetrachloride. I. II.I NTRODUCTION EPATOTOXICITY implies chemical-driven liver damage. Liver plays central role in transformation and clearance of most chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses and sometime even when introduced within therapeutic ranges, may injure the organ. Chemicals that cause liver injury are called hepatotoxins [1]. Chemicals produce a wide variety of clinical and pathological hepatic injury. Biochemical markers (i.e. alanine transferase, alkaline phosphatase and bilirubin) are often used to indicate liver damage [2], [3]. Liver damage is further characterized into hepatocellular (predominantly initial Alanine transferase elevation) and cholestatic type (initial alkaline phosphatase rise). However they are not mutually exclusive and mixed type

Podocyte-Specific GLUT4-Deficient Mice Have Fewer and Larger Podocytes and Are Protected From Diabetic Nephropathy

Podocytes are a major component of the glomerular filtration barrier, and their ability to sense insulin is essential to prevent proteinuria. Here we identify the insulin downstream effector GLUT4 as a key modulator of podocyte function in diabetic nephropathy (DN). Mice with a podocyte-specific deletion of GLUT4 (G4 KO) did not develop albuminuria despite having larger and fewer podocytes than wild-type (WT) mice. Glomeruli from G4 KO mice were protected from diabetes-induced hypertrophy, mesangial expansion, and albuminuria and failed to activate the mammalian target of rapamycin (mTOR) pathway. In order to investigate whether the protection observed in G4 KO mice was due to the failure to activate mTOR, we used three independent in vivo experiments. G4 KO mice did not develop lipopolysaccharide-induced albuminuria, which requires mTOR activation. On the contrary, G4 KO mice as well as WT mice treated with the mTOR inhibitor rapamycin developed worse adriamycin-induced nephropathy than WT mice, consistent with the fact that adriamycin toxicity is augmented by mTOR inhibition. In summary, GLUT4 deficiency in podocytes affects podocyte nutrient sensing, results in fewer and larger cells, and protects mice from the development of DN. This is the first evidence that podocyte hypertrophy concomitant with podocytopenia may be associated with protection from proteinuria.