Query: Dox induced cardiotoxicity in zebrafish

title: Investigating the toxicity of ATA nanoparticles in vitro and cardioprotective effects of ATA on DOX induced cardiotoxicity in zebrafish

title: A novel compound DT 010 protects against doxorubicin induced cardiotoxicity in zebrafish and H9c2 cells by inhibiting reactive oxygen species mediated apoptotic and autophagic pathways
abstract: Doxorubicin (Dox) is an effective anti cancer agent but limited by its cardiotoxicity, thus the search for pharmacological agents for enhancing anti cancer activities and protecting against cardiotoxicity has been a subject of great interest. We have previously reported the synergistic anti cancer effects of a novel compound DT 010. In the present study, we further investigated the cardioprotective effects of DT 010 in zebrafish embryos in vivo and the molecular underlying mechanisms in H9c2 cardiomyocytes in vitro. We showed that DT 010 prevented the Dox induced morphological distortions in the zebrafish heart and the associated cardiac impairments, and especially improved ventricular functions. By using H9c2 cells model, we showed that DT 010 directly inhibited the generation of reactive oxygen species by Dox and protected cell death and cellular damage. We further observed that DT 010 protected against Dox induced myocardiopathy via inhibiting downstream molecular pathways in response to oxidative stress, including reactive oxygen species mediated MAPK signaling pathways ERK and JNK, and apoptotic pathways involving the activation of caspase 3, caspase 7, and PARP signaling. Recent studies also suggest the importance of alterations in cardiac autophagy in Dox cardiotoxicity. We further showed that DT 010 could inhibit the induction of autophagosomes formation by Dox via regulating the upstream Akt/AMPK/mTOR signaling. Since Dox induced cardiotoxicity is multifactorial, our results suggest that multi functional agent such as DT 010 might be an effective therapeutic agent for combating cardiotoxicity associated with chemotherapeutic agents such as Dox.

title: Evaluating a novel cardioprotective agent against DOX induced cardiotoxicity in transgenic zebrafish model

title: Tanshinone IIA Restores Dynamic Balance of Autophagosome/Autolysosome in Doxorubicin Induced Cardiotoxicity via Targeting Beclin1/LAMP1
abstract: Clinical use of the anti cancer drug doxorubicin (DOX) is largely limited due to its severe cardiotoxicity. Dysregulation of autophagy is implicated in DOX induced cardiotoxicity (DIC) Prior studies have indicated that Beclin1 and lysosomal associated membrane proteins 1 (LAMP1) are critical mediators of autophagy. In this work, by assessing autophagic flux in a DOX stimulated H9C2 model, we observed autolysosome accumulation caused by interruption of autolysosome degradation. Tanshinone IIA (TSA) is a well known small molecule that exerts impressive cardioprotective effects on heart failure. Here, we investigated the regulation of TSA in DOX treated zebrafish, mice, and H9C2 models. Results demonstrated that TSA remarkably improved heart function and reversed pathological changes in vivo, while TSA restored autophagic flux by promoting autolysosome degradation and autophagosome formation. Further experiments demonstrated that these effects were mediated through upregulation of Beclin1 and LAMP1. The mTOR agonist MHY1485 was shown to abrogate the effect of TSA via the UNC 51 like kinase 1 (ULK1) Beclin1/TFEB LAMP1 signaling pathway in vitro, demonstrating that TSA protects against DIC by promoting autophagy via the Beclin1/LAMP1 signaling pathway. We further employed a U87 model to assess whether TSA would compromise the antitumor activity of DOX. Intriguingly, the co treatment of TSA was able to synergistically inhibit proliferative activity. Collectively, in this study we uncover the novel insight that TSA is able to reduce the cardiotoxicity of DOX without compromising antitumor activity.

title: Synthesis of Isosteviol analogues as potential protective agents against Doxorubicin induced cardiomyopathy in zebrafish embryos.
abstract: Doxorubicin (DOX) is a powerful anthracycline antibiotic agent which is widely used to treat various types of cancers. Despite efficacy, it displays severe cardiotoxic side effects. Discovery of novel and effective protective agents against DOX induced cardiotoxicity has been a subject of great interest. Herein, we report the synthesis of two series of analogues of Isosteviol (ISV) 1 with modifications at C 16, C 19 positions as the first series and at C 15, C 16 positions as the other series. Interestingly second series analogues have shown a potential protective effect against DOX induced cardiotoxicity in zebrafish embryos in vivo. Further, we have demonstrated that the synthesized new analogues of ISV, prevented the morphological distortions caused due to DOX cardiotoxicity in zebrafish heart and the associated cardiac impairments.

title: Cardiotoxicity evaluation of anthracyclines in zebrafish (Danio rerio)
abstract: Drug induced cardiotoxicity is a leading factor for drug withdrawals, and limits drug efficacy and clinical use. Therefore, new alternative animal models and methods for drug safety evaluation have been given great attention. Anthracyclines (ANTs) are widely prescribed anticancer agents that have a cumulative dose relationship with cardiotoxicity. We performed experiments to study the toxicity of ANTs in early developing zebrafish embryos, especially their effects on the heart. LC50 values for daunorubicin, pirarubicin, doxorubicin (DOX) epirubicin and DOX liposome at 72 h post fertilization were 122.7 mM, 111.9 mM, 31.2 mM, 108.3 mM and 55.8 mM, respectively. At the same time, zebrafish embryos were exposed to ANTs in three exposure stages and induced incomplete looping of the heart tube, pericardia edema and bradycardia in a dose dependent manner, eventually leading to death. DOX caused the greatest heart defects in the treatment stages and its liposome reduced the effects on the heart, while daunorubicin produced the least toxicity. Genes and proteins related to heart development were also identified to be sensitive to ANT exposure and downregulated by ANTs. It revealed ANTs could disturb the heart formation and development. ANTs induced cardiotoxicity in zebrafish has similar effects in mammalian models, indicating that zebrafish may have a potential value for assessment of drug induced developmental cardiotoxicity.

title: A novel agent attenuates cardiotoxicity and improves antitumor activity of doxorubicin in breast cancer cells
abstract: Doxorubicin (Dox) is a well known chemotherapeutic agent used in the treatment of various cancers. However, Dox induced cardiotoxicity limits its further clinical use. We have previously reported a small molecular named biotin conjugated ADTM analog (BAA) that exhibits cytoprotective effects against oxidative stress induced cell injury in cardiomyoblast H9c2 cells. Here, the protective effects of BAA, indexed by attenuation of the cardiotoxicity induced by Dox as well as synergistic antitumor activity that increases the chemotherapeutic efficacy of Dox were investigated. Our results demonstrated that BAA significantly ameliorated Dox induced toxicity in the H9c2 cells and zebrafish models. In addition, BAA attenuated Dox induced endoplasmic reticulum (ER) stress in H9c2 cells. An ER stress inhibitor, 4 phenylbutyric acid, reversed the protective effect of BAA in H9c2 cells. In contrast, in human breast tumor MDA MB 231 cells, BAA significantly enhanced Dox induced cytotoxicity through upregulating Dox induced ER stress response. Taken together, our findings indicate that Dox combined with BAA can significantly enhance its antitumor activity in breast cancer cells and reduce its cardiotoxicity, at least in part, by mediating ER stress activation.

title: A Novel Danshensu Derivative Prevents Cardiac Dysfunction and Improves the Chemotherapeutic Efficacy of Doxorubicin in Breast Cancer Cells
abstract: Doxorubicin (Dox) is an anthracycline antibiotic widely used in clinics as an anticancer agent. However, the use of Dox is limited by its cardiotoxicity. We have previously shown that a Danshensu (DSS) derivative, ADTM, displayed strong cardioprotective effects. With improved chemical stability and activity, a novel DSS derivative, D006, based on the structure of ADTM, was synthesized. In the present study, the protective effects of D006, indexed by attenuation of the cardiotoxicity induced by Dox as well as chemosensitizing effects that increase the antitumor activity of Dox, were investigated. Our results showed that D006 was more potent than either parental compound, or their use in combination, in ameliorating Dox induced toxicity in H9c2 cells. In our zebrafish model, D006, but not DSS, alone significantly preserved the ventricular function of zebrafish after Dox treatment. Moreover, D006 upregulated mitochondrial biogenesis and increased mtDNA copy number after Dox treatment of H9c2 cells. D006 promoted the expression of HO 1 protein in a time dependent manner while the HO 1 inhibitor, Znpp, reversed the protective effects of D006. In human breast tumor MCF 7 cells, D006 enhanced Dox induced cytotoxicity by increasing apoptosis. In conclusion, our results indicate that a new DSS derivative exhibits promising protective effects against Dox induced cardiotoxicity both in vivo and in vitro, an effect at least partially mediated by induction of HO 1 expression and the activation of mitochondrial biogenesis. Meanwhile, D006 also potentiated the anti cancer effects of Dox in breast tumor cells.  2016.

title: Cardioprotective and chemosensitizing effects of novel Danshensu derivatives
abstract: To investigate the cardioprotective effect of novel danshensu derivatives against doxorubicin(Dox)cardiotoxicity and their synergistic anti tumor effect with Dox on breast cancer cells. Two new Danshensu derivatives were synthesized by conjugation with tetramethylpyrizine and/or4 (3 thioxo 3 H 1,2 dithiol 4 yl) benzoic acid and tested for protective effects against Dox induced cardiotoxicity in cell and zebrafish.H9c2 cardiomyoblasts were co treated with Dox and Danshensu derivatives for 24 h and then were measured for cell viability and cytotoxicity by MTT and LDH assays.The expression levels of mitochondrial biogenesis related proteins PGC 1a,NRF 1and Nrf2 were detected by Western blotting and qPCR.Moreover,in a Dox induced cardiotoxicity model of zebrafish,zebrafish embryos were treated with Dox for 36 h,followed by measurement of numerous ventricular function parameters including heart rate,stroke volume,cardiac output and fractional shortening.In addition,the synergistic anti tumor effects of the Danshensu derivatives and Dox had been studied in MCF 7 breast cancer cells.The effects of the Danshensu derivatives on the cell death and metabolism of MCF 7 cells were measured using apoptosis assay and Seahorse Metabolic Analyzers respectively. Our results showed that the Danshensu derivatives were more potent than the parental compounds in ameliorating Dox induced cytotoxicity in H9c2 cells and significantly preserving stroke volume of heart function in Dox treated zebrafish.Further mechanistic studies identified that the danshensu derivatives increased mitochondrial copy numbers and protein expressions of PGC 1a,NRF 1 and Nrf2 in H9c2 cells.In addition,the Danshensu derivatives enhanced Dox induced apoptosis,and decreased glycolysis and mitochondrial function in MCF 7 tumor cells. Our results revealed that two new Danshensu derivatives displayed promising cardioprotective effects against Dox induced cardiotoxicity both in vivo and in vitro,at least partially through activatin

title: Mechanistic study on the cardioprotective and chemosensitizing effects of a novel danshensu derivative
abstract: Doxorubicin (Dox) is an anthracycline antibiotic which is widely used in clinics as an anticancer agent. However, the use of Dox is limited by its cardiotoxicity. Our previous studies have shown that a Danshensu derivative ADTM displayed strong cardioprotective effects in an oxidative stress induced cell injury model in H9c2 cardiomyocytes and an acute myocardial ischemia model in rat  We are developing more potent cardioprotective danshensu derivative based on ADTM structure for management of the cardiotoxic side effect of Dox. In the present study, we investigated the protective and chemosensitizing effects of a novel Danshensu derivative D006 against cardiotoxicity induced by Dox and in increasing the antitumor activity of Dox respectively. Our results showed that D006 was approximately 30 fold more potent than ADTM in ameliorating Dox induced cardiotoxicity in H9c2 cells. In the zebrafish model, D006 but not ADTM or Danshensu alone, significantly preserved stroke volume of heart function after Dox treatment. In addition, D006 enhanced Dox induced apoptosis as well as ROS production in MCF 7 tumor cells. Mitochondrial biogenesis, a process involved in the formation of new mitochondrial, which depends on the expression of PGC 1. Recent studies showed that suppressed cardiac mitochondrial biogenesis and decreased mtDNA contents may play vital roles in the pathogenesis of Dox induced cardiomyopathy [2] Further mechanistic studies verified that D006 increased the expression of PGC 1b in H9c2 cells. Moreover, D006 upregulated mitochondrial biogenesis and increased mtDNA copy number after Dox treatment in H9c2 cells. Our results revealed that a new danshensu derivative displayed promising cardioprotective effects against Dox induced cardiotoxicity both in vivo and in vitro, at least partially through activating mitochondrial biogenesis. In addition, the new danshensu derivative also potentiated the anticancer effects of Dox in breast tumor cells.  danshensu, doxorubicin, cardioprotection, mitochondrial biogenesis, anticancer References:  Cui, G. et al. (2013)   Miyagawa, K. et al. (2010) Hypertension.2010 55(3):738 46.