scholarly journals Zebrafish Models of Cancer Therapy-Induced Cardiovascular Toxicity

2021 ◽  
Vol 8 (2) ◽  
pp. 8
Author(s):  
Sarah Lane ◽  
Luis Alberto More ◽  
Aarti Asnani
Keyword(s):  
Cancer Therapy ◽  
High Throughput ◽  
Early Developmental Stage ◽  
Transgenic Zebrafish ◽  
Cardiovascular Toxicity ◽  
Zebrafish Model ◽  
In Vivo Models ◽  
Mechanisms Of Toxicity

Purpose of review: Both traditional and novel cancer therapies can cause cardiovascular toxicity in patients. In vivo models integrating both cardiovascular and cancer phenotypes allow for the study of on- and off-target mechanisms of toxicity arising from these agents. The zebrafish is the optimal whole organism model to screen for cardiotoxicity in a high throughput manner, while simultaneously assessing the role of cardiotoxicity pathways on the cancer therapy’s antitumor effect. Here we highlight established zebrafish models of human cardiovascular disease and cancer, the unique advantages of zebrafish to study mechanisms of cancer therapy-associated cardiovascular toxicity, and finally, important limitations to consider when using the zebrafish to study toxicity. Recent findings: Cancer therapy-associated cardiovascular toxicities range from cardiomyopathy with traditional agents to arrhythmias and thrombotic complications associated with newer targeted therapies. The zebrafish can be used to identify novel therapeutic strategies that selectively protect the heart from cancer therapy without affecting antitumor activity. Advances in genome editing technology have enabled the creation of several transgenic zebrafish lines valuable to the study of cardiovascular and cancer pathophysiology. Summary: The high degree of genetic conservation between zebrafish and humans, as well as the ability to recapitulate cardiotoxic phenotypes observed in patients with cancer, make the zebrafish an effective model to study cancer therapy-associated cardiovascular toxicity. Though this model provides several key benefits over existing in vitro and in vivo models, limitations of the zebrafish model include the early developmental stage required for most high-throughput applications.

scholarly journals DNAzymes, Novel Therapeutic Agents in Cancer Therapy: A Review of Concepts to Applications

2021 ◽  
Vol 2021 ◽  
pp. 1-21
Author(s):  
I. B. K. Thomas ◽  
K. A. P. Gaminda ◽  
C. D. Jayasinghe ◽  
D. T. Abeysinghe ◽  
R. Senthilnithy
Keyword(s):  
Nucleic Acid ◽  
Cancer Therapy ◽  
Cancer Drug ◽  
Clinical Settings ◽  
Full Potential ◽  
In Vivo Models ◽  
Recent Advances ◽  
Catalytic Dna

The past few decades have witnessed a rapid evolution in cancer drug research which is aimed at developing active biological interventions to regulate cancer-specific molecular targets. Nucleic acid-based therapeutics, including ribozymes, antisense oligonucleotides, small interference RNA (siRNA), aptamer, and DNAzymes, have emerged as promising candidates regulating cancer-specific genes at either the transcriptional or posttranscriptional level. Gene-specific catalytic DNA molecules, or DNAzymes, have shown promise as a therapeutic intervention against cancer in various in vitro and in vivo models, expediting towards clinical applications. DNAzymes are single-stranded catalytic DNA that has not been observed in nature, and they are synthesized through in vitro selection processes from a large pool of random DNA libraries. The intrinsic properties of DNAzymes like small molecular weight, higher stability, excellent programmability, diversity, and low cost have brought them to the forefront of the nucleic acid-based therapeutic arsenal available for cancers. In recent years, considerable efforts have been undertaken to assess a variety of DNAzymes against different cancers. However, their therapeutic application is constrained by the low delivery efficiency, cellular uptake, and target detection within the tumour microenvironment. Thus, there is a pursuit to identify efficient delivery methods in vivo before the full potential of DNAzymes in cancer therapy is realized. In this light, a review of the recent advances in the use of DNAzymes against cancers in preclinical and clinical settings is valuable to understand its potential as effective cancer therapy. We have thus sought to firstly provide a brief overview of construction and recent improvements in the design of DNAzymes. Secondly, this review stipulates the efficacy, safety, and tolerability of DNAzymes developed against major hallmarks of cancers tested in preclinical and clinical settings. Lastly, the recent advances in DNAzyme delivery systems along with the challenges and prospects for the clinical application of DNAzymes as cancer therapy are also discussed.

scholarly journals The Good, the Bad, the Question–H19 in Hepatocellular Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1261 ◽  
Author(s):  
Lysann Tietze ◽  
Sonja M. Kessler
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Therapy ◽  
Liver Cancer ◽  
Primary Liver Cancer ◽  
Human Patient ◽  
In Vivo Models ◽  
Study Results ◽  
Novel Target

Hepatocellular carcinoma (HCC), the most common primary liver cancer, is challenging to treat due to its typical late diagnosis, mostly at an advanced stage. Therefore, there is a particular need for research in diagnostic and prognostic biomarkers and therapeutic targets for HCC. The use of long noncoding (lnc) RNAs can widen the list of novel molecular targets improving cancer therapy. In hepatocarcinogenesis, the role of the lncRNA H19, which has been known for more than 30 years now, is still controversially discussed. H19 was described to work either as a tumor suppressor in vitro and in vivo, or to have oncogenic features. This review attempts to survey the conflicting study results and tries to elucidate the potential reasons for the contrary findings, i.e., different methods, models, or readout parameters. This review encompasses in vitro and in vivo models as well as studies on human patient samples. Although the function of H19 in HCC remains elusive, a short outlook summarizes some ideas of using the H19 locus as a novel target for liver cancer therapy.

scholarly journals Evaluation of CML TKI Induced Cardiovascular Toxicity and Development of Potential Rescue Strategies in a Zebrafish Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Shan Cheng ◽  
Pan Jin ◽  
Heying Li ◽  
Duanqing Pei ◽  
Xiaodong Shu
Keyword(s):  
Adverse Events ◽  
Kinase Inhibitors ◽  
Angiotensin Receptor Blockers ◽  
Clinical Stage ◽  
Confocal Imaging ◽  
Transgenic Zebrafish ◽  
Cardiovascular Toxicity ◽  
Zebrafish Model ◽  
T315i Mutation

Tyrosine kinase inhibitors (TKIs) to BCR-ABL1 have been successfully used to treat chronic myeloid leukemia (CML), however, multiple TKI-associated adverse events have been reported and become an emerging problem in patients. The mechanisms of TKI-induced toxicity are not fully understood and it remains challenging to predict potential cardiovascular toxicity of a compound. In this study, we established a zebrafish model to evaluate potential in vivo cardiovascular toxicity of TKIs. We treated the endothelium labeled Tg(kdrl:EGFP) transgenic zebrafish embryos with TKIs then performed confocal imaging to evaluate their vascular structure and function. We found that among FDA approved CML TKIs, ponatinib (the only approved TKI that is efficacious to T315I mutation) is the most toxic one. We then evaluated safety profiles of several clinical stage kinase inhibitors that can target T315I and found that HQP1351 treatment leads to vasculopathies similar to those induced by ponatinib while the allosteric ABL inhibitor asciminib does not induce noticeable cardiovascular defects, indicating it could be a promising therapeutic reagent for patients with T315I mutation. We then performed proof-of-principle study to rescue those TKI-induced cardiovascular toxicities and found that, among commonly used anti-hypertensive drugs, angiotensin receptor blockers such as azilsartan and valsartan are able to reduce ponatinib or HQP1351 induced cardiovascular toxicities. Together, this study establishes a zebrafish model that can be useful to evaluate cardiovascular toxicity of TKIs as well as to develop strategies to minimize TKI-induced adverse events.

scholarly journals Pioneer neutrophils release chromatin within in vivo swarms

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Hannah M Isles ◽  
Catherine A Loynes ◽  
Sultan Alasmari ◽  
Fu Chuen Kon ◽  
Katherine M Henry ◽  
...  
Keyword(s):  
Tissue Injury ◽  
Damage Model ◽  
Neutrophil Migration ◽  
Initial Step ◽  
Transgenic Zebrafish ◽  
In Vivo Models ◽  
Essential Components ◽  
Cellular Components

Neutrophils are rapidly recruited to inflammatory sites where their coordinated migration forms clusters, a process termed neutrophil swarming. The factors that modulate early stages of neutrophil swarming are not fully understood, requiring the development of new in vivo models. Using transgenic zebrafish larvae to study endogenous neutrophil migration in a tissue damage model, we demonstrate that neutrophil swarming is a conserved process in zebrafish immunity, sharing essential features with mammalian systems. We show that neutrophil swarms initially develop around an individual pioneer neutrophil. We observed the violent release of extracellular cytoplasmic and nuclear fragments by the pioneer and early swarming neutrophils. By combining in vitro and in vivo approaches to study essential components of neutrophil extracellular traps (NETs), we provide in-depth characterisation and high-resolution imaging of the composition and morphology of these release events. Using a photoconversion approach to track neutrophils within developing swarms, we identify that the fate of swarm-initiating pioneer neutrophils involves extracellular chromatin release and that the key NET components gasdermin, neutrophil elastase, and myeloperoxidase are required for the swarming process. Together our findings demonstrate that release of cellular components by pioneer neutrophils is an initial step in neutrophil swarming at sites of tissue injury.

scholarly journals Lipid-Based Nanocarriers Provide Prolonged Anticancer Activity for Palbociclib: In Vitro and in Vivo Evaluations

2021 ◽  
Author(s):  
Parichehr Hassanzadeh ◽  
Elham Arbabi ◽  
Fatemeh Rostami
Keyword(s):  
Breast Cancer ◽  
Cancer Therapy ◽  
Cell Cycle Progression ◽  
Critical Role ◽  
Survival Rates ◽  
Physicochemical Characteristics ◽  
In Vivo Models ◽  
Estrogen Receptor Positive

Breast cancer therapy has remained one of the major healthcare challenges. Based on the critical role of cyclin-dependent kinase 4/6 (CDK 4/6) in cell cycle progression, targeting this signaling appears promising for cancer therapy. Palbociclib, a selective CDKs 4/6 inhibitor, is the first-line treatment for estrogen receptor-positive breast cancer. However, poor absorption or side effects may negatively affect its efficiency. This prompted us to incorporate palbociclib into the nanostructured lipid carriers (NLCs) and evaluate the anticancer effect of the nanoformulation (Pa-NLCs) in in vitro and in vivo models of breast cancer. Pa-NLCs were developed by high-pressure homogenization followed by assessment of the physicochemical characteristics and bioactivities in MCF-7 breast cancer cells and female Wistar rats exposed to the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). The prepared Pa-NLCs demonstrated suitable physicochemical characteristics, including the controlled release pattern, efficient cellular uptake, and cytotoxicity, while free palbociclib failed to show significant effects. Rats treated with Pa-NLCs exhibited significantly reduced tumor volumes, increased survival rates, and histopathological improvement. Free palbociclib was significantly less efficient than Pa-NLCs. Pa-NLCs, by improving the pharmacological profile of palbociclib and providing longer-lasting effects, can be considered as a promising nanoformulation against breast cancer.

scholarly journals Role of endothelial microRNA 155 on capillary leakage in systemic inflammation

Critical Care ◽  
2021 ◽  
Vol 25 (1) ◽  
Author(s):  
Valerie Etzrodt ◽  
Temitayo O. Idowu ◽  
Heiko Schenk ◽  
Benjamin Seeliger ◽  
Antje Prasse ◽  
...  
Keyword(s):  
Vascular Leakage ◽  
Transgenic Zebrafish ◽  
Wildtype Mouse ◽  
Dependent Manner ◽  
Capillary Leakage ◽  
In Vivo Models ◽  
Junction Protein

Abstract Background Capillary leakage is a key contributor to the pathological host response to infections. The underlying mechanisms remain incompletely understood, and the role of microRNAs (MIR) has not been investigated in detail. We hypothesized that specific MIRs might be regulated directly in the endothelium thereby contributing to vascular leakage. Methods SmallRNA sequencing of endotoxemic murine pulmonary endothelial cells (ECs) was done to detect regulated vascular MIRs. In vivo models: transgenic zebrafish (flk1:mCherry/l-fabp:eGFP-DPB), knockout/wildtype mouse (B6.Cg-Mir155tm1.1Rsky/J); disease models: LPS 17.5 mg/kgBW and cecal ligation and puncture (CLP); in vitro models: stimulated human umbilical vein EC (HUVECs), transendothelial electrical resistance. Results Endothelial MIR155 was identified as a promising candidate in endotoxemic murine pulmonary ECs (25 × upregulation). Experimental overexpression in a transgenic zebrafish line and in HUVECs was sufficient to induce spontaneous vascular leakage. To the contrary, genetic MIR155 reduction protects against permeability both in vitro and in endotoxemia in vivo in MIR155 heterozygote knockout mice thereby improving survival by 40%. A tight junction protein, Claudin-1, was down-regulated both in endotoxemia and by experimental MIR155 overexpression. Translationally, MIR155 was detectable at high levels in bronchoalveolar fluid of patients with ARDS compared to healthy human subjects. Conclusions We found that MIR155 is upregulated in the endothelium in mouse and men as part of a systemic inflammatory response and might contribute to the pathophysiology of vascular leakage in a Claudin-1-dependent manner. Future studies have to clarify whether MIR155 could be a potential therapeutic target.

scholarly journals Endoglin regulates PI3-kinase/Akt trafficking and signaling to alter endothelial capillary stability during angiogenesis

2012 ◽  
Vol 23 (13) ◽  
pp. 2412-2423 ◽  
Author(s):  
Nam Y. Lee ◽  
Christelle Golzio ◽  
Catherine E. Gatza ◽  
Arun Sharma ◽  
Nicholas Katsanis ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Cell Function ◽  
Capillary Tube ◽  
Transforming Growth Factor Β ◽  
Transgenic Zebrafish ◽  
Zebrafish Model ◽  
Interacting Protein ◽  
Endothelial Cell Function

Endoglin (CD105) is an endothelial-specific transforming growth factor β (TGF-β) coreceptor essential for angiogenesis and vascular homeostasis. Although endoglin dysfunction contributes to numerous vascular conditions, the mechanism of endoglin action remains poorly understood. Here we report a novel mechanism in which endoglin and Gα-interacting protein C-terminus–interacting protein (GIPC)–mediated trafficking of phosphatidylinositol 3-kinase (PI3K) regulates endothelial signaling and function. We demonstrate that endoglin interacts with the PI3K subunits p110α and p85 via GIPC to recruit and activate PI3K and Akt at the cell membrane. Opposing ligand-induced effects are observed in which TGF-β1 attenuates, whereas bone morphogenetic protein-9 enhances, endoglin/GIPC-mediated membrane scaffolding of PI3K and Akt to alter endothelial capillary tube stability in vitro. Moreover, we employ the first transgenic zebrafish model for endoglin to demonstrate that GIPC is a critical component of endoglin function during developmental angiogenesis in vivo. These studies define a novel non-Smad function for endoglin and GIPC in regulating endothelial cell function during angiogenesis.

scholarly journals Anti-Inflammatory Activity of Exopolysaccharides from Phormidium sp. ETS05, the Most Abundant Cyanobacterium of the Therapeutic Euganean Thermal Muds, Using the Zebrafish Model

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 582 ◽  
Author(s):  
Raffaella Margherita Zampieri ◽  
Alessandra Adessi ◽  
Fabrizio Caldara ◽  
Alessia Codato ◽  
Mattia Furlan ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Chronic Inflammatory Disease ◽  
Bioactive Molecules ◽  
In Vitro Tests ◽  
Transgenic Zebrafish ◽  
Zebrafish Model ◽  
Beneficial Effects ◽  
Anti Inflammatory

The Euganean Thermal District (Italy) represents the oldest and largest thermal center in Europe, and its therapeutic mud is considered a unique product whose beneficial effects have been documented since Ancient Roman times. Mud properties depend on the heat and electrolytes of the thermal water, as well as on the bioactive molecules produced by its biotic component, mainly represented by cyanobacteria. The investigation of the healing effects of compounds produced by the Euganean cyanobacteria represents an important goal for scientific validation of Euganean mud therapies and for the discovering of new health beneficial biomolecules. In this work, we evaluated the therapeutic potential of exopolysaccharides (EPS) produced by Phormidium sp. ETS05, the most abundant cyanobacterium of the Euganean mud. Specifically, Phormidium EPS resulted in exerting anti-inflammatory and pro-resolution activities in chemical and injury-induced zebrafish inflammation models as demonstrated using specific transgenic zebrafish lines and morphometric and expression analyses. Moreover, in vivo and in vitro tests showed no toxicity at all for the EPS concentrations tested. The results suggest that these EPS, with their combined anti-inflammatory and pro-resolution activities, could be one of the most important therapeutic molecules present in the Euganean mud and confirm the potential of these treatments for chronic inflammatory disease recovery.

MYST3/NCOA2-Induced Acute Myeloid Leukemia in Transgenic Fish

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5329-5329
Author(s):  
Julia Zhuravleva ◽  
Jérôme Paggetti ◽  
Laurent Martin ◽  
Arlette Hammann ◽  
Eric Solary ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Transgenic Zebrafish ◽  
Zebrafish Model ◽  
Transgenic Expression ◽  
Acute Myeloid

Abstract The MYST3/NCOA2 (MOZ/TIF2) fusion gene generated by the inv(8)(p11q13) chromosomal abnormality was described in a specific subgroup of acute myeloid leukemias (AML) that represents less than 5% of AML4/5. This abnormality fuses MYST3 (MOZ), a member of the MYST family of histone acetyl-transferases (HAT) to NCOA2 (TIF2), a member of the p160 HAT family. The transforming properties of MYST3/NCOA2 were demonstrated in mouse committed myeloid progenitors in vitro and in vivo. Hematopoiesis is very similar in zebrafish and in higher vertebrates. Homologues of a large number of genes involved in mammalian myelopoiesis were identified in this animal model. We have recently shown that ncoa2 (tif2) played a role in zebrafish primitive hematopoiesis. This animal also represents a model for investigating leukemogenesis. Transgenic expression of rag2-EGFP-mMyc or rag2-ICN1-EGFP induces a T-cell acute lymphoblastic leukemia (ALL) whereas transgenic expression of the ETV6/RUNX1 fusion gene induces a B-cell type ALL. We generated a transgenic zebrafish in which the MYST3/NCOA2 fusion gene was expressed under control of the spi1 (pu.1) promoter. An AML developed in two of 180 MYST3/NCOA2-EGFP-expressing embryos, 14 and 26 months after injection of the fusion gene in a one cell embryo, respectively. This leukemia was characterized by an extensive invasion of kidneys by myeloid blast cells. This model, which is the first zebrafish model of acute myeloid leukemia, demonstrates the oncogenic potency of MYST3/NCOA2 fusion gene.

Sign in / Sign up

Export Citation Format

Share Document