scholarly journals The Anti-Tumoral Potential of Phosphonate Analog of Sulforaphane in Zebrafish Xenograft Model

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3219
Author(s):  
Magdalena Rudzinska-Radecka ◽  
Łukasz Janczewski ◽  
Anna Gajda ◽  
Marlena Godlewska ◽  
Malgorzata Chmielewska-Krzesinska ◽  
...  
Keyword(s):  
Morphological Changes ◽  
Xenograft Model ◽  
Living Organism ◽  
Significant Inhibition ◽  
Zebrafish Embryos ◽  
Cancer Cell Growth ◽  
Strong Activity ◽  
Hatching Time ◽  
Fluorescence Dye

Isothiocyanates (ITCs) show strong activity against numerous human tumors. Five structurally diverse ITCs were tested in vivo using the zebrafish embryos 6 and 48 h post-fertilization (hpf). The survival rate, hatching time, and gross morphological changes were assessed 24, 48, and 72 h after treatment with all compounds in various doses (1–10 µM). As a result, we selected a phosphonate analog of sulforaphane (P-ITC; 1–3 µM) as a non-toxic treatment for zebrafish embryos, both 6 and 48 hpf. Furthermore, the in vivo anti-cancerogenic studies with selected 3 µM P-ITC were performed using a set of cell lines derived from the brain (U87), cervical (HeLa), and breast (MDA-MB-231) tumors. For the experiment, cells were labeled using red fluorescence dye Dil (1,1′-Dioctadecyl-3,3,3′,3′-Tetramethylindocarbocyanine, 10 μg/mL) and injected into the hindbrain ventricle, yolk sac region and Cuvier duct of zebrafish embryos. The tumor size measurement after 48 h of treatment demonstrated the significant inhibition of cancer cell growth in all tested cases by P-ITC compared to the non-treated controls. Our studies provided evidence for P-ITC anti-cancerogenic properties with versatile activity against different cancer types. Additionally, P-ITC demonstrated the safety of use in the living organism at various stages of embryogenesis.

scholarly journals Edelfosine nanoemulsions inhibit tumor growth of triple negative breast cancer in zebrafish xenograft model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sofia M. Saraiva ◽  
Carlha Gutiérrez-Lovera ◽  
Jeannette Martínez-Val ◽  
Sainza Lores ◽  
Belén L. Bouzo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Xenograft Model ◽  
Skin Barrier ◽  
Zebrafish Embryos ◽  
Biorelevant Media

AbstractTriple negative breast cancer (TNBC) is known for being very aggressive, heterogeneous and highly metastatic. The standard of care treatment is still chemotherapy, with adjacent toxicity and low efficacy, highlighting the need for alternative and more effective therapeutic strategies. Edelfosine, an alkyl-lysophospholipid, has proved to be a promising therapy for several cancer types, upon delivery in lipid nanoparticles. Therefore, the objective of this work was to explore the potential of edelfosine for the treatment of TNBC. Edelfosine nanoemulsions (ET-NEs) composed by edelfosine, Miglyol 812 and phosphatidylcholine as excipients, due to their good safety profile, presented an average size of about 120 nm and a neutral zeta potential, and were stable in biorelevant media. The ability of ET-NEs to interrupt tumor growth in TNBC was demonstrated both in vitro, using a highly aggressive and invasive TNBC cell line, and in vivo, using zebrafish embryos. Importantly, ET-NEs were able to penetrate through the skin barrier of MDA-MB 231 xenografted zebrafish embryos, into the yolk sac, leading to an effective decrease of highly aggressive and invasive tumoral cells’ proliferation. Altogether the results demonstrate the potential of ET-NEs for the development of new therapeutic approaches for TNBC.

scholarly journals High expression of PSMC2 promotes gallbladder cancer through regulation of GNG4 and predicts poor prognosis

Oncogenesis ◽  
2021 ◽  
Vol 10 (5) ◽  
Author(s):  
Dawei Zhu ◽  
Xing Gu ◽  
Zhengyu Lin ◽  
Dandan Yu ◽  
Jing Wang
Keyword(s):  
Gallbladder Cancer ◽  
Malignant Tumor ◽  
Xenograft Model ◽  
Tumor Grade ◽  
Significant Inhibition ◽  
Mechanistic Study ◽  
Downstream Target ◽  
Advanced Tumor

AbstractGallbladder cancer (GBC) is a common malignant tumor of the biliary tract, which accounts for 80–95% of biliary tumors worldwide, and is the leading cause of biliary malignant tumor-related death. This study identified PSMC2 as a potential regulator in the development of GBC. We showed that PSMC2 expression in GBC tissues is significantly higher than that in normal tissues, while high PSMC2 expression was correlated with more advanced tumor grade and poorer prognosis. The knockdown of PSMC2 in GBC cells induced significant inhibition of cell proliferation, colony formation and cell motility, while the promotion of cell apoptosis. The construction and observation of the mice xenograft model also confirmed the inhibitory effects of PSMC2 knockdown on GBC development. Moreover, our mechanistic study recognized GNG4 as a potential downstream target of PSMC2, knockdown of which could aggravate the tumor suppression induced by PSMC2 knockdown in vitro and in vivo. In conclusion, for the first time, PSMC2 was revealed as a tumor promotor in the development of GBC, which could regulate cell phenotypes of GBC cells through the interaction with GNG4, and maybe a promising therapeutic target in GBC treatment.

Metaphase-Based Cytogenetic Approach Identifies Radiation-Induced Chromosome and Chromatid Aberrations in Zebrafish Embryos

2021 ◽  
Author(s):  
Halida Thanveer Asana Marican ◽  
Hongyuan Shen
Keyword(s):  
Animal Model ◽  
Radiation Exposure ◽  
Progenitor Cells ◽  
Chromosome Aberrations ◽  
Structural Changes ◽  
Current Knowledge ◽  
Living Organism ◽  
Zebrafish Embryos ◽  
Radiation Induced

Metaphase-based cytogenetic methods based on scoring of chromosome aberrations for the estimation of the radiation dose received provide a powerful approach for evaluating the associated risk upon radiation exposure and form the bulk of our current knowledge of radiation-induced chromosome damages. They mainly rely on inducing quiescent peripheral lymphocytes into proliferation and blocking them at metaphases to quantify the damages at the chromosome level. However, human organs and tissues demonstrate various sensitivity towards radiation and within them, self-proliferating progenitor/stem cells are believed to be the most sensitive populations. The radiation-induced chromosome aberrations in these cells remain largely unknown, especially in the context of an intact living organism. Zebrafish is an ideal animal model for research into this aspect due to their small size and the large quantities of progenitor cells present during the embryonic stages. In this study, we employ a novel metaphase-based cytogenetic approach on zebrafish embryos and demonstrate that chromosome-type and chromatid-type aberrations could be identified in progenitor cells at different cell-cycle stages at the point of radiation exposure. Our work positions zebrafish at the forefront as a useful animal model for studying radiation-induced chromosome structural changes in vivo.

Peperomin E Induces Apoptosis and Cytoprotective Autophagy in Human Prostate Cancer DU145 Cells In Vitro and In Vivo

Planta Medica ◽  
2021 ◽  
Author(s):  
Min Lin ◽  
Qiannan Zhu ◽  
Yunzhi Li ◽  
Jigang Pan
Keyword(s):  
Prostate Cancer ◽  
Morphological Changes ◽  
Xenograft Model ◽  
Du145 Cell ◽  
Human Prostate ◽  
Human Prostate Cancer ◽  
Tumor Mouse Model ◽  
Du145 Cells

AbstractPeperomin E was first isolated from Peperomia dindygulensis, an anticarcinogenic herb, and exhibited anticancer activity in many cancer cell lines. To date, it is unknown whether peperomin E has an effect on human prostate cancer DU145 cells in vitro and in vivo. In this study, we used MTT to assess the proliferation inhibition activity of peperomin E in DU145 cells in vitro and observed the cell morphological changes by a phase contrast microscope. A DU145 cell xenograft tumor mouse model was used to evaluate the efficacy of peperomin E in vivo. Apoptosis rates were measured by flow cytometry, and protein expression levels were analyzed by western blot. The results showed that peperomin E significantly inhibited the proliferation of DU145 cells in vitro and reduced the weight and volume of tumors in vivo. Peperomin E also significantly induced the apoptosis and autophagic response of DU145 cells. The autophagic inhibitors LY294002 and chloroquine enhanced peperomin E-mediated inhibition of DU145 cell proliferation and induction of DU145 cell apoptosis. The results also showed that the Akt/mTOR pathway participated in peperomin E-induced autophagy in DU145 cells. In summary, our finding showed that peperomin E had an effect on DU145 cells in vitro and in a nude mouse DU145 cell xenograft model in vivo, demonstrated that peperomin E could significantly induce apoptosis and the autophagic response in DU145 cells and that autophagy played a cytoprotective role in peperomin E-treated DU145 cells. These results suggest that the combination of peperomin E treatment and autophagic inhibition has potential for the treatment of prostate cancer.

Zebrafish Avatar to Develop Precision Breast Cancer Therapies.

2021 ◽  
Vol 21 ◽  
Author(s):  
Debora Corsinovi ◽  
Alice Usai ◽  
Miriam De Sarlo ◽  
Martina Giannaccini ◽  
Michela Ori
Keyword(s):  
Breast Cancer ◽  
Cancer Research ◽  
High Throughput Screening ◽  
Drug Testing ◽  
Xenograft Model ◽  
Breast Cancer Research ◽  
Tumor Xenograft ◽  
Breast Cancer Cell Lines ◽  
Zebrafish Embryos

Background: Zebrafish (Danio rerio) is a vertebrate that has become a popular alternative model for the cellular and molecular study of human tumors and for drug testing and validating approaches. Notably, zebrafish embryos, thanks to their accessibility, allow rapid collection of in vivo results prodromal to validation in the murine models in respect to the 3R principles. The generation of tumor xenograft in zebrafish embryos and larvae, or zebrafish avatar, represents a unique opportunity to study tumor growth, angiogenesis, cell invasion and metastatic dissemination, interaction between tumor and host in vivo avoiding immunogenic rejection, representing a promising platform for the translational research and personalized therapies. Objective: In this mini-review we report recent advances in breast cancer research and drug testing that took advantage of the zebrafish xenograft model using both breast cancer cell lines and patient’s biopsy. Conclusion: Patient derived xenograft, together with the gene editing, the omics biotechnology, the in vivo time lapse imaging and the high-throughput screening that are already set up and largely used in zebrafish, could represent a step forward towards precision and personalized medicine in the breast cancer research field.

AKT Activity Regulates Sensitivity of Multiple Myeloma Cells to mTor Inhibitors.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 646-646
Author(s):  
Patrick Frost ◽  
Bao Hoang ◽  
Joseph Gera ◽  
Anushree Sharma ◽  
Yijiang Shi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Xenograft Model ◽  
Mtor Inhibitors ◽  
Significant Inhibition ◽  
Differential Sensitivity ◽  
Angiogenic Factor ◽  
Inhibition Of Proliferation ◽  
In Vivo Growth

Abstract Inhibitors of the mammalian target of rapamycin (mTOR), such as rapamycin and CCI-779, have potential as anti-tumor agents against multiple myeloma (MM). In a murine xenograft model, CCI-779 demonstrated efficacy against in vivo growth of OPM-2 and 8226 MM cells. In this model, OPM-2 tumors (ED50=2 mg/kg) were considerably more sensitive than 8226 (ED50=20 mg/kg) tumors. CCI-779-induced anti-tumor responses were associated with significant inhibition of proliferation and angiogenesis and concomitant upregulation of apoptosis. OPM-2 cells were also significantly more sensitive to these CCI-779-mediated effects. Other tumor models have demonstrated that heightened AKT activity induces hypersensitivity to mTOR inhibitors. As OPM-2 cells express high levels of activated AKT (due to PTEN mutations) and 8226 cells contain predominantly quiescent AKT, this regulatory role for AKT may be present in MM cells as well. To further test this, we stably expressed an activated AKT allele in U266 (U266myr-AKT) MM cells. The in vivo growth of U266myr-AKT cells was considerably more sensitive than control U266 cells to the anti-tumor effects of CCI-779. The differential sensitivity induced by AKT activation was mirrored in an enhanced sensitivity to CCI-779-mediated apoptosis and inhibition of angiogenesis. Since previous studies demonstrated the ability of AKT/mTOR to regulate the expression of vascular endothelial growth factor (VEGF), we hypothesized that MM cells with heightened AKT activity may be more sensitive to the CCI-779-mediated inhibition of this critical angiogenic factor. In vitro, mTOR inhibitor, rapamycin, was markedly more effective at inhibiting VEGF secretion from U266myr-AKT than control cells. Our results demonstrate that AKT regulates the sensitivity of MM cells to the anti-tumor effects of mTOR inhibitors and that this may be mediated through the inhibition of AKT-dependent survival and growth factors.

In vivo activity of R1530 (R) alone and in combination with docetaxel (D) and bevacizumab (B) in a prostate carcinoma (PCa) xenograft model

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16124-e16124
Author(s):  
K. D. Kolinsky ◽  
Y. Zhang ◽  
K. Packman ◽  
B. Higgins
Keyword(s):  
Xenograft Model ◽  
Optimal Dose ◽  
P Value ◽  
Clinical Testing ◽  
Cancer Cell Growth ◽  
Multikinase Inhibitor ◽  
R And D ◽  
Final Study ◽  
M Phase

e16124 Background: R is a multikinase inhibitor currently in phase I clinical testing. Its inhibitory profile includes several kinases that play critical roles in cancer cell growth and division leading to disruption at M-phase and antiangiogenic effects. Studies were conducted to evaluate the efficacy and tolerability of R alone and in combination with D and B in the 22rv1 androgen independent PCa model. Methods: Initially TGI of optimal dose (OD) R, D and B were evaluated. Then the TGI and increased life span (ILS) of the minimum efficacious dose (MED) and 2/3 OD R ± 2/3 OD D was tested. A final study compared doublets of 2/3 OD R + 2/3 OD D, 2/3 OD D + OD B, 2/3 OD R + OD B, and triplet of 2/3 OD D + 2/3 OD R+ 2/3 OD B. Results: All treatment groups were tolerated and there was no antagonism. TGI and ILS results are listed below ( Table ). Conclusions: The OD of R B and D showed monotherapy TGI in this model. MED R + 2/3 OD D gave ILS statistically better (sb) than singlets but TGI was sb than MED R but not the D singlet. 2/3 OD R + 2/3 OD D produced sb TGI and ILS than each singlet. TGI and ILS with 2/3 OD R is sb than 2/3 OD D. TGI and ILS of 2/3 OD R + 2/3 OD D was sb than the 2/3 OD D + OD B but not the 2/3 OD R + B doublet. TGI and ILS was sb for 2/3 OD R + OD B versus 2/3 OD D + OD B. The TGI of the triplet was equivalent to the 2/3 OD R + 2/3 OD D doublet, but ILS was sb in the triplet. Also, the TGI and ILS was sb for triplet versus 2/3 OD D + OD B. TGI and ILS of the triplet was equal to 2/3 OD R + OD B. In general, the results demonstrate that the shared mechanism of mitotic disruption by R and D do not render antagonism, but in fact, allow for potentiated TGI and ILS. Also of note is the equally superior TGI and ILS provided by R + B and R + B + D. In general, the preclinical results generated support clinical testing of these agents in PCa. * p value for all. [Table: see text] [Table: see text]

scholarly journals Chinese Herbal Medicine Ganoderma tsugae Displays Potential Anti-Cancer Efficacy on Metastatic Prostate Cancer Cells

2019 ◽  
Vol 20 (18) ◽  
pp. 4418 ◽  
Author(s):  
Wen-Chin Huang ◽  
Meng-Shiun Chang ◽  
Shih-Yin Huang ◽  
Ching-Ju Tsai ◽  
Pin-Hung Kuo ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Growth ◽  
Cancer Progression ◽  
Metastatic Prostate Cancer ◽  
Xenograft Model ◽  
Ethanol Extract ◽  
Cancer Cell Growth ◽  
Medicine Quality

Resistance to the current therapies is the main clinical challenge in the treatment of lethal metastatic prostate cancer (mPCa). Developing novel therapeutic approaches with effective regimes and minimal side effects for this fatal disease remain a priority in prostate cancer study. In the present study, we demonstrated that a traditional Chinese medicine, quality-assured Ganoderma tsugae ethanol extract (GTEE), significantly suppressed cell growth and metastatic capability and caused cell cycle arrest through decreasing expression of cyclins in mPCa cells, PC-3 and DU145 cells. GTEE also induced caspase-dependent apoptosis in mPCa cells. We further showed the potent therapeutic efficacy of GTEE by inhibiting subcutaneous PC-3 tumor growth in a xenograft model. The in vitro and in vivo efficacies on mPCa cells were due to blockade of the PI3K/Akt and MAPK/ERK signaling pathways associated with cancer cell growth, survival and apoptosis. These preclinical data provide the molecular basis for a new potential therapeutic approach toward the treatment of lethal prostate cancer progression.

scholarly journals Extra-Intestinal Effects of C. difficile Toxin A and B: An In Vivo Study Using the Zebrafish Embryo Model

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2575
Author(s):  
Federica Tonon ◽  
Stefano Di Bella ◽  
Gabriele Grassi ◽  
Roberto Luzzati ◽  
Paolo Ascenzi ◽  
...  
Keyword(s):  
Natriuretic Peptide ◽  
Zebrafish Embryo ◽  
Vascular System ◽  
Morphological Changes ◽  
Vital Signs ◽  
Zebrafish Embryos ◽  
Toxin A ◽  
Cardiovascular Damage ◽  
Starting Point

C.difficile infection (CDI) is not a merely “gut-confined” disease as toxemia could drive the development of CDI-related extra-intestinal effects. These effects could explain the high CDI-associated mortality, not just justified by diarrhea and dehydration. Here, the extra-intestinal effects of toxin A (TcdA) and B (TcdB) produced by C. difficile have been studied in vivo using the zebrafish embryo model. Noteworthy, protective properties of human serum albumin (HSA) towards toxins-induced extra-intestinal effects were also addressed. Zebrafish embryos were treated with TcdA, TcdB and/or HSA at 24 h post-fertilization. Embryos were analyzed for 48 h after treatment to check vital signs and morphological changes. Markers related to cardio-vascular damage and inflammation were evaluated by Real-Time quantitative PCR and/or western blotting. Both toxins induced cardiovascular damage in zebrafish embryos by different mechanisms: (i) direct toxicity (i.e., pericardial edema, cardiac chambers enlargement, endothelial alteration); (ii) increased hormonal production and release (i.e., atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)), (iii) alteration of the vascular system through the increase of the vascular endothelial growth factor (VEGF-A) levels, as well as of its receptors, (iv) pro-inflammatory response through high cytokines production (i.e., CXCL8, IL1B, IL6 and TNFα) and (v) cell-mediated damage due to the increase in neutrophils number. In addition to cardiovascular damage, we observe skin alteration and inflammation. Finally, our data indicate a protective effect of HSA toward the toxins induced extra-intestinal effects. Together, our findings can serve as a starting point for humans’ studies to substantiate and understand the extra-intestinal effects observed in CDI patients.

scholarly journals Mutant-selective degradation by BRAF-targeting PROTACs

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shanique Alabi ◽  
Saul Jaime-Figueroa ◽  
Zhan Yao ◽  
Yijun Gao ◽  
John Hines ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Xenograft Model ◽  
Braf Inhibitor ◽  
Therapeutic Window ◽  
Missense Mutations ◽  
Cancer Cell Growth ◽  
Selective Degradation ◽  
Approved Drugs ◽  
Mutant Braf

AbstractOver 300 BRAF missense mutations have been identified in patients, yet currently approved drugs target V600 mutants alone. Moreover, acquired resistance inevitably emerges, primarily due to RAF lesions that prevent inhibition of BRAF V600 with current treatments. Therefore, there is a need for new therapies that target other mechanisms of activated BRAF. In this study, we use the Proteolysis Targeting Chimera (PROTAC) technology, which promotes ubiquitination and degradation of neo-substrates, to address the limitations of BRAF inhibitor-based therapies. Using vemurafenib-based PROTACs, we achieve low  nanomolar degradation of all classes of BRAF mutants, but spare degradation of WT RAF family members. Our lead PROTAC outperforms vemurafenib in inhibiting cancer cell growth and shows in vivo efficacy in a Class 2 BRAF xenograft model. Mechanistic studies reveal that BRAFWT is spared due to weak ternary complex formation in cells owing to its quiescent inactivated conformation, and activation of BRAFWT sensitizes it to degradation. This study highlights the degree of selectivity achievable with degradation-based approaches by targeting mutant BRAF-driven cancers while sparing BRAFWT, providing an anti-tumor drug modality that expands the therapeutic window.

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