Induction of mitochondria-mediated apoptosis and suppression of tumor growth in zebrafish xenograft model by cyclic dipeptides identified from Exiguobacterium acetylicum

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.

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The PPARγ agonist pioglitazone crosses the blood–brain barrier and reduces tumor growth in a human xenograft model

Cancer Chemotherapy and Pharmacology ◽

10.1007/s00280-013-2084-2 ◽

2013 ◽

Vol 71 (4) ◽

pp. 929-936 ◽

Cited By ~ 37

Author(s):

Christian Grommes ◽

J. Colleen Karlo ◽

Andrew Caprariello ◽

D’Arbra Blankenship ◽

Anne DeChant ◽

...

Keyword(s):

Tumor Growth ◽

Blood Brain Barrier ◽

Xenograft Model ◽

Brain Barrier ◽

Blood Brain ◽

Pparγ Agonist

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Cytotoxic effects and tolerability of gemcitabine and axitinib in a xenograft model for c-myc amplified medulloblastoma

Scientific Reports ◽

10.1038/s41598-021-93586-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Stefanie Schwinn ◽

Zeinab Mokhtari ◽

Sina Thusek ◽

Theresa Schneider ◽

Anna-Leena Sirén ◽

...

Keyword(s):

Fluorescence Microscopy ◽

Tumor Growth ◽

Intensive Therapy ◽

Xenograft Model ◽

Light Sheet ◽

Tumor Control ◽

Orthotopic Model ◽

Group 3 ◽

Light Sheet Fluorescence Microscopy

AbstractMedulloblastoma is the most common high-grade brain tumor in childhood. Medulloblastomas with c-myc amplification, classified as group 3, are the most aggressive among the four disease subtypes resulting in a 5-year overall survival of just above 50%. Despite current intensive therapy regimens, patients suffering from group 3 medulloblastoma urgently require new therapeutic options. Using a recently established c-myc amplified human medulloblastoma cell line, we performed an in-vitro-drug screen with single and combinatorial drugs that are either already clinically approved or agents in the advanced stage of clinical development. Candidate drugs were identified in vitro and then evaluated in vivo. Tumor growth was closely monitored by BLI. Vessel development was assessed by 3D light-sheet-fluorescence-microscopy. We identified the combination of gemcitabine and axitinib to be highly cytotoxic, requiring only low picomolar concentrations when used in combination. In the orthotopic model, gemcitabine and axitinib showed efficacy in terms of tumor control and survival. In both models, gemcitabine and axitinib were better tolerated than the standard regimen comprising of cisplatin and etoposide phosphate. 3D light-sheet-fluorescence-microscopy of intact tumors revealed thinning and rarefication of tumor vessels, providing one explanation for reduced tumor growth. Thus, the combination of the two drugs gemcitabine and axitinib has favorable effects on preventing tumor progression in an orthotopic group 3 medulloblastoma xenograft model while exhibiting a favorable toxicity profile. The combination merits further exploration as a new approach to treat high-risk group 3 medulloblastoma.

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Intratumoral Canine Distemper Virus Infection Inhibits Tumor Growth by Modulation of the Tumor Microenvironment in a Murine Xenograft Model of Canine Histiocytic Sarcoma

International Journal of Molecular Sciences ◽

10.3390/ijms22073578 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3578

Author(s):

Federico Armando ◽

Adnan Fayyad ◽

Stefanie Arms ◽

Yvonne Barthel ◽

Dirk Schaudien ◽

...

Keyword(s):

Tumor Microenvironment ◽

Virus Infection ◽

Tumor Growth ◽

Canine Distemper Virus ◽

Xenograft Model ◽

Histiocytic Sarcoma ◽

Oncolytic Viruses ◽

Canine Distemper ◽

Murine Xenograft Model ◽

The Impact

Histiocytic sarcomas refer to highly aggressive tumors with a poor prognosis that respond poorly to conventional treatment approaches. Oncolytic viruses, which have gained significant traction as a cancer therapy in recent decades, represent a promising option for treating histiocytic sarcomas through their replication and/or by modulating the tumor microenvironment. The live attenuated canine distemper virus (CDV) vaccine strain Onderstepoort represents an attractive candidate for oncolytic viral therapy. In the present study, oncolytic virotherapy with CDV was used to investigate the impact of this virus infection on tumor cell growth through direct oncolytic effects or by virus-mediated modulation of the tumor microenvironment with special emphasis on angiogenesis, expression of selected MMPs and TIMP-1 and tumor-associated macrophages in a murine xenograft model of canine histiocytic sarcoma. Treatment of mice with xenotransplanted canine histiocytic sarcomas using CDV induced overt retardation in tumor progression accompanied by necrosis of neoplastic cells, increased numbers of intratumoral macrophages, reduced angiogenesis and modulation of the expression of MMPs and TIMP-1. The present data suggest that CDV inhibits tumor growth in a multifactorial way, including direct cell lysis and reduction of angiogenesis and modulation of MMPs and their inhibitor TIMP-1, providing further support for the concept of its role in oncolytic therapies.

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Regulatory T cells promote glioma cell stemness through TGF-β–NF-κB–IL6–STAT3 signaling

Cancer Immunology Immunotherapy ◽

10.1007/s00262-021-02872-0 ◽

2021 ◽

Cited By ~ 1

Author(s):

Shasha Liu ◽

Chaoqi Zhang ◽

Boqiao Wang ◽

Huanyu Zhang ◽

Guohui Qin ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Tumor Growth ◽

Xenograft Model ◽

Malignant Growth ◽

Cancer Stemness ◽

The Core ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway ◽

Tumorigenic Potential

AbstractGlioma stem cells (GSCs) contribute to the malignant growth of glioma, but little is known about the interaction between GSCs and tumor microenvironment. Here, we found that intense infiltration of regulatory T cells (Tregs) facilitated the qualities of GSCs through TGF-β secretion that helped coordinately tumor growth. Mechanistic investigations indicated that TGF-β acted on cancer cells to induce the core cancer stem cell-related genes CD133, SOX2, NESTIN, MUSASHI1 and ALDH1A expression and spheres formation via NF-κB–IL6–STAT3 signaling pathway, resulting in the increased cancer stemness and tumorigenic potential. Furthermore, Tregs promoted glioma tumor growth, and this effect could be abrogated with blockade of IL6 receptor by tocilizumab which also demonstrated certain level of therapeutic efficacy in xenograft model. Additionally, expression levels of CD133, IL6 and TGF-β were found to serve as prognosis markers of glioma patients. Collectively, our findings reveal a new immune-associated mechanism underlying Tregs-induced GSCs. Moreover, efforts to target this network may be an effective strategy for treating glioma.

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Utidelone inhibits growth of colorectal cancer cells through ROS/JNK signaling pathway

Cell Death and Disease ◽

10.1038/s41419-021-03619-6 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Fuli Li ◽

Tinglei Huang ◽

Yao Tang ◽

Qingli Li ◽

Jianzheng Wang ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Growth ◽

Xenograft Model ◽

Jnk Pathway ◽

Epothilone B ◽

Colorectal Cancer Cells ◽

M Phase ◽

Jnk Signaling Pathway ◽

Microtubule Stabilizing Agent

AbstractUtidelone (UTD1), a novel microtubule stabilizing agent, is an epothilone B analogue which was produced by genetic engineering. UTD1 has exhibited broad antitumor activity in multiple solid tumors. However, its activity and mechanism in colorectal cancer (CRC) remain to be studied. In this study, UTD1 dramatically inhibited CRC cell proliferation (with 0.38 µg/ml, 0.77 µg/ml IC50 in RKO and HCT116, respectively) in vitro. Immunofluorescence staining showed that UTD1 induced the formation of microtubule bundling and asters in RKO cells. Flow cytometry analysis demonstrated that UTD1 induced cell cycle to arrest in G2/M phase, subsequent apoptosis. Significantly, UTD1 exhibited stronger effect on inducing apoptosis than paclitaxel and 5-FU, especially in HCT15 cells which is ABCB1 high-expression. UTD1 exposure cleaved caspase-3 and poly ADP-ribose polymerase (PARP), decreased mitochondrial membrane potential, released cytochrome c, increased the production of active oxygen and activated c-Jun N-terminal kinase (JNK), suggesting ROS/JNK pathway was involved in this process. Moreover, UTD1 inhibited tumor growth and was more effective and safer compared with paclitaxel and 5-FU in RKO xenograft in nude mice. Taken together, our findings first indicate that UDT1 inhibits tumor growth in CRC xenograft model and may be a promising agent for CRC treatment.

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