scholarly journals EXOSC10/Rrp6 is essential for the eight-cell embryo/morula transition

2021 ◽  
Author(s):  
Fabrice G Petit ◽  
Soazik P Jamin ◽  
Pierre-Yves Kernanec ◽  
Guillaume Halet ◽  
Michael Primig
Keyword(s):  
Ribosome Biogenesis ◽  
Early Embryogenesis ◽  
Cancer Drug ◽  
Rrna Processing ◽  
Maternal Mrna ◽  
Anti Cancer ◽  
Cell Embryo ◽  
Morula Stage ◽  
Human Ortholog

The mouse 3′-5′ exoribonuclease EXOSC10/Rrp6 is required for rRNA processing, gametogenesis, brain development, erythropoiesis and blood cell enhancer function. The human ortholog is essential for mitosis in cancer cells and its enzymatic activity is inhibited by the anti-cancer drug 5-fluorouracil. Little is known, however, about the role of Exosc10 during embryo development and organogenesis. We generated an Exosc10 knockout model and find that Exosc10-/- mice show an embryonic lethal phenotype. We demonstrate that Exosc10 maternal mRNA is present in mutant oocytes and that the gene is expressed during early embryogenesis. Furthermore, we observe that EXOSC10 localizes to the periphery of nucleolar precursor bodies and nucleoli in blastomeres, which is consistent with the protein's role in rRNA processing. Finally, we infer from genotyping data obtained with samples harvested at embryonic days e7.5, e6.5 and e4.5 and embryos cultured in vitro that Exosc10-/- mutants arrest at the eight-cell embryo/morula transition. Our results demonstrate a novel essential role for Exosc10 during early embryogenesis, and they are consistent with earlier work showing that impaired ribosome biogenesis causes a developmental arrest at the morula stage.

Stereocomplexation Assisted Assembly of Poly(γ-glutamic Acid)-graft-polylactide Nano-micelles and Their Efficacy as Anticancer Drug Carrier

2018 ◽  
Vol 18 (2) ◽  
pp. 302-311
Author(s):  
Shulin Dai ◽  
Yucheng Feng ◽  
Shuyi Li ◽  
Yuxiao Chen ◽  
Meiqing Liu ◽  
...  
Keyword(s):  
Glutamic Acid ◽  
Drug Carrier ◽  
Drug Loading ◽  
Drug Carriers ◽  
Cancer Drug ◽  
Drug Release Profile ◽  
Sustained Drug Release ◽  
Anti Cancer ◽  
Physical Interactions

Background: Micelles as drug carriers are characterized by their inherent instability due to the weak physical interactions that facilitate the self-assembly of amphiphilic block copolymers. As one of the strong physical interactions, the stereocomplexation between the equal molar of enantiomeric polylactides, i.e., the poly(L-lactide) (PLLA) and poly(D-lactide) (PDLA), may be harnessed to obtain micelles with enhanced stability and drug loading capacity and consequent sustained release. </P><P> Aims/Methods: In this paper, stereocomplexed micelles gama-PGA-g-PLA micelles) were fabricated from the stereocomplexation between poly(gama-glutamic acid)-graft-PLLA gama-PGA-g-PLA) and poly(gamaglutamic acid)-graft-PDLA gama-PGA-g-PLA). These stereocomplexed micelles exhibited a lower CMC than the corresponding enantiomeric micelles. Result: Furthermore, they showed higher drug loading content and drug loading efficiency in addition to more sustained drug release profile in vitro. In vivo imaging confirmed that the DiR-encapsulated stereocomplexed gama-PGA-g-PLA micelles can deliver anti-cancer drug to tumors with enhanced tissue penetration. Overall, gama-PGA-g-PLA micelles exhibited greater anti-cancer effects as compared with the free drug and the stereocomplexation may be a promising strategy for fabrication of anti-cancer drug carriers with significantly enhanced efficacy.

Prevascularized, Co-Culture Model for Breast Cancer Drug Development

2012 ◽  
Author(s):  
Lauren Marshall ◽  
Isabel Löwstedt ◽  
Paul Gatenholm ◽  
Joel Berry
Keyword(s):  
Breast Cancer ◽  
Drug Development ◽  
Three Dimensional ◽  
Human Tumor ◽  
3D Models ◽  
Cancer Drug ◽  
Cancer Therapies ◽  
Anti Cancer

The objective of this study was to create 3D engineered tissue models to accelerate identification of safe and efficacious breast cancer drug therapies. It is expected that this platform will dramatically reduce the time and costs associated with development and regulatory approval of anti-cancer therapies, currently a multi-billion dollar endeavor [1]. Existing two-dimensional (2D) in vitro and in vivo animal studies required for identification of effective cancer therapies account for much of the high costs of anti-cancer medications and health insurance premiums borne by patients, many of whom cannot afford it. An emerging paradigm in pharmaceutical drug development is the use of three-dimensional (3D) cell/biomaterial models that will accurately screen novel therapeutic compounds, repurpose existing compounds and terminate ineffective ones. In particular, identification of effective chemotherapies for breast cancer are anticipated to occur more quickly in 3D in vitro models than 2D in vitro environments and in vivo animal models, neither of which accurately mimic natural human tumor environments [2]. Moreover, these 3D models can be multi-cellular and designed with extracellular matrix (ECM) function and mechanical properties similar to that of natural in vivo cancer environments [3].

scholarly journals Frontiers in Anti-cancer Drug Discovery: Challenges and Perspectives of Metformin as Anti-angiogenic Add-on Therapy in Glioblastoma

2021 ◽  
Author(s):  
Laura Guarnaccia ◽  
Stefania Elena Navone ◽  
Matteo Maria Masseroli ◽  
Melissa Balsamo ◽  
Manuela Caroli ◽  
...  
Keyword(s):  
Target Therapy ◽  
Cancer Drug ◽  
Cancer Drug Discovery ◽  
Average Survival ◽  
Anti Cancer ◽  
Tumor Neovascularization ◽  
Novel Therapeutic Strategies

Glioblastoma (GBM) is the most common primitive tumor in adult central nervous system (CNS), classified as grade IV according to WHO 2016 classification. GBM shows a poor prognosis with an average survival of approximately 15 months, representing an extreme therapeutic challenge. One of its distinctive and aggressive features is aberrant angiogenesis, which drives tumor neovascularization, representing a promising candidate for molecular target therapy. Although several pre-clinical studies and clinical trials have shown promising results, anti-angiogenic drugs have not led to a significant improvement in overall survival (OS), suggesting the necessity of identifying novel therapeutic strategies. Metformin, an anti-hyperglycemic drug of the Biguanides family, used as first line treatment in Type 2 Diabetes Mellitus (T2DM), demonstrated in vitro and in vivo antitumoral efficacy in many different tumors, including GBM. From this evidence, a process of repurposing of the drug has begun, leading to the demonstration of the inhibition of various oncopromoter mechanisms and, consequently, to the identification of the molecular pathways involved. Here, we review and discuss the potential metformin&rsquo;s antitumoral effects on GBM, inspecting if it could properly act as an anti-angiogenic compound to be considered as a safely add-on therapy in the treatment and management of GBM patients.

scholarly journals Coherent Raman Scattering Microscopy in Oncology Pharmacokinetic Research

2021 ◽  
Vol 12 ◽  
Author(s):  
Junjie Zeng ◽  
Wenying Zhao ◽  
Shuhua Yue
Keyword(s):  
Raman Scattering ◽  
High Speed ◽  
Cancer Drug ◽  
Cancer Drugs ◽  
High Speed Imaging ◽  
Coherent Raman Scattering ◽  
Anti Cancer ◽  
Coherent Raman

The high attrition rates of anti-cancer drugs during clinical development remains a bottleneck problem in pharmaceutical industry. This is partially due to the lack of quantitative, selective, and rapid readouts of anti-cancer drug activity in situ with high resolution. Although fluorescence microscopy has been commonly used in oncology pharmacological research, fluorescent labels are often too large in size for small drug molecules, and thus may disturb the function or metabolism of these molecules. Such challenge can be overcome by coherent Raman scattering microscopy, which is capable of chemically selective, highly sensitive, high spatial resolution, and high-speed imaging, without the need of any labeling. Coherent Raman scattering microscopy has tremendously improved the understanding of pharmaceutical materials in the solid state, pharmacokinetics of anti-cancer drugs and nanocarriers in vitro and in vivo. This review focuses on the latest applications of coherent Raman scattering microscopy as a new emerging platform to facilitate oncology pharmacokinetic research.

scholarly journals In vitro modeling of hepatocellular carcinoma molecular subtypes for anti-cancer drug assessment

2018 ◽  
Vol 50 (1) ◽  
pp. e419-e419 ◽  
Author(s):  
Hadassa Hirschfield ◽  
C Billie Bian ◽  
Takaaki Higashi ◽  
Shigeki Nakagawa ◽  
Tizita Z Zeleke ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Subtypes ◽  
Cancer Drug ◽  
In Vitro Modeling ◽  
Anti Cancer

The Design and Synthesis of Novel Phenothiazine Derivatives as Potential Cytotoxic Agents

2019 ◽  
Vol 17 (1) ◽  
pp. 57-67
Author(s):  
Yepeng Luan ◽  
Jinyi Liu ◽  
Jianjun Gao ◽  
Jinhua Wang
Keyword(s):  
Cell Lines ◽  
High Efficiency ◽  
Human Cancer ◽  
Human Tumor ◽  
Cytotoxic Agents ◽  
Cancer Drug ◽  
Human Cancer Cell Lines ◽  
Incidence And Mortality ◽  
Anti Cancer

Background: Cancer incidence and mortality have been increasing and cancer is still the leading cause of death all over the world. Despite the enormous progress in cancer treatment, many patients died of ineffective chemotherapy and drug resistance. Therefore, the design and development of anti-cancer drugs with high efficiency and low toxicity is still one of the most challenging tasks. Tricyclic heterocycles, such as phenothiazine, are always important sources of scaffolds for anti-cancer drug discovery. Methods: In this work, ten new urea-containing derivatives of phenothiazine coupled with different kinds of amine motifs at the endpoint through a three carbon long spacer were designed and synthesized. The structures of the synthesized compounds were elucidated and confirmed by 1H NMR and HRMS. All the synthesized compounds were tested for their antitumor activity in vitro against the proliferation of PC-3 cells, and the compounds with best potency entered further cytotoxicity evaluations against other 22 human tumor cell lines. Mechanism was also studied. Results: From all data, it showed that among all 10 target compounds, TTi-2 showed the best effect in inhibiting the proliferation of 23 human cancer cell lines while TTi-2 without obvious inhibitory effect on normal cell. Furthermore, our results also showed that TTi-2 could inhibit migration, invasion and colony formation of MDA-MB-231 cells. Finally, TTi-2 can induce arrest of cell cycle at G0/G1 phase and cell apoptosis by activating the caspase 3 activity. Conclusion: All these results suggested that TTi-2 might be used as a promising lead compound for anticancer drug development.

scholarly journals New Anti-Cancer Strategy to Suppress Colorectal Cancer Growth Through Inhibition of ATG4B and Lysosome Function

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1523 ◽  
Author(s):  
Yuanyuan Fu ◽  
Qianqian Gu ◽  
Li Luo ◽  
Jiecheng Xu ◽  
Yuping Luo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Therapy ◽  
Therapeutic Strategy ◽  
Screening Method ◽  
Cancer Drug ◽  
Autophagic Flux ◽  
Single Target ◽  
Anti Cancer

Autophagy inhibition has been proposed to be a potential therapeutic strategy for cancer, however, few autophagy inhibitors have been developed. Recent studies have indicated that lysosome and autophagy related 4B cysteine peptidase (ATG4B) are two promising targets in autophagy for cancer therapy. Although some inhibitors of either lysosome or ATG4B were reported, there are limitations in the use of these single target compounds. Considering multi-functional drugs have advantages, such as high efficacy and low toxicity, we first screened and validated a batch of compounds designed and synthesized in our laboratory by combining the screening method of ATG4B inhibitors and the identification method of lysosome inhibitors. ATG4B activity was effectively inhibited in vitro. Moreover, 163N inhibited autophagic flux and caused the accumulation of autolysosomes. Further studies demonstrated that 163N could not affect the autophagosome-lysosome fusion but could cause lysosome dysfunction. In addition, 163N diminished tumor cell viability and impaired the development of colorectal cancer in vivo. The current study findings indicate that the dual effect inhibitor 163N offers an attractive new anti-cancer drug and compounds having a combination of lysosome inhibition and ATG4B inhibition are a promising therapeutic strategy for colorectal cancer therapy.

scholarly journals Effects of light-activated diazido-Pt IV complexes on cancer cells in vitro

2013 ◽  
Vol 371 (1995) ◽  
pp. 20120118 ◽  
Author(s):  
Patrick J. Bednarski ◽  
Katharina Korpis ◽  
Aron F. Westendorf ◽  
Steffi Perfahl ◽  
Renate Grünert
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Calf Thymus Dna ◽  
Cross Resistance ◽  
Cancer Drug ◽  
Cancer Cell Growth ◽  
Calf Thymus ◽  
Anti Cancer ◽  
Cellular Dna

Various Pt IV diazides have been investigated over the years as light-activatable prodrugs that interfere with cell proliferation, accumulate in cancer cells and cause cell death. The potencies of the complexes vary depending on the substituted amines (pyridine=piperidine>ammine) as well as the coordination geometry ( trans diazide> cis ). Light-activated Pt IV diazides tend to be less specific than cisplatin at inhibiting cancer cell growth, but cells resistant to cisplatin show little cross-resistance to Pt IV diazides. Platinum is accumulated in the cancer cells to a similar level as cisplatin, but only when activated by light, indicating that reactive Pt species form photolytically. Studies show that Pt also becomes attached to cellular DNA upon the light activation of various Pt IV diazides. Structures of some of the photolysis products were elucidated by LC–MS/MS; monoaqua- and diaqua-Pt II complexes form that are reactive towards biomolecules such as calf thymus DNA. Platination of calf thymus DNA can be blocked by the addition of nucleophiles such as glutathione and chloride, further evidence that aqua-Pt II species form upon irradiation. Evidence is presented that reactive oxygen species may be generated in the first hours following photoactivation. Cell death does not take the usual apoptotic pathways seen with cisplatin, but appears to involve autophagy. Thus, photoactivated diazido-Pt IV complexes represent an interesting class of potential anti-cancer agents that can be selectively activated by light and kill cells by a mechanism different to the anti-cancer drug cisplatin.

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