Inhibition of Cancer Stem-Like Phenotype by Curcumin and Deguelin in CAL-62 Anaplastic Thyroid Cancer Cells

2019 ◽  
Vol 19 (15) ◽  
pp. 1887-1898 ◽  
Author(s):  
Mehmet A. Kocdor ◽  
Hakan Cengiz ◽  
Halil Ates ◽  
Hilal Kocdor
Keyword(s):  
Stem Cell ◽  
Thyroid Cancer ◽  
Quantitative Estimation ◽  
Anaplastic Thyroid Cancer ◽  
Natural Compounds ◽  
Stress Index ◽  
Sod Activity ◽  
In Vivo Models ◽  
Anti Cancer

Background: Anaplastic Thyroid Cancer (ATC) is one of the most lethal and aggressive human malignancies. Studies have shown that Cancer Stem-Cell (CSC) phenotype is mainly responsible for ATC aggressiveness. Cytostatic compounds are mostly ineffective because of multidrug resistance mechanisms driven by the CSC phenotype. Taxanes have limited efficacy. Recently, CSC inhibition using plant-derived, less toxic compounds, which have anti-cancer efficacy, has become a novel treatment modality. The aim of the study was to evaluate the anti-cancer activity of two natural compounds (curcumin and deguelin) on ATC cells and their CSC properties. In addition, the efficacies of these compounds were compared with that of docetaxel. Methods: Besides control, five treatment groups were formed. ATC cells (CAL-62) were treated with curcumin, deguelin, docetaxel, and their combinations (curcumin+docetaxel, deguelin+docetaxel) at previously determined IC50 doses. Stemness was analyzed by quantitative estimation of sphere formation in matrigel, expression of several cell surface markers (CD133, CD90, Nanog, and OCT3/4) using flow cytometry, and quantification of the hypoxic status [Oxidative Stress Index (OSI) and Superoxide Dismutase (SOD) activity]. The anti-cancer efficacies of these compounds and their combinations were evaluated by determining the alterations in the cell cycle, apoptosis, and tumoral cell migration. Results: Both the natural compounds (particularly curcumin) significantly suppressed the spheroid formation and cellular motility in matrigel as well as suppressed the accumulation of cells in the G0/1 phase, in which the maximum CSC activity is observed. The compounds did not suppress the expression of CSC markers, but twothirds of the cells expressed CD90. Deguelin was found to be particularly effective in inducing apoptosis similar to docetaxel at IC50 concentrations. Curcumin reduced the OSI and deguelin enhanced the SOD activity, even in docetaxel pre-treated cells. Conclusion: A large proportion of anaplastic tumors might consist of heterogeneous CSC population. Curcumin and deguelin have anti-cancer and several anti-stem cell activities against ATC cells. These natural compounds are capable of altering the aggressive behavior of ATC cells through the inhibition of the CSC phenotype. As a novel therapeutic target, CD90 should be investigated in other ATC cell lines and in vivo models.

scholarly journals Anti-cancer Activity of Paclitaxel, Lenvatinib and Radiation Combination Therapy on Anaplastic Thyroid Cancer in Vitro and in Vivo

2019 ◽  
Vol 35 (2) ◽  
pp. 19-25
Author(s):  
Shiyeol Jun ◽  
Soo Young Kim ◽  
Seok-Mo Kim ◽  
Ki Cheong Park ◽  
Hee Jun Kim ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Combination Therapy ◽  
Anaplastic Thyroid Cancer ◽  
Anti Cancer ◽  
Cancer Activity

Identification of Natural Compounds to Inhibit Sonic Hedgehog Pathway in Oral Cancer

2021 ◽  
Vol 21 ◽  
Author(s):  
Hitarth Patel ◽  
Jigna Joshi ◽  
Apexa Raval ◽  
Franky Shah
Keyword(s):  
Stem Cell ◽  
Binding Energy ◽  
Oral Cancer ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Treatment Resistance ◽  
Natural Compounds ◽  
Anti Cancer ◽  
Cancer Agent ◽  
Hedgehog Inhibitor

Background: Conventional treatment resistance remains a significant problem in cancer care. Cancer stem cells might play a major role in treatment resistance, and as a result, basic stem cell pathways are instrumental in cancer. Sonic Hedgehog signaling has not been widely studied in oral cancer, and being one of the major cancer stem cell pathways, targeting it with natural compounds could open many opportunities in the treatment scenario. Objective: The objective of the study was to identify the role of various natural compounds as an anti-cancer agent for oral cancer by targeting the Hedgehog signaling pathway. Methods: The selection of natural compounds were identified through literature review and NPACT database. The protein (3M1N and 3MXW) and ligand molecules were retrieved through the PDB and PubChem database. To carry out docking experiments, the AutoDock 4.2 program was used to study the interaction between the identified protein and ligand. Results: Among the 13 identified natural compounds, the top three were selected based on their binding energy. The higher the binding energy on the negative side, the better the interaction formed between protein and ligand. The natural compound showing best results with 3M1N protein were Butein, Biochanin-A, and Curcumin, whereas, with 3MXW, Zerumbone, Curcumin, and Butein were identified. Conclusion: The identified natural compounds have shown better binding energy to bind the Hh ligands in the absence/presence of a known Sonic Hedgehog inhibitor. Based on the results, natural compounds can be utilized in the current treatment modality for oral cancer either as an individual anti-cancer agent or in combination with the known Sonic Hedgehog inhibitor to curb the increasing incidence rate. Yet, in-vitro evidence in lab setup is required.

Accept or Reject: The Role of Immune Tolerance in the Development of Stem Cell Therapies and Possible Future Approaches

2020 ◽  
pp. 019262332091824
Author(s):  
Richard Haworth ◽  
Michaela Sharpe
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Stem ◽  
Immune Recognition ◽  
Cell Of Origin ◽  
In Vivo Models ◽  
Cell Product ◽  
A Cell

In 2011, Goldring and colleagues published a review article describing the potential safety issues of novel stem cell-derived treatments. Immunogenicity and immunotoxicity of the administered cell product were considered risks in the light of clinical experience of transplantation. The relative immunogenicity of mesenchymal stem cells, embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs) was being addressed through in vitro and in vivo models. But the question arose as to whether the implanted cells needed to be identical to the recipient in every respect, including epigenetically, to evade immune recognition? If so, this set a high bar which may preclude use of many cells derived from iPSCs which have vestiges of a fetal phenotype and epigenetic memory of their cell of origin. However, for autologous iPSCs, the immunogenicity reduces once the surface antigen expression profile becomes close to that of the parent somatic cells. Therefore, a cell product containing incompletely differentiated cells could be more immunogenic. The properties of the administered cells, the immune privilege of the administration site, and the host immune status influence graft success or failure. In addition, the various approaches available to characterize potential immunogenicity of a cell therapy will be discussed.

Synergistic anticancer activity of sorafenib, paclitaxel, and radiation therapy on anaplastic thyroid cancer in vitro and in vivo

Head & Neck ◽  
2020 ◽  
Vol 42 (12) ◽  
pp. 3678-3684
Author(s):  
Soo Young Kim ◽  
Seok‐Mo Kim ◽  
Hojin Chang ◽  
Hang‐Seok Chang ◽  
Cheong Soo Park ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Thyroid Cancer ◽  
Anticancer Activity ◽  
Anaplastic Thyroid Cancer

scholarly journals The ROMP: A Powerful Approach to Synthesize Novel pH-Sensitive Nanoparticles for Tumor Therapy

Biomolecules ◽  
2019 ◽  
Vol 9 (2) ◽  
pp. 60 ◽  
Author(s):  
Philippe Bertrand ◽  
Christophe Blanquart ◽  
Valérie Héroguez
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Tumor Therapy ◽  
Systemic Toxicity ◽  
Oxide Shell ◽  
Cancer Drugs ◽  
Native Form ◽  
In Vivo Models ◽  
Anti Cancer

Fast clearance, metabolism, and systemic toxicity are major limits for the clinical use of anti-cancer drugs. Histone deacetylase inhibitors (HDACi) present these defects, despite displaying promising anti-tumor properties on tumor cells in vitro and in in vivo models of cancer. The specific delivery of anti-cancer drugs into the tumor should improve their clinical benefit by limiting systemic toxicity and by increasing the anti-tumor effect. This paper deals with the synthesis of the polymeric nanoparticle platform, which was produced by Ring-Opening Metathesis Polymerization (ROMP), able to release anti-cancer drugs in dispersion, such as histone deacetylase inhibitors, into mesothelioma tumors. The core-shell nanoparticles (NPs) have stealth properties due to their poly(ethylene oxide) shell and can be viewed as universal nano-carriers on which any alkyne-modified anti-cancer molecule can be grafted by click chemistry. A cleavage reaction of the chemical bond between NPs and drugs through the contact of NPs with a medium presenting an acidic pH, which is typically a cancer tumor environment or an acidic intracellular compartment, induces a controlled release of the bioactive molecule in its native form. In our in vivo syngeneic model of mesothelioma, a highly selective accumulation of the particles in the tumor was obtained. The release of the drugs led to an 80% reduction of tumor weight for the best compound without toxicity. Our work demonstrates that the use of theranostic nanovectors leads to an optimized delivery of epigenetic inhibitors in tumors, which improves their anti-tumor properties in vivo.

Efficacy of adavosertib therapy against anaplastic thyroid cancer

2021 ◽  
Author(s):  
Yu-Ling Lu ◽  
Yu-Tung Huang ◽  
Ming-Hsien Wu ◽  
Ting-Chao Chou ◽  
Richard J Wong ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Tumor Growth ◽  
Single Agent ◽  
Xenograft Model ◽  
Anaplastic Thyroid Cancer ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Cancer Tumor

Wee1 is a kinase that regulates the G2/M progression by inhibition of CDK1, which is critical for ensuring DNA damage repair before initiation of mitotic entry. Targeting Wee1 may be a potential strategy in the treatment of anaplastic thyroid cancer, a rare but lethal disease. The therapeutic effects of adavosertib, a Wee1 inhibitor for anaplastic thyroid cancer was evaluated in this study. Adavosertib inhibited cell growth in three anaplastic thyroid cancer cell lines in a dose-dependent manner. Cell cycle analysis revealed cells were accumulated in the G2/M phase. Adavosertib induced caspase-3 activity and led to apoptosis. Adavosertib monotherapy showed significant retardation of the growth of two anaplastic thyroid cancer tumor models. The combination of adavosertib with dabrafenib and trametinib revealed strong synergism in vitro and demonstrated robust suppression of tumor growth in vivo in anaplastic thyroid cancer xenograft models with BRAFV600E mutation. The combination of adavosertib with either sorafenib or lenvatinib also demonstrated synergism in vitro and had strong inhibition of tumor growth in vivo in an anaplastic thyroid cancer xenograft model. No appreciable toxicity appeared in mice treated with either single agent or combination treatment. Our findings suggest adavosertib holds the promise for the treatment of patients with anaplastic thyroid cancer.

Human Nucleophosmin (NPM1) Perturbs Myeloid Development in Zebrafish in Vivo

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 308-308
Author(s):  
Niccolò Bolli ◽  
Elspeth Payne ◽  
Clemens Grabher ◽  
Adam Johnston ◽  
John Kanki ◽  
...  
Keyword(s):  
Cell Death ◽  
Stem Cell ◽  
Myeloid Cells ◽  
Genetic Alterations ◽  
Developmental Expression ◽  
In Vivo Models ◽  
Hematopoietic Stem ◽  
Cytoplasmic Transport ◽  
Dependent Cell

Abstract The most frequent genetic alterations in adult cases of Acute Myeloid Leukemia (AML) are mutations in the human nucleophosmin (hNPM1) gene. In about 30% of AMLs this nucleolar phosphoprotein is aberrantly localized to the cytoplasm (hNPMc) due to these mutations affecting the protein’s nuclear shuttling. hNPMc AMLs exhibit distinctive clinical and biological features that have led to its WHO classification as a distinct myeloid neoplasm. Despite its prominent association with AML, in vitro and in vivo models of hNPMc transformation in myeloid cells are lacking and its role in this process remains poorly understood. To further our understanding of hNPM function we are using the zebrafish vertebrate model system that is ideally suited for the in vivo analysis of cellular function and development during embryonic hematopoiesis. Importantly, the wide variety of blood cell types and key cellular factors regulating hematopoiesis are highly conserved between mammals and zebrafish. To investigate the in vivo role of hNPMc in hematopoiesis, we injected mRNAs encoding hNPM1wt and the leukemia-associated mutant hNPMc into one-cell stage zebrafish embryos. By fusing GFP to these hNPM proteins, we were able to follow the developmental expression of hNPM1 and its subcellular localization during embryogenesis. Analysis using confocal microscopy showed that NPMc is localized to the cell cytoplasm, while NPM1wt is found in nucleoli, as in human and mouse cells. These studies demonstrate the conservation of the nuclear-cytoplasmic transport functions of the human proteins in the zebrafish and further support its validity as a model to analyze and determine hNPM function. We also observed that hNPMc is expressed at far lower levels than its wild-type counterpart and is almost undetectable at 36hpf while hNPMwt continues to be expressed. Unlike mammals, two endogenous zebrafish NPM1 proteins were identified and named, zNpm1a and zNpm1b. Both zNpm1a and zNpm1b proteins are ubiquitously expressed in the embryo and demonstrated nucleolar localization. Expression of hNPMwt resulted in its colocalization with endogenous zNpm while hNPMc was able to bring about the export of both zebrafish proteins to the cytoplasm through heterotypic interactions. Co-immunoprecipitation experiments confirmed the interaction between human and zebrafish NPM1 proteins and zNpm1a and zNpm1b were both able to bind and co-immunoprecipitate with hNPM1 and hNPMc. These experiments suggest that transient hNPMc expression during zebrafish hematopoiesis may mimic its function in human leukemic blasts and provide clues to its functional role in AML. Comparable protein levels of either hNPMwt or hNPMc were expressed in embryos, confirmed by western blot at 22–24 hpf, and analyzed by whole mount in situ hybridization (WISH) using antisense RNA markers of specific hematopoietic lineages. Expression of hNPMc caused an increase in cMYB expression at 36 hpf, indicating an increase in the hematopoietic stem cell compartment. Furthermore, myeloid precursors (PU.1 at 22 hpf) also showed an increase upon hNPMc expression; however, mature myeloid cell (MPO and L-plastin at 26 hpf) levels were not increased relative to those in control hNPMwt injected embryos. Interestingly, the expression of hNPMc in p53 mutant embryos resulted in elevated levels of both PU.1 and MPO expressing cells, suggesting that hNPMc in zebrafish can activate p53 dependent cell cycle arrest, senescence or cell death in PU.1 cells prior to differentiation. These in vivo studies of hNPMc function during zebrafish hematopoietic differentiation suggest that hNPMc expression may increase the stem cell/ myeloid precursor compartment and can activate a p53 dependent cell death response in myeloid cells. Taking advantage of the zebrafish system in these continuing studies will further address how hNPMc expression may contribute to leukemogenesis.

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