scholarly journals Quantitative Analysis of Cell Aggregation Dynamics Identifies HDAC Inhibitors as Potential Regulators of Cancer Cell Clustering

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5840
Author(s):  
Fabien Gava ◽  
Julie Pignolet ◽  
Sébastien Déjean ◽  
Odile Mondésert ◽  
Renaud Morin ◽  
...  

Characterization of the molecular mechanisms involved in tumor cell clustering could open the way to new therapeutic strategies. Towards this aim, we used an in vitro quantitative procedure to monitor the anchorage-independent cell aggregation kinetics in a panel of 25 cancer cell lines. The analysis of the relationship between selected aggregation dynamic parameters and the gene expression data for these cell lines from the CCLE database allowed identifying genes with expression significantly associated with aggregation parameter variations. Comparison of these transcripts with the perturbagen signatures from the Connectivity Map resource highlighted that they were strongly correlated with the transcriptional signature of most histone deacetylase (HDAC) inhibitors. Experimental evaluation of two HDAC inhibitors (SAHA and ISOX) showed that they inhibited the initial step of in vitro tumor cell aggregation. This validates our findings and reinforces the potential interest of HDCA inhibitors to prevent metastasis spreading.

Biomedicines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 92
Author(s):  
Bashir Lawal ◽  
Yen-Lin Liu ◽  
Ntlotlang Mokgautsi ◽  
Harshita Khedkar ◽  
Maryam Rachmawati Sumitra ◽  
...  

Signal transducer and activator of transcription 3 (STAT3) is a transcriptional regulator of a number of biological processes including cell differentiation, proliferation, survival, and angiogenesis, while cyclin-dependent kinases (CDKs) are a critical regulator of cell cycle progression. These proteins appear to play central roles in angiogenesis and cell survival and are widely implicated in tumor progression. In this study, we used the well-characterized US National Cancer Institute 60 (NCI60) human tumor cell lines to screen the in vitro anti-cancer activities of our novel small molecule derivatives (NSC765690 and NSC765599) of salicylanilide. Furthermore, we used the DTP-COMPARE algorithm and in silico drug target prediction to identify the potential molecular targets, and finally, we used molecular docking to assess the interaction between the compounds and prominent potential targets. We found that NSC765690 and NSC765599 exhibited an anti-proliferative effect against the 60 panels of NCI human cancer cell lines, and dose-dependent cytotoxic preference for NSCLC, melanoma, renal, and breast cancer cell lines. Protein–ligand interactions studies revealed that NSC765690 and NSC765599 were favored ligands for STAT3/CDK2/4/6. Moreover, cyclization of the salicylanilide core scaffold of NSC765690 mediated its higher anti-cancer activities and had greater potential to interact with STAT3/CDK2/4/6 than did NSC765599 with an open-ring structure. NSC765690 and NSC765599 met the required safety and criteria of a good drug candidate, and are thus worthy of further in-vitro and in-vivo investigations in tumor-bearing mice to assess their full therapeutic efficacy.


2013 ◽  
Vol 41 (05) ◽  
pp. 1153-1168 ◽  
Author(s):  
Manyu Liu ◽  
Weizhang Wang ◽  
Xiaobo Li ◽  
Dayu Shi ◽  
Hanfang Mei ◽  
...  

Although Wedelia chinensis, an herb in traditional Chinese medicine, has been widely used for the treatment of inflammation, the effects of W. chinensis on cancer cell growth and the related molecular mechanisms behind these effects have largely remained unexplored to date. In the present study, W. chinensis plant extracts were obtained using either ethanol (E), petroleum ether (PE), ethyl acetate (EA) or butyl alcohol (BA). Then, extracts were examined for bioactivity in vitro via MTT assay in five human cancer cell lines. Our results showed that one subfraction of the EA extract (EA6) was cytotoxic to nasopharyngeal carcinoma (NPC) CNE-1 cells, among all cell lines evaluated. Treatment of CNE-1 cells with EA6 resulted in significant G2/M cell cycle arrest and modest apoptosis. EA6 induced Chk1 activation and inhibition of Chk1 in CNE-1 cells by RNA interference (RNAi) markedly abrogated EA6-mediated G2/M arrest and abolished EA6-induced cytotoxicity. EA6 treatment resulted in notable reduction of c-myc expression in CNE-1 cells, whereas silencing Chk1 inhibited such effects of EA6. Our results indicate that Chk1 is a novel molecular target of EA6 in NPC cells and also suggest an intervention strategy for NPC by EA6 exploring its molecular mechanisms of action.


2018 ◽  
Vol 29 (14) ◽  
pp. 1704-1717 ◽  
Author(s):  
Anushree C. Gulvady ◽  
Fatemeh Dubois ◽  
Nicholas O. Deakin ◽  
Gregory J. Goreczny ◽  
Christopher E. Turner

The focal adhesion proteins Hic-5 and paxillin have been previously identified as key regulators of MDA-MB-231 breast cancer cell migration and morphologic mesenchymal-amoeboid plasticity in three-dimensional (3D) extracellular matrices (ECMs). However, their respective roles in other cancer cell types have not been evaluated. Herein, utilizing 3D cell–derived matrices and fibronectin-coated one-dimensional substrates, we show that across a variety of cancer cell lines, the level of Hic-5 expression serves as the major indicator of the cells primary morphology, plasticity, and in vitro invasiveness. Domain mapping studies reveal sites critical to the functions of both Hic-5 and paxillin in regulating phenotype, while ectopic expression of Hic-5 in cell lines with low endogenous levels of the protein is sufficient to induce a Rac1-dependent mesenchymal phenotype and, in turn, increase amoeboid-mesenchymal plasticity and invasion. We show that the activity of vinculin, when coupled to the expression of Hic-5 is required for the mesenchymal morphology in the 3D ECM. Taken together, our results identify Hic-5 as a critical modulator of tumor cell phenotype that could be utilized in predicting tumor cell migratory and invasive behavior in vivo.


2021 ◽  
Author(s):  
Adriana Albini ◽  
Marco M. G. Festa ◽  
Nadja Ring ◽  
Denisa Baci ◽  
Michael Rehman ◽  
...  

Background. Cardiovascular toxicities still remain one of the most undesirable side effects in cancer patients receiving chemotherapy, and cardiotoxicity has been detected associated with many therapeutic regimens. A number of mechanisms are reported for these effects, some of which are related to inflammation, oxygen radical generation, mitochondrial damage. Extra-virgin olive oil (EVOO) is rich in cancer preventive polyphenols endowed with anti-inflammatory, antioxidant activities which could exert protective effects on the heart cells. One very interesting derivative of EVOO preparation is represented by purified extract form waste waters. Here, we investigated the anti-cancer activity when combined with chemotherapeutics as well as potential cardioprotective activities of a polyphenol-rich extract from waste product of the EVOO, named A009. Methods and Results. Mice bearing prostate cancer (PCa) xenografts were treated with cisplatin with and without A009. Tumor cell growth was reduced by cis and by A009 and further hindered by the combination. The effects of the A009 extract on cardiovascular toxicities was investigated in vivo. The hearts of mice were analyzed, and the mitochondria were studied by transmission electron microscopy. A protection activity by A009 was observed. To confirm the in vivo data obtained with cisplatin therapy, tumor cell lines and rat cardiomyocytes were treated with cisplatin in vitro with and without A009. A009 enhanced cisplatin and 5FU reduced cancer cell growth while did not further affect co-treated rat cardiomyocytes. Another frequently used chemotherapeutic agent 5-fluorouracil (5FU), was also tested in this assay similar effects were observed. The cardioprotective effects of the A009 extract towards 5 FU chemotherapy were further investigated in a second system of in vitro cultures, on cardiomyocytes freshly isolated from mice pups. These cells were treated with 5-fluorouracil and A009. Wastewater extract mitigated the toxicity of the fluoropyrimidine. Conclusions. In vivo, we found synergisms of A009 and cisplatin in prostate cancer treatment. Hearts of mice xenografted with PCa cell lines and receiving co-treatment of A009 extracts along with cisplatin had reduced mitochondria damage compared to chemotherapy alone, indicating a cardioprotective role. A009 in vitro was additive to cisplatin and 5FU to reduce cancer cell growth while did not further affect rat cardiomyocytes cell cultures treated with cisplatin and 5FU. The A009 extract also rescued the proliferation rate of neonatal murine cardiomyocytes treated with 5-Fluorouracil. Our study demonstrates that the polyphenol-rich purified A009 extracts enhances the effect of chemotherapy in vitro and in vivo but mitigates effects on heart and heart cells. It could therefore represent a potential candidate for cardiovascular prevention in patients undergoing cancer chemotherapy.


Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2683
Author(s):  
Rosemary A. Poku ◽  
Kylee J. Jones ◽  
Megan Van Baren ◽  
Jamie K. Alan ◽  
Felix Amissah

Polyunsaturated fatty acids (PUFAs) and non-steroidal anti-inflammatory drugs (NSAIDs) show anticancer activities through diverse molecular mechanisms. However, the anticancer capacities of either PUFAs or NSAIDs alone is limited. We examined whether combining NSAIDs with docosahexaenoic (DHA), commonly derived from fish oils, would possibly synergize their anticancer activity. We determined the viability of lung cancer cell lines (NCI-H1573, A549, NCI-H1299, and NCI-H1975) after exposure to DHA and various NSAIDs. We further conducted cell apoptosis assays and analyzed apoptosis-associated proteins and some key proteins in the RAS/MEK/ERK and PI3K/Akt pathways using western blot analysis. We also determined the impact of the treatment on the expression of inducible cancer-related genes using nCounter PanCancer Pathways gene expression analysis. The results showed that the combination of DHA and NSAIDs increased suppression of cell viability in all the lung cancer cell lines tested compared to each of the compounds used alone, with diclofenac being the most potent NSAID tested. This synergistic effect is especially significant in A549 and NCI-H1573 cells. The combination treatment was more effective at inhibiting clonogenic cell growth and anchorage-independent growth in soft agar, inducing caspase-dependent apoptosis, and altering expression of critical proteins in the RAS/MEK/ERK and PI3K/Akt pathways. The data from this study demonstrate that DHA combined with low dose diclofenac provides greater anticancer potential, which can be further developed for chemoprevention and adjunct therapy in lung cancer.


Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5077-5077
Author(s):  
Ping-Chiao Tsai ◽  
Peter Dvorak ◽  
Naveen Bangia ◽  
Scott Olejniczak ◽  
Myron S. Czuczman ◽  
...  

Abstract Abstract 5077 Cell adhesion plays an important role in the cell-cell communication and provides important signals for cell survival, migration and aggregation. Pre-clinical studies have been conducted to investigate differences in the expression of adhesion molecules on the surface of malignant B-cells in an attempt to explain differences in the clinical behavior and patterns of disease dissemination between non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Of interest CLL cells have lower levels of both adhesion molecules and CD20 when compared to follicular lymphomas (FL). It is unclear if the expression of adhesion molecules affects rituximab activity or if rituximab disrupts cell-to-cell interactions. To this end, we studied cell aggregation and expression of adhesion molecules in a panel of rituximab-senstive (RSCL) and rituximab-chemotherapy lymphoma cell lines (RRCL) that have been extensively characterized by our group (Czuczman MS. et al. Clin Cancer Res. 2008; 14:1561-70). Homotypic adhesion of B-cells is known to due to the interaction of ICAM-1(CD54) and LFA-1(CD11a). Expression of CD54 and its ligand CD11a was studied by Amnis ImageStream Technology analysis not only in RSCL and RRCL, but also in several intermediate passages obtained during the generation of RRCL process. To further define the role of CD54 in B-cell aggregation and rituximab activity, RSCL were exposed to RPMI, rituximab (10mg/ml), isotype (10mg/ml) with or without a blocking anti-CD54 monoclonal antibody (mAb) (0.25mg/ml) and patterns of cell aggregation were evaluated by inverted light microscopy and photographs were captured at different time intervals. Cell death and down-stream signaling was evaluated at various times after rituximab treatment. Differences in the expression levels of CD54 correlated with CD20 levels in NHL samples. RRCL were found to have lower mean CD54 density. Gradual loss of CD54 was observed during repeated exposure to escalating doses of rituximab, indicating potential CD54 regulation through rituximab-CD20 signaling. No difference in the CD11a was observed between RSCL and RRCL. RSCL aggregate and form clusters under typical culture conditions whereas RRCL do not aggregate in vitro. Exposure of RSCL to rituximab induced a rapid cell clustering in RSCL. Blocking CD54 using mAbs prevented spontaneous and rituximab-induced cell clustering, resulting in a phenotype similar to the RRCL. Of interest in vitro exposure to anti-CD54 mAb resulted in apoptosis of RSCL, suggesting cell adhesion is important for survival in B-cell lymphomas. The decrease in cell aggregation following CD54 blocking was not reduced by inhibition of caspase activation suggesting that cell death was not the dominant factor in preventing cell clustering in CD54-neutralized RSCL. In summary, we observed a loss of CD54, CD20 and cell aggregation during the process of acquiring resistance to rituximab. Furthermore, blocking of CD54 appears to abolish the clustering effects of rituximab in vitro. Loss of CD54 is observed in rituximab-chemotherapy cross-resistant cell lines and may disrupt signaling events thereby contributing to resistance to rituximab and chemotherapy drugs. Disclosures: No relevant conflicts of interest to declare.


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