scholarly journals Drug Sensitivity Screening and Targeted Pathway Analysis Reveal a Multi-Driver Proliferative Mechanism and Suggest a Strategy of Combination Targeted Therapy for Colorectal Cancer Cells

Molecules ◽  
2019 ◽  
Vol 24 (3) ◽  
pp. 623 ◽  
Author(s):  
Jinyan Shen ◽  
Li Li ◽  
Tao Yang ◽  
Niuliang Cheng ◽  
Gongqin Sun
Keyword(s):  
Colorectal Cancer ◽  
Targeted Therapy ◽  
Cell Lines ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Oncogenic Signaling ◽  
Colorectal Cancer Cells ◽  
Colorectal Cancer Cell Lines ◽  
Map Kinase Pathway ◽  
Oncogenic Signaling Pathways

Treatment of colorectal cancer mostly relies on traditional therapeutic approaches, such as surgery and chemotherapy. Limited options of targeted therapy for colorectal cancer narrowly focus on blocking cancer-generic targets VEGFR and EGFR. Identifying the oncogenic drivers, understanding their contribution to proliferation, and finding inhibitors to block such drivers are the keys to developing targeted therapy for colorectal cancer. In this study, ten colorectal cancer cell lines were screened against a panel of protein kinase inhibitors blocking key oncogenic signaling pathways. The results show that four of the 10 cell lines did not respond to any kinase inhibitors significantly, the other six were mildly inhibited by AZD-6244, BMS-754807, and/or dasatinib. Mechanistic analyses demonstrate that these inhibitors independently block the MAP kinase pathway, IR/IGF-1R/AKT pathway, and Src kinases, suggesting a multi-driver nature of proliferative signaling in these cells. Most of these cell lines were potently and synergistically inhibited by pair-wise combinations of these drugs. Furthermore, seven of the 10 cell lines were inhibited by the triple combination of AZD-6244/BMS-754807/dasatinib with IC50’s between 10 and 84 nM. These results suggest that combination targeted therapy may be an effective strategy against colorectal cancer.

Action of a library of O-glycosylation inhibitors on the growth of human colorectal cancer cells in culture

2005 ◽  
Vol 33 (4) ◽  
pp. 721-723 ◽  
Author(s):  
G. Patsos ◽  
V. Hebbe-Viton ◽  
R. San Martin ◽  
C. Paraskeva ◽  
T. Gallagher ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
Cell Lines ◽  
Growth Patterns ◽  
Limited Information ◽  
Human Colorectal Cancer ◽  
Human Colorectal Cancer Cell ◽  
Colorectal Cancer Cells ◽  
Colorectal Cancer Cell Lines

O-glycosylation is thought to play a significant role in the regulation of cell growth. However, only limited information is available, and few specific and selective inhibitors have been found. We have synthesized a library of O-glycosylation inhibitors based on benzyl-O-N-acetyl-D-galactosamine. These inhibitors were tested with an established series of human colorectal cancer cell lines, which model the adenoma-carcinoma sequence. Cancer cells were incubated with the inhibitors, and examined for cell growth patterns, and cellular and subcellular glycosylation using a range of lectins with confocal microscopy. The specificity of O-glycan inhibition was confirmed for the library, relative to other forms of glycosylation. All inhibitors tested resulted in smaller cell yields. However, a differential effect on O-glycosylation was detected using the lectins showing variation of localization at a subcellular level in the various cell lines. Further differential action of the inhibitor library was observed for apoptosis and on the cell cycle with the cell lines tested. This work demonstrates that O-glycosylation is closely involved in the regulation of cell growth in colorectal cancer cells and that the generation of a library of low-molecular-mass inhibitors offers a valuable means of examining this regulation at the molecular level.

scholarly journals Identification of Two Kinase Inhibitors with Synergistic Toxicity with Low-Dose Hydrogen Peroxide in Colorectal Cancer Cells In vitro

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 122 ◽  
Author(s):  
Eric Freund ◽  
Kim-Rouven Liedtke ◽  
Lea Miebach ◽  
Kristian Wende ◽  
Amanda Heidecke ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Colorectal Cancer ◽  
Hydrogen Peroxide ◽  
Protein Kinase ◽  
Tumor Cells ◽  
Low Dose ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Colorectal Cancer Cells

Colorectal carcinoma is among the most common types of cancers. With this disease, diffuse scattering in the abdominal area (peritoneal carcinosis) often occurs before diagnosis, making surgical removal of the entire malignant tissue impossible due to a large number of tumor nodules. Previous treatment options include radiation and its combination with intraperitoneal heat-induced chemotherapy (HIPEC). Both options have strong side effects and are often poor in therapeutic efficacy. Tumor cells often grow and proliferate dysregulated, with enzymes of the protein kinase family often playing a crucial role. The present study investigated whether a combination of protein kinase inhibitors and low-dose induction of oxidative stress (using hydrogen peroxide, H2O2) has an additive cytotoxic effect on murine, colorectal tumor cells (CT26). Protein kinase inhibitors from a library of 80 substances were used to investigate colorectal cancer cells for their activity, morphology, and immunogenicity (immunogenic cancer cell death, ICD) upon mono or combination. Toxic compounds identified in 2D cultures were confirmed in 3D cultures, and additive cytotoxicity was identified for the substances lavendustin A, GF109203X, and rapamycin. Toxicity was concomitant with cell cycle arrest, but except HMGB1, no increased expression of immunogenic markers was identified with the combination treatment. The results were validated for GF109203X and rapamycin but not lavendustin A in the 3D model of different colorectal (HT29, SW480) and pancreatic cancer cell lines (MiaPaca, Panc01). In conclusion, our in vitro data suggest that combining oxidative stress with chemotherapy would be conceivable to enhance antitumor efficacy in HIPEC.

scholarly journals An Integrated Bioinformatics Analysis Repurposes an Antihelminthic Drug Niclosamide for Treating HMGA2-Overexpressing Human Colorectal Cancer

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1482 ◽  
Author(s):  
Leung ◽  
Chou ◽  
Huang ◽  
Yang
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Gene Signature ◽  
Cancer Cell Lines ◽  
Colorectal Cancer Cell ◽  
Sequencing Analysis ◽  
Colorectal Cancer Cells ◽  
Colorectal Cancer Cell Lines

Aberrant overexpression of high mobility group AT-hook 2 (HMGA2) is frequently found in cancers and HMGA2 has been considered an anticancer therapeutic target. In this study, a pan-cancer genomics survey based on Cancer Cell Line Encyclopedia (CCLE) and The Cancer Genome Atlas (TCGA) data indicated that HMGA2 was mainly overexpressed in gastrointestinal cancers including colorectal cancer. Intriguingly, HMGA2 overexpression had no prognostic impacts on cancer patients’ overall and disease-free survivals. In addition, HMGA2-overexpressing colorectal cancer cell lines did not display higher susceptibility to a previously identified HMGA2 inhibitor (netroposin). By microarray profiling of HMGA2-driven gene signature and subsequent Connectivity Map (CMap) database mining, we identified that S100 calcium-binding protein A4 (S100A4) may be a druggable vulnerability for HMGA2-overexpressing colorectal cancer. A repurposing S100A4 inhibitor, niclosamide, was found to reverse the HMGA2-driven gene signature both in colorectal cancer cell lines and patients’ tissues. In vitro and in vivo experiments validated that HMGA2-overexpressing colorectal cancer cells were more sensitive to niclosamide. However, inhibition of S100A4 by siRNAs and other inhibitors was not sufficient to exert effects like niclosamide. Further RNA sequencing analysis identified that niclosamide inhibited more cell-cycle-related gene expression in HMGA2-overexpressing colorectal cancer cells, which may explain its selective anticancer effect. Together, our study repurposes an anthelminthic drug niclosamide for treating HMGA2-overexpression colorectal cancer.

scholarly journals Surface-bound galectin-4 regulates gene transcription and secretion of chemokines in human colorectal cancer cell lines

Tumor Biology ◽  
2017 ◽  
Vol 39 (3) ◽  
pp. 101042831769168 ◽  
Author(s):  
U Subrahmanyeswara Rao ◽  
Prema S Rao
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Cell Surface ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Colorectal Cancer Cell ◽  
Colorectal Tumorigenesis ◽  
Colorectal Cancer Cells ◽  
Colorectal Cancer Cell Lines

One long-term complication of chronic intestinal inflammation is the development of colorectal cancer. However, the mechanisms linking inflammation to the colorectal tumorigenesis are poorly defined. Previously, we have demonstrated that galectin-4 is predominantly expressed in the luminal epithelia of the gastrointestinal tract, and its loss of expression plays a key role in the colorectal tumorigenesis. However, the mechanism by which galectin-4 regulates inflammation-induced tumorigenesis is unclear. Here, we show that galectin-4 secreted by the colorectal cancer cell lines was bound to the cell surface. Neutralization of surface-bound galectin-4 with anti-galectin-4 antibody resulted in increased cell proliferation with concomitant secretion of several chemokines into the extracellular medium. Neutralization of the surface-bound galectin-4 also resulted in the up-regulation of transcription of 29 genes, several of which are components of multiple inflammation signaling pathways. In an alternate experiment, binding of recombinant galectin-4 protein to cell surface of the galectin-4-negative colorectal cancer cells resulted in increased p27, and decreased cyclin D1 and c-Myc levels, leading to cell cycle arrest and apoptosis. Together, these data demonstrated that surface-bound galectin-4 is a dual function protein—down-regulating cell proliferation and chemokine secretion in galectin-4-expressing colorectal cancer cells on one hand and inducing apoptosis in galectin-4-negative colorectal cancer cells on the other hand.

Omentin-1 Promotes the Proliferation, Invasion, Migration and Angiogenesis of Colorectal Cancer Cells

2019 ◽  
Vol 9 (5) ◽  
pp. 673-678
Author(s):  
Hua Ye ◽  
Hui Luo ◽  
Yun Tu ◽  
Liao Cui
Keyword(s):  
Colorectal Cancer ◽  
Western Blot ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Colorectal Cancer Cell ◽  
Colorectal Cancer Cells ◽  
Colorectal Cancer Cell Lines

Colorectal cancer (CRC) is one of the common malignant tumors of digestive system, which the incidence of CRC has been on the rise in recent years. Omentin-1 is reported to be increased in plasma of CRC patients. The present study aimed to investigate whether Omentin-1 could promote the proliferation, invasion, migration and angiogenesis of colorectal cancer cells. ELISA assay and western blot analysis detected the Omentin-1 level in plasma of CRC patients and western blot analysis and RT-qPCR analysis detected the Omentin-1 level in colorectal cancer cell lines. The transfection effects were verified by western blot analysis. The cell proliferation, invasion and migration were determined by CCK-8 assay, wound healing assay and transwell assay. The expression of MMP2, MMP9, VEGF and AngII was analyzed by western blot analysis. The results showed that Omentin-1 was increased in plasma of CRC patients and colorectal cancer cell lines. Omentin-1 overexpression promoted the proliferation, invasion, migration and angiogenesis of colorectal cancer cells. And, up-regulation of Omentin-1 increased the expression of MMP2, MMP9, VEGF and AngII. In conclusion, our data suggested that Omentin-1 promoted the proliferation, invasion, migration and angiogenesis of colorectal cancer cells.

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