5 results on '"Cohen GM"'
Search Results
2. BH3 profiling and a toolkit of BH3-mimetic drugs predict anti-apoptotic dependence of cancer cells.
- Author
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Butterworth M, Pettitt A, Varadarajan S, and Cohen GM
- Subjects
- Amino Acid Sequence, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Apoptosis drug effects, Benzothiazoles pharmacology, Biomimetic Materials chemistry, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Cell Line, Tumor, Humans, Isoquinolines pharmacology, Molecular Sequence Data, Neoplasms pathology, Peptide Fragments chemistry, Proto-Oncogene Proteins chemistry, Sulfonamides pharmacology, Biomimetic Materials pharmacology, Neoplasms drug therapy, Neoplasms metabolism, Peptide Fragments analysis, Proto-Oncogene Proteins analysis, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors
- Abstract
Background: Anti-apoptotic BCL-2 family members antagonise apoptosis by sequestering their pro-apoptotic counterparts. The balance between the different BCL-2 family members forms the basis of BH3 profiling, a peptide-based technique used to predict chemosensitivity of cancer cells. Recent identification of cell-permeable, selective inhibitors of BCL-2, BCL-XL and MCL-1, further facilitates the determination of the BCL-2 family dependency of cancer cells., Methods: We use BH3 profiling in combination with cell death analyses using a chemical inhibitor toolkit to assess chemosensitivity of cancer cells., Results: Both BH3 profiling and the inhibitor toolkit effectively predict chemosensitivity of cells addicted to a single anti-apoptotic protein but a combination of both techniques is more instructive when cell survival depends on more than one anti-apoptotic protein., Conclusions: The inhibitor toolkit provides a rapid, inexpensive and simple means to assess the chemosensitivity of tumour cells and in conjunction with BH3 profiling offers much potential in personalising cancer therapy.
- Published
- 2016
- Full Text
- View/download PDF
3. Increased sensitivity to TRAIL-induced apoptosis occurs during the adenoma to carcinoma transition of colorectal carcinogenesis.
- Author
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Hague A, Hicks DJ, Hasan F, Smartt H, Cohen GM, Paraskeva C, and MacFarlane M
- Subjects
- Adenoma metabolism, Animals, Antineoplastic Agents metabolism, Apoptosis Regulatory Proteins, Blotting, Western, Carcinoma metabolism, Cell Line, Tumor, Colorectal Neoplasms metabolism, Electrophoresis, Polyacrylamide Gel, Flow Cytometry, GPI-Linked Proteins, Humans, Mice, Mice, Nude, Receptors, TNF-Related Apoptosis-Inducing Ligand, Receptors, Tumor Necrosis Factor, Member 10c, TNF-Related Apoptosis-Inducing Ligand, Tumor Necrosis Factor Decoy Receptors, Adenoma pathology, Apoptosis, Carcinoma pathology, Cell Transformation, Neoplastic, Colorectal Neoplasms pathology, Membrane Glycoproteins metabolism, Receptors, Tumor Necrosis Factor metabolism, Tumor Necrosis Factor-alpha metabolism
- Abstract
The death ligand TRAIL (Apo2L) has potential for cancer therapy, since tumour cells are thought to be more sensitive than normal cells. We investigated whether sensitivity to TRAIL increases during the adenoma to carcinoma transition of colorectal carcinogenesis. Under the same culture conditions, we compared the extent of TRAIL-induced apoptosis in four premalignant adenoma and three carcinoma cell lines. Although TRAIL induced some apoptosis in adenoma cultures, the carcinoma cell lines were significantly more sensitive (P<0.001). This finding was recapitulated in an in vitro model of tumour progression in which conversion of the adenoma cell line AA/C1 to a tumorigenic phenotype was associated with increased TRAIL sensitivity (P<0.001). Increased TRAIL sensitivity during colorectal carcinogenesis has been previously attributed to changes in the balance between TRAIL receptors TRAIL-R1 and -R2 and "decoy" receptors TRAIL-R3 and -R4 during malignant progression. To address this, cell surface receptor expression was measured by flow cytometry. In summary, during colorectal carcinogenesis, there is a marked increase in sensitivity to TRAIL-induced apoptosis associated with progression from benign to malignant tumour that could be exploited for colon cancer therapy, but alterations in cell surface TRAIL receptor expression may not be the primary reason for this change.
- Published
- 2005
- Full Text
- View/download PDF
4. Conjugation of 1-naphthol by human colon and tumour tissue using different experimental systems.
- Author
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Gibby EM and Cohen GM
- Subjects
- Animals, Cell Line, Humans, Mice, Mice, Nude, Neoplasm Transplantation, Organ Culture Techniques, Subcellular Fractions metabolism, Transplantation, Heterologous, Colon metabolism, Colonic Neoplasms metabolism, Naphthols metabolism
- Abstract
The metabolism of 1-naphthol, a model phenolic substrate, to its glucuronic acid and sulphate ester conjugates has been studied in short-term organ cultures of normal human colon and tumour tissue, subcellular fractions of these tissues, human colonic tumour cell lines and human colonic tumour xenografts. Normal colonic tissue, in short-term organ culture, formed more 1-naphthyl sulphate than glucuronic acid conjugates. In contrast the colonic tumours, under the same conditions, produced more 1-naphthyl beta-D-glucuronide than 1-naphthyl sulphate. A marked interindividual variation in sulphate ester and glucuronic acid conjugation was noted in both normal and tumorous colon. The conjugation of 1-naphthol was also investigated, using subcellular fractions, where the metabolism found with normal colon reflected that observed utilizing short-term organ culture, but that from colonic tumour samples did not. Cell lines derived from human colonic adenocarcinomas metabolised 1-naphthol almost exclusively to its glucuronic acid conjugate. Xenografts derived from human colonic tumours formed similar conjugates to surgical samples in culture. Thus somewhat different results were obtained dependent on the experimental model chosen. However, in all colonic tumour systems studied, when the cells remained intact and where tissue architecture was maintained, 1-naphthol was metabolised predominantly to its glucuronic acid conjugate.
- Published
- 1984
- Full Text
- View/download PDF
5. Selective toxicity of 1-naphthol to human colorectal tumour tissue.
- Author
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Wilson GD, d'Arcy Doherty M, and Cohen GM
- Subjects
- Cell Line, Cell Survival drug effects, Colon drug effects, Humans, Naphthols metabolism, Naphthoquinones pharmacology, Neoplasm Proteins biosynthesis, Organ Culture Techniques, Time Factors, Colonic Neoplasms metabolism, Naphthols pharmacology, Rectal Neoplasms metabolism
- Abstract
1-Naphthol was selectively toxic to human colorectal tumours compared to corresponding normal colonic tissue removed at surgery and maintained in short-term organ culture. Nineteen of 24 tumours studied have shown a significant differential response. Three human colonic adenocarcinoma xenografts, in the short-term organ culture system, displayed the same response to 1-naphthol as primary tumours removed at surgery. 1-Naphthol, 1,2- and 1,4-naphthoquinone were also toxic to two human colonic adenocarcinoma cell lines, LoVo and COLO 206. The selective toxicity of 1-naphthol is mediated in part through an accumulation of 1-naphthol in the tumour tissue due to impaired conjugation by the tumour. The higher concentrations of 1-naphthol may then exert their toxicity either directly or by formation of naphthoquinones. Some indirect evidence was obtained for the possible involvement of 1,2- or 1,4-naphthoquinone in the cytotoxicity of 1-naphthol. Our studies suggest that further studies are warranted of the possible use of 1-naphthol or related compounds as antitumour agents.
- Published
- 1985
- Full Text
- View/download PDF
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