thiourea and Carcinoma

The study investigated the ability of ataxia-telangiectasia mutated (ATM)/Rad3-related (ATR) signaling pathway to influence the proliferation, apoptosis, and radiosensitivity of nasopharyngeal carcinoma (NPC) cells.. NPC tissues and corresponding adjacent normal tissues were collected from 143 NPC patients. The NPC CNE2 cells were assigned into a control group, X-ray group, CGK-733 group, and X-ray+CGK-733 group. The mRNA levels of ATM and ATR were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR) and the protein levels of ATM and ATR using western blotting. The positive expression of ATM and ATR in tissues and nude mouse tumor tissues was determined by immunohistochemistry. Cell proliferation, migration, invasion, and apoptosis rates were analyzed by the 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide (MTT) assay, scratch test, transwell assay, and flow cytometry, respectively. A nude mouse model of NPC was established to observe tumor volume and growth.. The mRNA levels of ATR and ATM and the expression of ATR and ATM protein in NPC tissues were significantly higher than those in adjacent normal tissues. The colony formation assay showed that the colony-forming rate decreased, showing radiation dose-dependent and CGK-733 concentration-dependent manners. Expression of ATM, ATR, Chk1, and Chk2 was evidently increased in the X-ray, CGK-733, and X-ray+CGK-733groups compared with the control group, and the aforementioned expression was highest in the X-ray+CGK-733 group among the four groups. The cell proliferation, invasion, and migration were decreased, tumor volume decreased and cell apoptosis increased in the X-ray, CGK-733, and X-ray+CGK-733 groups compared with the control group; the X-ray+CGK-733 group exhibited lowest cell proliferation, invasion and migration, smallest tumor volume, and highest cell apoptosis among the four groups.. Inhibition of ATM/ATR signaling pathway reduces proliferation and enhances apoptosis and radiosensitivity of NPC cells.

Topics: Aged; Animals; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Benzeneacetamides; Carcinoma; Cell Line, Tumor; Female; Humans; Immunohistochemistry; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Radiation Tolerance; Random Allocation; RNA, Messenger; Signal Transduction; Thiourea; Xenograft Model Antitumor Assays

The major obstacle of successful tumor treatment with carboplatin (CBP) is the development of drug resistance. In the present study, we found that following treatment with CBP the amount of platinum which enters the human laryngeal carcinoma (HEp2)-derived CBP-resistant (7T) cells is reduced relative to the parental HEp2. As a consequence, the formation of reactive oxidative species (ROS) is reduced, the induction of endoplasmic reticulum (ER) stress is diminished, the amount of inter- and intrastrand cross-links is lower, and the induction of apoptosis is depressed. In HEp2 cells, ROS scavenger tempol, inhibitor of ER stress salubrinal, as well as gene silencing of ER stress marker CCAAT/enhancer-binding protein (CHOP) increases their survival and renders them as resistant to CBP as 7T cell subline but did not influence the survival of 7T cells. Our results suggest that in HEp2 cells CBP-induced ROS is a stimulus for ER stress. To the contrary, despite the ability of CBP to induce formation of ROS and activate ER stress in 7T cells, the cell death mechanism in 7T cells is independent of ROS induction and activation of ER stress. The novel signaling pathway of CBP-driven toxicity that was found in the HEp2 cell line, i.e. increased ROS formation and induction of ER stress, may be predictive for therapeutic response of epithelial cancer cells to CBP-based therapy.

Topics: Apoptosis; Blotting, Southwestern; Blotting, Western; Carboplatin; Carcinoma; Cell Line, Tumor; Cell Survival; Cinnamates; Cyclic N-Oxides; DNA Primers; Drug Resistance, Neoplasm; Endoplasmic Reticulum Stress; Gene Silencing; Humans; Laryngeal Neoplasms; Platinum; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; Signal Transduction; Spin Labels; Thiourea

The tumor suppressor p53 is often inactivated in breast cancer cells because the overexpression of its repressors (e.g., MDM2 and MDMX). Restoration of p53 activity by small molecules through counteracting p53 repressors can lead to in vivo tumor regression and is therefore considered a promising strategy for treatments of cancer. Recent efforts in high-throughput drug screening and rational drug design have identified several structurally diverse small-molecule p53 activators, including a pseudourea derivative XI-011 (NSC146109). This small molecule strongly activates p53 while selectively inhibiting growth of transformed cells without inducing genotoxicity, indicating its potential as a drug lead for p53-targeted therapy. However, the mechanism(s) by which XI-011 activates p53 and the effects of XI-011 on growth of breast cancer cells are currently unknown. Here, we report that XI-011 promoted breast cancer cells to undergo apoptosis through activating p53 and inducing expression of proapoptotic genes. Importantly, we found that activation of p53 by this small molecule was achieved through a novel mechanism, that is, inhibition of MDMX expression. XI-011 repressed the MDMX promoter, resulting in down-regulation of MDMX messenger RNA level in MCF-7 cells. In line with these results, XI-011 decreased the viability of breast cancer cells expressing low levels of MDMX in a less-efficient manner. Interestingly, XI-011 acted additively with the MDM2 antagonist Nutlin-3a to inhibit growth of breast cancer cells. We conclude that XI-011 belongs to a novel class of small-molecule p53 activators that target MDMX and could be of value in treating breast cancer.

Topics: Anthracenes; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Breast Neoplasms; Carcinoma; Cell Cycle Proteins; Cell Line, Tumor; Down-Regulation; Drug Evaluation, Preclinical; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Models, Biological; Molecular Weight; Nuclear Proteins; Piperazines; Proto-Oncogene Proteins; Thiourea; Tumor Cells, Cultured; Tumor Suppressor Protein p53

Premature or stress-induced senescence is a major cellular response to chemotherapy in solid tumors and contributes to successful treatment. However, senescent tumor cells are resistant to apoptosis and may also reenter the cell cycle. We set out to find a means to specifically induce senescent tumor cells to undergo cell death and not to reenter the cell cycle that may have general application in cancer therapy.. We investigated the mechanisms regulating cell survival in drug-induced senescent tumor cells. Using immunofluorescence and flow cytometry-based techniques, we established the status of the ataxia telangiectasia mutated (ATM) signaling pathway in these cells. We assayed the requirement of ATM signaling and p21(CIP1) expression for survival in premature senescent tumor cells using pharmacologic inhibitors and antisense oligonucleotides.. The ATM/ATR (ATM- and Rad3-related) signaling pathway was found to be constitutively active in drug-induced senescent tumor cells. We found that blocking ATM/ATR signaling with pharmacologic inhibitors, including the novel ATM inhibitors KU55933 and CGK733, induced senescent breast, lung, and colon carcinoma cells to undergo cell death. We show that the mechanism of action of this effect is directly via p21(CIP1), which acts downstream of ATM. This is in contrast to the effects of ATM inhibitors on normal, untransformed senescent cells.. Blocking ATM and/or p21(CIP1) following initial treatment with a low dose of senescence-inducing chemotherapy is a potentially less toxic and highly specific treatment for carcinomas.

Topics: Ataxia Telangiectasia Mutated Proteins; Benzeneacetamides; Breast Neoplasms; Carcinoma; Cell Cycle; Cell Cycle Proteins; Cell Survival; Cellular Senescence; Colonic Neoplasms; Cyclin-Dependent Kinase Inhibitor p21; DNA Damage; DNA-Binding Proteins; Drug Evaluation, Preclinical; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Lung Neoplasms; Morpholines; Protein Serine-Threonine Kinases; Pyrones; Thiourea; Tumor Cells, Cultured; Tumor Suppressor Proteins

Retinoic acid analogues, called retinoids, have shown promise in clinical trials in preventing breast and ovarian cancers. Classic retinoids bind to retinoic acid receptors, which regulate cell growth. Some novel retinoids, such as fenretinide, i.e., N-(4-hydroxyphenyl)retinamide (4-HPR), induce apoptosis through retinoic acid receptor-independent mechanisms; however, they appear to do so only at concentrations above those achieved in clinical chemoprevention trials. At lower concentrations (< or =1 microM), 4-HPR acts like classic retinoids, by inducing differentiation through a receptor-dependent mechanism. Our goal was to compare the effects of novel receptor-independent (apoptotic) retinoids with those of classic growth-inhibitory retinoids at clinically achievable doses on growth, differentiation, and apoptosis in ovarian tissue.. Four receptor-independent (apoptotic) and seven growth-inhibitory retinoids, including synthetic, low-toxicity compounds called heteroarotinoids, were administered at concentrations of 1 microM to organotypic cultures of ovarian primary and cancer cell lines: OVCAR-3, Caov-3, and SK-OV-3. After fixation, embedding, and sectioning, the growth fraction was quantified by measuring expression of the proliferation marker Ki-67/myb, differentiation was assessed by expression of mucin, and apoptosis was evaluated by the TUNEL assay. Spearman correlation analysis was performed on the data, and all P values were two-sided.. All 11 retinoids reversed characteristics associated with the cancerous phenotype in all neoplastic cultures. Glandular structures were observed consistently in retinoid-treated, but not in untreated, OVCAR-3 and Caov-3 cultures. All retinoids decreased growth fractions, and some increased mucin expression. All receptor-independent retinoids and two receptor-dependent retinoids induced apoptosis, and the induction correlated significantly with increased expression of the mucin MUC1 (r =.83; P =.03). Retinoids with ester-linking groups did not induce apoptosis but decreased the growth fraction in correlation with MUC1 induction (r = -.93; P =.02).. At clinically achievable concentrations, all retinoids tested decrease the growth fraction, induce differentiation and apoptosis. Induction of MUC1 expression is implicated in the mechanisms of action.

Topics: Antineoplastic Agents; Apoptosis; Benzoates; Biomarkers, Tumor; Carcinoma; Drug Screening Assays, Antitumor; Female; Fenretinide; Gene Expression Regulation, Neoplastic; Humans; In Situ Nick-End Labeling; Ki-67 Antigen; Mucin-1; Ovarian Neoplasms; Phenotype; Retinoids; Statistics, Nonparametric; Thiourea; Tumor Cells, Cultured

Topics: Carcinoma; Cell Line; Culture Techniques; Humans; Mouth Neoplasms; Poliovirus; Thiourea

Topics: Animals; Antineoplastic Agents; Carcinoma; Carcinoma 256, Walker; Carcinoma, Ehrlich Tumor; Female; Injections, Intraperitoneal; Injections, Subcutaneous; Liver Neoplasms; Lymphoma, Non-Hodgkin; Male; Melanoma; Mice; Neoplasm Transplantation; Neoplasms, Experimental; Osteosarcoma; Rats; Sarcoma, Experimental; Thiourea; Urea

Topics: Animals; Ascites; Carcinoma; Carcinoma, Ehrlich Tumor; Chemical Phenomena; Chemistry; Chromatography; Guanidines; Mercaptoethanol; Mercury; Oxidoreductases; Research; Spectrophotometry; Tetrahydrofolate Dehydrogenase; Thiourea

Topics: Amino Acids; Animals; Ascites; Biological Transport; Carcinoma; Carcinoma, Ehrlich Tumor; Dinitrophenols; Glutamates; Glutamic Acid; Iodoacetates; Mice; Ouabain; Research; Thiourea

Topics: Breast Neoplasms; Bromides; Carcinoma; Humans; Isografts; Radiation Effects; Serotonin; Thiourea

Topics: Animals; Carcinoma; Ear Canal; Ear, External; Neoplasms; Rats; Sebaceous Gland Neoplasms; Sebaceous Glands; Thiourea