Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Detection of tumor-associated alterations in peritumoral normal mucosa may give insight into the molecular pathogenesis of oral cancer. In the present study, 100 archival oral squamous cell carcinomaswith adjacent nontumorous mucosa were immunohistochemically investigated with antibodies against p53, Mdm2, Bcl-2, WAF1, MIB1, epidermal growth factor receptor (EGF-R), and various CD44 isoforms. Additionally a standardized argyrophilic nucleolar organizer region (AgNOR)-associated proteins analysis was performed. No correlation was found between p53, Mdm2, Bcl-2, and WAF1 immunophenotypes of the respective tumors and adjacent mucosa. The proliferation-associated markers MIB1 and AgNORs showed a statistically significant sequential increase from normal to dysplastic mucosa to invasive carcinoma. Investigation of various CD44 adhesion molecules revealed a highly variable expression pattern in overt carcinomas with a significantly decreased expression of CD44 v4 and v9 variants and unaltered strong expression of v5 and v6 isoforms compared with normal oral epithelium. We conclude that proliferation markers (MIB1 and AgNORs), as well as selected CD44 isoforms, represent useful markers for the assessment of precancerous lesions. They may be utilized for screening patients at high risk for the development of oral cancer.
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PMID:Immunophenotypic analysis of normal mucosa and squamous cell carcinoma of the oral cavity. 989 90

Human oral cancer cells may have any of several genetic changes, but the role of the bcl-2 oncogene is relatively unexplored. To find out if this gene plays a significant role and whether it could act as a target for gene therapy of oral cancer, we have examined the effects of an anti-bcl-2 ribozyme on the phenotype of oral cancer cells. A hammer-head ribozyme was designed to cleave the bcl-2 transcript after nucleotide 279 and was confirmed to be effective against a synthetic bcl-2 transcript. A gene encoding the ribozyme was cloned into an adenovirus vector and transferred to the human oral cancer cell lines 686LN, 1483, and Tu183. Over a 6-day period, the growth of each cancer cell line was reduced, whereas growth of the fibroblast cell line FS7 was less inhibited. Inhibition of the oral cancer cells could be attributed to apoptosis, as indicated by the detection of histone-associated DNA fragments in an immunoassay. Northern blots showed no detectable reduction in the level of bcl-2 mRNA of Tu183 cells, but Western blots showed a reduction of Bcl-2 protein at 24 h after infection with the ribozyme-expressing adenovirus vector. The results imply that (a) expression of the bcl-2 oncogene is necessary for the survival of oral cancer cells, (b) the bcl-2 gene transcript presents a target for gene therapy by ribozymes, and (c) an adenovirus vector is a suitable method for transfection of the ribozyme-expressing gene.
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PMID:Induction of apoptosis in oral cancer cells by an anti-bcl-2 ribozyme delivered by an adenovirus vector. 1065 52

Chemopreventives are chemicals that prevent the formation of cancers such as oral cancer. They can take the form of nutrients or synthetic molecules, and their fundamental characteristic is that they do not produce disease processes that would result in debilitating symptoms. Current evidence indicates that they function by modifying the oxidative state of transforming cells. Biomarkers can take the form of genetic and molecular indicators, which characterize the function of chemopreventives and cancer processes such as oral carcinogenesis. Biomarkers cannot provide all the required information for risk assessment or possible activity of the chemopreventives. Other methods, such as epidemiological analyses and techniques, must be used to enhance our understanding of the risk for oral cancer in human populations. One common epidemiologic method, the questionnaire, helps to determine the use and carcinogenic potential of tobacco and alcohol during oral carcinogenesis. Genetic and molecular changes in human patient populations may result in a reduction in the number and function of tumor suppressor genes. If these changes are to be assessed, the tissues (e.g., buccal mucosa) must be accessible and harvested in a reliable and consistent manner for the acquisition of DNA, mRNA, and protein. Oral tissues provide sufficient quantities of these molecules and, under stringent conditions, the quality required for the isolation of these molecular constituents. In conjunction with epidemiologic techniques, various genotypic polymorphisms, such as glutathione-S-transferase (GSTM1) or cytochrome P450 (CYP450A1), have indicated a loss in carcinogen detoxification or the processing of internal growth control signals. Biomarkers are composed of a large diverse group of genetic and molecular structures. Some of these biomarkers are indicators for programmed cell death (PCD), while others describe malignant tumor growth. Many of these classes of molecules are oxidative-responsive (e.g., tumor suppressor p53, Bcl-2, growth factors, immune-derived proteins, and death-inducing molecules) and induce PCD by triggering a cascade of cysteine proteases and regulators (e.g., caspases, death receptors). This pathway results in cell-cycle alterations and DNA fragmentation. It is hoped that a detailed knowledge of the processes involved in malignant transformation will better define the biomarker-screening tools for oral cancer. These tools will enhance our ability to predict the incidence of cancer, detect early malignant change, and quantitate chemoprevention during oral carcinogenesis. Chemopreventives such as the retinoids have already demonstrated their ability to suppress potential malignant changes in pre-malignant oral leukoplakias and decrease the incidence of second head-and-neck cancer primaries. It is our hope that this review will increase investigators' interest in developing new screening and detection systems for oral cancer.
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PMID:Biomarkers and molecular epidemiology and chemoprevention of oral carcinogenesis. 1068 2

Deregulation of oncogenes and tumor suppressor genes involved in apoptosis has been associated with tumor development and progression. To investigate the involvement of apoptosis regulating proteins in oral cancer in Indian patients, primarily associated with chewing tobacco habits, immunohistochemical expression of bcl-2 and bax was examined in 63 oral squamous cell carcinomas, and 31 putative premalignant lesions. Our studies revealed overexpression of tumor specific cytoplasmic bcl-2 in 56% and bax in 43% oral cancers. The oral cancers in the Indian patients are preceded by premalignant oral lesions; hence oral lesions were examined for bcl-2 and bax expression. We observed aberrant expression of bcl-2 in 16% oral lesions comprising leukoplakias and SMF and bax in 55% oral lesions. We have already reported, p53 expression in these oral cancers and lesions. It was noteworthy that 30% oral cancers demonstrated a p53+bcl2+ pattern, and 14% samples exhibited p53+bcl2+bax+ pattern. However, none of the oral lesions showed concurrent deregulation of p53 and bcl-2 or all the three genes. Interestingly 45% oral lesions were p53-bax+ as compared to 18% oral cancers; while 39% oral lesions were bcl2-bax+ as compared to 14% oral cancers, indicating overexpression of bax in oral lesions, in the absence of p53 and bcl-2 proteins. Significant correlation was observed between positive nodal status and bcl2+ (p=0.047) and p53+bcl-2+ (p=0.01) in oral cancers. Kaplan Meier survival analysis showed significantly (p=0.059) higher survival in patients with p53- oral tumors than with p53+ tumors. Our studies thus indicate frequent overexpression of apoptosis regulators bcl-2, bax and p53 proteins in oral cancers, and a subset of oral lesions, representing early events in oral car-cinogenesis. The aberrant bcl-2 expression and loss of p53 function observed, may play an important role in the tumorigenesis of oral cancers by allowing escape from apoptosis and enabling additional genetic alterations to accrue.
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PMID:Expression of bcl-2 and bax in chewing tobacco-induced oral cancers and oral lesions from India. 1217 74

In the current study, we examined the clinical characteristics and survival probability rates of 116 patients treated for squamous cell carcinoma (SCC) of the tongue. In 55 randomly selected patients these data were correlated with the immunohistological analysis of the tumor and apoptosis-related markers, p53, Bcl-2, c-erbB-2 (Her-2/neu), and to the apoptosis rate assessment by the terminal dUTP nick-end-labeling (TUNEL) method. The overall 5-year survival probability was 55%, which might be the result of the low incidence of smoking and/or alcohol consumption among the patients (21%), the early diagnosis (65% at Stages I-II) and the low histological grades (91% good-moderate). Radiotherapeutic or surgical treatment of the neck did not alter the survival probability achieved by local surgery for Stage I patients, but significantly improved survival for Stage II patients. Independent tumor-related variables which significantly worsened the probability of survival were found. Concomitant non-oral cancer was found to be a poor variable for prognosis prediction. Positive staining of p53, TUNEL (apoptosis rate), c-erbB-2 and Bcl-2 was found in 60, 48, 18 and 15% of the lesions, respectively (P<0.0001). The possible biological significance of these markers in tongue SCC is discussed in relation to the current literature, and an independent role for TUNEL and p53 is suggested.
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PMID:Squamous cell carcinoma of the tongue: the prevalence and prognostic roles of p53, Bcl-2, c-erbB-2 and apoptotic rate as related to clinical and pathological characteristics in a retrospective study. 1221 83

Bcl-2 inhibits most kinds of programmed cell death and provides a selective survival advantage to various cell types. The biological significance of Bcl-2 expression for the development and progression of oral cancer has still to be evaluated. The aim of our study was to estimate possible correlations between the Bcl-2 protein expression and some clinicopathological features of oral cancer. The study was conduced on 129 patients treated surgically for oral squamous cell carcinoma. The statistically significant relationships were observed between oral squamous cell cancer Bcl-2 expression and higher tumor grading (p<0.005), higher tumor mitotic index (p<0.005), higher index of atypical mitoses (p<0.001) as well as microfocal pattern of tumor invasive margin (p<0.001). The results suggest that positive Bcl-2 expression may be a valuable factor supplementing the established unfavorable histopathological features of oral squamous cell carcinoma.
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PMID:Correlation between Bcl-2 protein expression and some clinicopathological features of oral squamous cell carcinoma. 1281 80

The present study was to investigate the chemopreventive effects of tea pigments. In vitro study showed that tea pigments induced QR activity and GST activity in Hep G2 cells. Three animal models were used to observe the preventive effects of tea pigments on liver cancer, colorectal cancer and oral cancer. Oral administration of 0.1% tea pigments increased GST activity in rat liver by 18%, and this increase was accompanied by the significant increase of GST 1-1, 1-2, and 3-3 protein expression in rat liver. Tea pigments inhibited the proliferating cell nuclear antigen labeling index (PCNA-LI), the expression of Bcl-2 protein and ras-p21 protein, and induced the expression of Bax protein in rat colorectal cancer. PCNA-LI, silver-stained nucleolar organizer regions (AgNOR) and epidermal growth factor receptor (EGFR) expression were also inhibited by tea pigments in hamster oral cancer. Our results suggested that tea pigments had chemopreventive effects on cancer, and the anti-cancer properties may be due to the activation of detoxifying enzymes such as QR and GST, the inhibition of cell proliferation and the induction of apoptosis.
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PMID:[Studies on cancer chemoprevention by tea pigments]. 1496 10

We examined the mechanism involved in the induction of apoptosis in human oral cancer (B88) cells with 5-fluorouracil (5-FU) and cisplatin (CDDP) combination. Three different combination treatment sequences were evaluated: i) 5-FU administered simultaneously with CDDP for 72 h (sequence I); ii) CDDP administered for 24 h before 5-FU treatment for 48 h (sequence II); and iii) 5-FU administered for 24 h before CDDP treatment for 48 h (sequence III). When combining the two drugs at doses 40% of their respective cytotoxicity, the growth-suppressing ratios were 49, 55, and 40% in sequences I, II, and III, respectively. Caspase 3 was significantly activated in sequence II as compared to its level of activation in sequence I or III. The mitochondrial release of cytochrome c was much greater in sequence II than in sequence III. In addition, activation of caspase 8 was most strongly activated in sequence II as compared with sequences I and III. Activation of caspase-9 was also observed in sequence II, and, to a lesser extent, in sequence III. Finally, although Bcl-2 was reduced in sequence II, no significant change was observed in sequence III. Accordingly, the data presented here demonstrate that sequence II showing a significant increase in the induction of apoptosis of cancer cells, is superior to sequences I and III.
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PMID:Potentiation of induction of apoptosis by sequential treatment with cisplatin followed by 5-fluorouracil in human oral cancer cells. 1513 87

Celecoxib is a potent nonsteroid antiinflammatory drug (NSAID) that has shown great promise in cancer chemoprevention and treatment. The tumor suppression activity of celecoxib and other NSAIDs have been related to the induction of apoptosis in many cancer cell lines and animal models. While celecoxib is a specific inhibitor of cyclooxygenase (COX)-2, recent data indicate that its apoptotic properties may also be mediated through COX-independent pathways. In our study, we evaluated second generation celecoxib derivatives, lacking COX-2 inhibitory activity, in a premalignant and malignant human oral cell culture model to determine their potential anticancer effect and mechanisms responsible for the COX-independent apoptotic activity. Celecoxib and its derivatives delayed the progression of cells through the G(2)/M phase and induced apoptosis. The derivatives with apolar substituents at the terminal phenyl moiety of celecoxib greatly enhanced apoptosis and cell cycle delay. Apoptosis and cell cycle arrest appeared to be independent of derivative induced inhibition of PDK1 and phosphorylation of Akt and Erk1/2. Derivatives induced apoptosis was mediated by the cleavage and activation of caspase-9 and caspase-3, but not caspase 8, implicating the mitochondrial pathway for apoptosis induction. Inhibitors of caspase-3 and caspase-9 and cyclosporin A, a mitochondrial membrane potential stabilizer, attenuated derivative induced apoptosis. Inhibition of caspase-3 prevented the activation of caspase 8, while the inhibition of caspase-9 inhibitor blocked activation of both caspase 3 and 8 by the derivatives. Apoptosis was independent of Bcl-2. These results indicate that the second generation celecoxib derivatives induce apoptosis in human oral cancer lines by the disruption of mitochondrial membrane potential activating caspase 9 and downstream caspase 3 and 8. This suggests that the modification of the celecoxib structure can lead to highly effective COX-independent growth inhibitory and apoptotic agents in chemoprevention and therapy.
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PMID:Celecoxib derivatives induce apoptosis via the disruption of mitochondrial membrane potential and activation of caspase 9. 1549 25

Norcantharidin (NCTD), the demethylated analogue of cantharidin, has been used to treat human cancers in China since 1984. It was recently found to be capable of inducing apoptosis in human colon carcinoma, hepatoma and glioblastoma cells by way of an elusive mechanism. In this study, we demonstrated that NCTD also induces apoptosis in human oral cancer cell lines SAS (p53 wild-type phenotype) and Ca9-22 (p53 mutant) as evidenced by nuclear condensation, TUNEL labeling, DNA fragmentation and cleavage of PARP. Apoptosis induced by NCTD was both dose- and time-dependent. We found NCTD did not induce Fas and FasL, implying that it activated other apoptosis pathways. Our data showed that NCTD caused accumulation of cytosolic cytochrome c and activation of caspase-9, suggesting that apoptosis occurred via the mitochondria mediated pathway. NCTD enhanced the expression of Bax in SAS cells consistent with their p53 status. Moreover, we showed that NCTD downregulated the expression of Bcl-2 in Ca9-22 and Bcl-XL in SAS. Our results suggest that NCTD-induced apoptosis in oral cancer cells may be mediated by an increase in the ratios of proapoptotic to antiapoptotic proteins. Since oral cancer cells with mutant p53 or elevated Bcl-XL levels showed resistance to multiple chemotherapeutic agents, NCTD may overcome the chemoresistance of these cells and provide potential new avenues for treatment.
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PMID:Norcantharidin-induced apoptosis in oral cancer cells is associated with an increase of proapoptotic to antiapoptotic protein ratio. 1559 95


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