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

Previously, we designed a ribozyme that targets the H-ras oncogene at the 12th codon mutation site (Chang et al., 1997). Ribozymes have antisense molecule and site-specific ribonuclease potential. In this study, an adenoviral vector was used to transduce the H-ras ribozyme into laryngeal cancer cells (HEp-2). This served to downregulate the H-ras gene expression in which this ribozyme performed antisense activity due to HEp-2 cells containing wild-type alleles in the 12th H-ras codon. Together, our data demonstrated that the recombinant adenovirus encoding H-ras ribozyme can be broadly regarded as a cytotoxic gene therapy in laryngeal cancer cells regardless of containing wild-type or mutant ras gene. In addition, the mechanism through which the H-ras ribozyme inhibited tumor growth was apoptosis and involved both caspase- and mitochondria-mediated pathways. The activators caspase-8 and -9 as well as the effector caspase-3 in the induction phase of apoptosis and the substrate PARP of caspase-3 in the execution phase were activated 48h following the H-ras ribozyme treatment. Mitochondrial events characterized by the production of superoxide anion and the release of cytochrome c started at 24h. Mitochondrial transmembrane potential loss occurred 48h after the ribozyme treatment. However, Bcl-2 delayed cytochrome c release to the cytosol, but it could not protect the apoptosis effect, suggesting that cytochrome c release from mitochondria may not play a role in H-ras ribozyme-induced apoptosis.
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PMID:Recombinant adenovirus encoding H-ras ribozyme induces apoptosis in laryngeal cancer cells through caspase- and mitochondria-dependent pathways. 1241 27

Human papillomavirus type 16 (HPV 16) plays an etiological role in human laryngeal carcinoma. Apoptosis is closely associated with various biological processes including oncogenesis. This study investigated how HPV 16 oncoproteins E6 and E7 affect apoptosis in human laryngeal cancer cells. We established two human laryngeal cancer cell lines that expressed HPV 16 E6 and E7, respectively. Using these two cell lines, we found that both E6 and E7 exhibited an inhibitive effect on apoptosis induced by tumor necrosis factor alpha and cycloheximide. In both transfected cell lines, the expression of pro-apoptotic Bak was reduced and that of anti-apoptotic Bcl-2 was over-expressed. However, the expression of caspase-3 and caspase-8 was not significantly different between the E6- and E7-transfected cells and the control cells without HPV 16. p53 Protein was not detected in either the transfected or the non-transfected cells. Our study indicates that: (1) HPV 16 E6 and E7 oncoproteins are capable of inhibiting apoptosis in laryngeal squamous carcinoma cells; (2) the mechanism modulated by E6 and E7 involves the over-expression of Bcl-2 and the down-regulation of Bak; (3) the anti-apoptotic pathway is not related to the level of p53, caspase-3, or caspase-8. These results suggest that the dysregulation of apoptotic molecules Bak and Bcl-2 by HPV 16 E6 and E7 plays a role in the prolongation of cell survival, which may subsequently contribute to the development of human laryngeal cancer.
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PMID:Resistance to apoptosis of HPV 16-infected laryngeal cancer cells is associated with decreased Bak and increased Bcl-2 expression. 1503 64

Early stage laryngeal cancer can be effectively cured by radiotherapy or conservative laryngeal surgery. In the UK, radiotherapy is the preferred first line treatment. However, up to 25% of patients with T2 tumours will demonstrate locally persistent or recurrent disease at the original site, requiring salvage surgery to achieve a definitive cure. Patients experiencing treatment failure have a relatively poor prognosis. A retrospective analysis was conducted consisting of 124 patients with early stage (T1-T2, N0) laryngeal squamous cell carcinoma. In total, 62 patients who failed radiotherapy were matched for T stage, laryngeal subsite and smoking history to a group of 62 patients successfully cured by radiotherapy. Using immunohistochemistry the groups were compared for expression of apoptotic proteins: bcl-2, bcl-X(L), bax, bak and survivin. Radioresistant laryngeal cancer was associated with bcl-2 (P < 0.001) and bcl-X(L) (P = 0.005) expression and loss of bax expression (P = 0.012) in pretreatment biopsies. Bcl-2 has an accuracy of 71% in predicting radiotherapy outcome. The association between expression of bcl-2, bcl-X(L) and bax with radioresistant cancer suggests a potential mechanism by which cancer cells avoid the destructive effects of radiotherapy. Predicting radioresistance, using bcl-2, would allow the clinician to recommend conservative laryngeal surgery as an alternative first line treatment to radiotherapy.
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PMID:Bcl-2 expression predicts radiotherapy failure in laryngeal cancer. 1592 64

The carcinogenesis of human papillomaviruses type 16 (HPV-16) is mainly due to its two oncoproteins, E6 and E7. Their carcinogenic features in term of their relationship with Bcl-2 family are still unclear. We thus aimed to analyze the expression of Bcl-2 family members, Bcl-2, Bax, and Bak in laryngeal cancer cells transfected with the E6 or E7 and to determine the sensitivity of these cells to apoptotic stimuli. We employed two human laryngeal cancer cell lines, UMSCC12 and UMSCC11A in this study. These two cell lines were stably transfected with HPV16 E6, E7 or empty vector, pcDNA3.1. We found that E6 and E7 inhibited apoptosis induced by TNF-alpha/CHX in both UMSCC11A and UMSCC12 cells, enhanced the stability of Bcl-2 protein and increased the degradation of Bak protein. Furthermore, it was found that HPV-16 E7 statistically enhanced the expression of Bcl-2 in laryngeal cancer. The alteration of Bak by E6 and E7 was not through the influence on the Bak promoter, as the luciferase assay showed that neither E6 nor E7 changed the Bak promoter activity. We conclude that the evasion of apoptosis mediated by HPV-16 E6 and E7 is associated with increased Bcl-2 and decreased Bak in laryngeal carcinogenesis and that the decreased level of Bak by E6 and E7 is not caused by the regulation of the Bak promoter but by reducing its protein stability.
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PMID:Inhibition of apoptosis in human laryngeal cancer cells by E6 and E7 oncoproteins of human papillomavirus 16. 1766 39

Cucurbitacins are compounds isolated from various plant families, which have been used as folk medicines for centuries in countries such as India and China because of their wide spectrum of pharmacological activities such as cytotoxic, anti-inflammatory, and anticancer effects. Accumulated evidences have shown that cucurbitacin B inhibits the growth of numerous human cancer cell lines and tumor xenografts. To determine whether cucurbitacin B can inhibit the growth of laryngeal squamous cell carcinoma, in the present study we investigated the antitumor effect of cucurbitacin B on Hep-2 cells. Hep-2 cells were treated with different concentrations of cucurbitacin B for different time. Cell proliferation, cell cycle distribution, and cell apoptosis were evaluated using MTT assay, flow cytometry, and fluorescent microscopy. It was found that cucurbitacin B exhibited significant efficacy in growth inhibition, cell cycle arrest at G2/M phase, and apoptosis induction in a dose- and time-dependent manner. Measuring the modulation of regulators in the cell cycle, apoptosis and signal transductions by Western blot analysis showed that the effect of cucurbitacin B was due to suppression of the expression of p-STAT3, Bcl-2, and cyclin B1. Moreover, in vivo studies were performed in a mouse xenograft model, where cucurbitacin B inhibited tumor growth in a dose-dependent manner. In conclusion, the antitumor effect of cucurbitacin B on Hep-2 cells was due to the induction of cell cycle arrest as well as apoptosis. The possible mechanisms underlying the action might be attributed to the suppression of STAT3 phosphorylation. This investigation suggests a potential clinical application of cucurbitacin B for the treatment of laryngeal cancer patients.
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PMID:Inhibitory effects of cucurbitacin B on laryngeal squamous cell carcinoma. 1830 9

Combination therapy with multiple drugs is a common practice in the treatment of cancer. The promising clinical activity of docetaxel has promoted considerable interest in combining it with other antitumor agents. To determine whether cucurbitacin B can enhance chemosensitivity to docetaxel in laryngeal cancer, in the present study, we investigated the combined antitumor effect of cucurbitacin B with docetaxel on Hep-2, a human laryngeal cancer cell line. We treated Hep-2 cells with cucurbitacin B alone or in combination with docetaxel and evaluated cell growth, cell cycle distribution, and apoptosis using MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide) assay, flow cytometry, and fluorescent microscopy. Our results showed that, in comparison with single agent treatment, the combination of cucurbitacin B and docetaxel produced greater efficacy in growth inhibition, cell cycle arrest at G2/M phase, and apoptosis induction. Measuring the modulation of regulators in the cell cycle, apoptosis and signal transductions by Western blot analysis showed that the combination effect of cucurbitacin B and docetaxel was due to suppress the expression of p-STAT3 (signal transducers and activators of transcription 3), Bcl-2, and cyclin B1. Moreover, our in vivo studies were reproduced in a mouse xenograft model, where, the combination of cucurbitacin B with docetaxel synergestively inhibited tumor growth. Together, this investigation suggests that cucurbitacin B combined with docetaxel may be a feasible strategy to enhance the effects of chemotherapy in patients with laryngeal cancer.
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PMID:Combined antitumor activity of cucurbitacin B and docetaxel in laryngeal cancer. 1844 12

Interleukin-24 (IL-24)/melanoma differentiation associated gene-7 (mda-7) as a novel tumor-suppressor gene has potent antitumor activities in a broad spectrum of human cancers through the activation of various signaling pathways. However, the suppressive effect of adenovirus-mediated IL-24 (Ad-IL-24) expression on human laryngeal cancers is still elusive. In this study, we explored the therapeutic effect of Ad-IL-24 on human laryngeal cancers in vitro and in vivo in an athymic nude mouse model, using a Hep-2 human laryngocarcinoma cell line, and a WI-38 human diploid cell line served as a normal cell control. We demonstrated that Ad-IL-24 induced significant growth inhibition and apoptosis, upregulated the expression of P21, P27, and Bax, downregulated Bcl-2 expression, and activated caspase-3 in Hep-2 laryngeal tumor cells, while it exerted no direct effect on the in vitro proliferation of WI-38 normal diploid cells. Moreover, intratumoral injections of Ad-IL-24 in nude mice bearing Hep-2 tumors significantly suppressed the laryngeal xengrafted tumor growth and reduced microvessel density (MVD) and VEGF expression in tumors. This retarded tumor growth in vitro and in vivo elicited by Ad-IL-24 was closely associated with the upregulation of proliferation-related molecules P21 and P27, decrease in the ratio of anti- to proapoptotic molecules Bcl-2/Bax, followed by the activation of caspase-3, leading to apoptosis via intrinsic apoptotic pathways, and the reduced expression of proangiogenic factor VEGF involved in the inhibition of tumor angiogenesis. Thus, our results indicate that the potent, selective killing activity of Ad-IL-24 in laryngeal cancer cells, but not in normal cells, makes this vector a potential candidate for laryngeal cancer gene therapy.
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PMID:The in vitro and in vivo antitumor activity of adenovirus-mediated interleukin-24 expression for laryngocarcinoma. 2018 94

Photodynamic therapy (PDT) is a promising treatment modality for a variety of cancers. It utilizes light-absorbing compounds combined with direct illumination to generate reactive oxygen species in photosensitizer-targeted tumor cells resulting in the final photodamage of tumors. Recently, we demonstrated that a combination modality of 9-hydroxypheophorbide alpha (9-HPbD)-based PDT and carboplatin exerts enhanced cytotoxic and apoptotic effects on AMC-HN-3 laryngeal cancer cells. The present study aimed to investigate the potential apoptotic pathways initiated by 9-HPbD-PDT-mediated reactive oxygen species (ROS) in AMC-HN-3 cells. Cytotoxicity and apoptosis induced by 9-HPbD-PDT were exhibited in a ROS-dependent manner. Mitochondria and the endoplasmic reticulum (ER) were observed as preferential sites of 9-HPbD accumulation in AMC-HN-3 cells. ROS induced by 9-HPbD-PDT directly led to downregulated expression of Bcl-2, loss of mitochondrial membrane potential, release of cytochrome c from mitochondria, elevation of intracellular calcium due to ER stress, as well as induction of CHOP and activation of caspase-3, -8, -9 and -12. Our results demonstrated that ROS induced by 9-HPbD-PDT play a causative role in triggering mitochondrial events, ER stress and probable involvement of the extrinsic apoptotic pathway in AMC-HN-3 cells.
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PMID:Photoactivation of 9-hydroxypheophorbide alpha triggers apoptosis through the reactive oxygen species-mediated mitochondrial pathway and endoplasmic reticulum stress in AMC-HN-3 laryngeal cancer cells. 2019 22

We have previously shown that the simultaneous exposure of Hep-2 cells to cucurbitacin B and docetaxel significantly enhances anticancer activity of these cells by suppressing Stat3 activation and down-regulating the expression levels of key cell cycle and anti-apoptosis regulators. In order to determine whether cucurbitacin B can also enhance the sensitivity of Hep-2 laryngeal cells to cisplatin, we treated Hep-2 cells with either cucurbitacin B, cisplatin, or the combination and evaluated these cells for proliferation, cell cycle distribution, and apoptosis. Our results demonstrate that, in comparison to single agent cucurbitacin B or cisplatin treated cells, Hep-2 cells treated with a cucurbitacin B/cisplatin combination display synergistic effects on growth inhibition, cell cycle arrest, and apoptosis induction. Western blot analysis using protein extracts from Hep-2 cells treated with cucurbitacin B, cisplatin, or the combination largely recapitulated the observations made when treated with the cucurbitacin B/docetaxel combination. More specifically, Hep-2 cell lines treated with the cucurbitacin B/cisplatin combination demonstrated a significantly reduced level of p-Stat3 in comparison with single agent treated cells. In addition, cucurbitacin B/cisplatin treated Hep-2 cells also demonstrated a significant reduction in Bcl-2 and Cyclin B1 protein levels compared to single agent cucurbitacin B or cisplatin treated cells. Xenograft models containing Hep-2 cells in mice also demonstrated that this cucurbitacin B/cisplatin combination led to the synergistic inhibition of tumor growth. Taken together, these results suggest that the cucurbitacin B/cisplatin combination treatment may be a potentially useful therapeutic option for individuals diagnosed with laryngeal cancer.
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PMID:Cucurbitacin B, a small molecule inhibitor of the Stat3 signaling pathway, enhances the chemosensitivity of laryngeal squamous cell carcinoma cells to cisplatin. 2048 53

A novel drug named Dasatinib is a highly potent ATP-competitive orally active dual Src/Abl kinase inhibitor with anti-proliferative activity against solid tumors and CML (chronic myeloid leukaemia) cell lines. Dasatinib has been shown to have preclinical activity against human prostate, breast, pancreatic, lung, and head and neck cancer. To determine whether Dasatinib can inhibit the growth of laryngeal squamous cell carcinoma, in the present study, we investigated the antitumor effect of Dasatinib on Hep-2 cells. Hep-2 cells were treated with different concentrations of Dasatinib for different time. Cell proliferation, cell cycle distribution, and cell apoptosis were evaluated using MTT assay, flow cytometry, and fluorescent microscopy. It was found that Dasatinib exhibited significant efficacy in growth inhibition, cell cycle arrest at G0/G1 phase, and apoptosis induction in a dose- and time-dependent manner. Measuring the modulation of regulators in the cell cycle, apoptosis and signal transductions by western blot analysis showed that the effect of Dasatinib was due to suppression of the expression of Bax, Bcl-2, Caspase-3, and Caspase-8. Moreover, in vivo studies were performed in a nude mouse xenograft model, the new prescription (DDP + Dasatinib) was better than DDP alone in terms of therapeutic efficacy. In conclusion, the antitumor effect of Dasatinib on Hep-2 cells was due to the induction of cell cycle arrest as well as apoptosis. The possible mechanisms underlying the action might be attributed to the suppression of Src phosphorylation. This investigation suggests a potential clinical application of Dasatinib for the treatment of laryngeal cancer patients.
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PMID:Antitumor effects of Dasatinib on laryngeal squamous cell carcinoma in vivo and in vitro. 2340 69


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