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)

All human melanoma cell lines (assessed by annexin V and TUNEL assays) were resistant to apoptosis induction by TRAIL/Apo2L protein. TRAIL/Apo2L activated caspase-8 and caspase-3, but subsequent apoptotic events such as poly(ADP-ribose) polymerase cleavage and DNA fragmentation were not observed. To probe the molecular mechanisms of cellular resistance to apoptosis, melanoma cell lines were analyzed for expression of apoptosis regulators (apoptotic protease-associated factor-1, FLIP, caspase-8, caspase-9, caspase-3, cellular inhibitor of apoptosis, Bcl-2, or Bax); no correlation was observed. TRAIL/Apo2L was induced in melanoma cell lines by IFN-beta and had been correlated with apoptosis induction. Because IFN-beta induced other gene products that have been associated with apoptosis, it was postulated that one or more IFN-stimulated genes might sensitize cells to TRAIL/Apo2L. Melanoma cell lines were treated with IFN-beta for 16-24 h before treatment with TRAIL/Apo2L. Regardless of their sensitivity to either cytokine alone, >30% of cells underwent apoptosis in response to the combined treatment. Induction of apoptosis by IFN-beta and TRAIL/Apo2L in combination correlated with synergistic activation of caspase-9, a decrease in mitochondrial potential, and cleavage of poly(ADP-ribose) polymerase. Cleavage of X-linked inhibitor of apoptosis following IFN-beta and TRAIL/Apo2L treatment was observed in sensitive WM9, A375, or WM3211 cells but not in resistant WM35 or WM164 cells. Thus, in vitro IFN-beta and TRAIL/Apo2L combination treatment had more potent apoptotic and anti-growth effects when compared with either cytokine alone in melanoma cells lines.
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PMID:IFN-beta pretreatment sensitizes human melanoma cells to TRAIL/Apo2 ligand-induced apoptosis. 1209 88

Melanoma cells can undergo self-destruction via programmed cell death, i.e. apoptosis. In these tumours, the molecular components of apoptosis include positive (apoptotic) and negative (anti-apoptotic) regulators. The former include p53, Bid, Noxa, PUMA, Bax, TNF, TRAIL, Fas/FasL, PITSLRE, interferons, and c-KIT/SCF. The latter include Bcl-2, Bcl-X(L), Mcl-1, NF-(K)B, survivin, livin, and ML-IAP. Alternatively, some molecules such as TRAF-2, c-Myc, endothelins, and integrins may have either pro- or anti-apoptotic effects. Some of these molecules are of potential therapeutic use, such as: (1) p53, which influences resistance to chemotherapy; (2) Mcl-1 and Bcl-X(L), which can override apoptosis; (3) TRAIL, which has selective fatal effects on tumour cells; (4) NF-(K)B, which when downregulated sensitizes cells to TRAIL and TNF; (5) the PITSLRE kinases, whose alteration appears to result in Fas resistance; (6) interferons, which sensitize cells to other factors; and (7) survivin and other IAPs that inhibit apoptosis. This review summarizes the state of current knowledge about the key molecular components and mechanisms of apoptosis in melanoma, discusses potential therapeutic ramifications, and provides directions for future research.
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PMID:Apoptosis and melanoma: molecular mechanisms. 1451 53

Due to minimal success with non-surgical treatment options for melanoma, it is imperative that other compounds be tested for potential preventive/therapeutic use. We have tested the ability of the endogenous oestrogenic metabolite 2-methoxyestradiol (2-ME) to inhibit the growth of human melanoma cells in culture. 2-ME inhibited the growth of all the melanoma cells tested, without inhibiting the growth of non-tumorigenic cells. Microscopic observations showed that treated cells exhibit the characteristic features of apoptosis. Examination of the molecular mechanism in WM98-1 cells, using biochemical assays such as a modified TUNEL staining and DNA fragmentation, confirmed the induction of apoptosis following 2-ME treatment. Flow cytometry analysis showed that, following treatment, cells are arrested in the G(2)/M phase of the cell cycle. Western blot analysis of the G(2)/M regulatory proteins suggests that cdc2 is involved in the cell cycle block by Myt1 phosphorylation following 2-ME treatment. Furthermore, examination of the levels of apoptosis regulatory proteins showed that, while levels of p53, Bax and p21 are higher, that of anti-apoptotic Bcl-2 is undetectable in cells treated with 2-ME compared with untreated controls. Taken together these results have major implications for the use of 2-ME for melanoma management.
Melanoma Res 2003 Apr
PMID:Cell cycle block and apoptosis induction in a human melanoma cell line following treatment with 2-methoxyoestradiol: therapeutic implications? 1269 Feb 94

Melanoma begins with benign nevi and progresses to radial growth phase (RGP) and to vertical growth phase [(VGP), metastatic phenotype]. The molecular changes associated with these transitions are not yet well defined. However, transcriptional regulation of some genes that are critical in melanoma progression is beginning to be elucidated. The first part of this review will focus on our recent studies demonstrating that progression of human melanoma is associated with loss of expression of the transcription factor AP-2. In metastatic melanoma cells, this loss resulted in overexpression of MCAM/MUC18 and MMP-2, and lack of expression of c-KIT. In further investigations, we inactivated AP-2 in SB-2 primary cutaneous melanoma cells by using a dominant-negative AP-2, the AP-2B gene. Expression of AP-2B in SB-2 cells augmented their tumorigenicity in nude mice and upregulated MMP-2 expression and activity. We have also recently demonstrated that loss of AP-2 expression in metastatic melanoma cells resulted in overproduction of the thrombin receptor, PAR-1. Other studies have shown that AP-2 regulates additional genes involved in melanoma development and progression, including E-cadherin, p21/WAF-1, HER2, Bcl-2, FAS/APO-1, IGF-R-1, and VEGF. We propose that loss of AP-2 is crucial in the development of malignant melanoma. Additionally, the transition of melanoma cells from RGP to VGP is associated with overexpression of two transcription factors, CREB and ATF-1, both of which may act as survival factors for human melanoma cells. The second part of the review will briefly discuss the role of other transcription factors, including ATF-2, SNAIL, MITF, and NFkappaB in the progression of human melanoma and will summarize recent knowledge on how changes in the expression of these transcription factors contribute to acquisition of the metastatic phenotype in human melanoma.
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PMID:Transcriptional regulation of metastasis-related genes in human melanoma. 1274 83

1alpha,25-Dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] has been shown to induce cell growth arrest and to possess differentiation-inducing behaviour in both primary melanocytes and melanoma cell lines. Moreover, in several melanoma cell lines it has been demonstrated that the antiproliferative action is accompanied by an increase in apoptosis. In contrast, here we show that physiological concentrations of 1,25-(OH)(2)D(3) did not induce apoptosis in primary melanocytes despite a cell growth inhibitory effect. Furthermore, treatment with 1,25-(OH)(2)D(3) made melanocytes resistant to several inductors of programmed cell death, including tumour necrosis factor-alpha and ultraviolet radiation. The antiapoptotic effect of 1,25-(OH)(2)D(3) was completely abolished by the addition of N,N-dimethylsphingosine, which blocks the formation of the sphingolipid degradation product sphingosine 1-phosphate (S1P), suggesting a crucial role for this sphingolipid in 1,25-(OH)(2)D(3)-mediated cytoprotection. Indeed, stimulation of melanocytes with S1P also resulted in an antiapoptotic action. In addition, S1P induced cell growth arrest of human melanocytes. This was an unexpected finding, as S1P is generally known as a potent mitogenic molecule in a variety of cells, including fibroblasts. As both 1,25-(OH)(2)D(3) and S1P have been identified to modify the Bcl-2/Bax ratio in epithelial cells, we also measured the expressions of these proteins; however, treatment of melanocytes with either 1,25-(OH)(2)D(3) or S1P did not alter the Bcl-2/Bax ratio. In conclusion, 1,25-(OH)(2)D(3) was shown to protect human melanocytes from apoptosis by formation of S1P, which is opposite to its apoptotic action in diverse melanoma cell lines.
Melanoma Res 2003 Aug
PMID:Antiapoptotic action of 1alpha,25-dihydroxyvitamin D3 in primary human melanocytes. 1288 59

Malignant melanoma cells have been reported to be highly resistant to chemotherapeutic agents. To gain insight into the molecular mechanisms underlying chemotherapeutic drug resistance, we examined the role of the Bcl-2 family members Bcl-2 and Bax in cell death in the melanoma cell line G361 following stimulation with cisplatin (CDDP) or dacarbazine (DTIC). Trypan blue dye exclusion showed that both CDDP and DTIC induced death of G361 cells. Apoptotic and necrotic cell death could be distinguished by flow cytometry using combined staining with annexin V and 7-amino-actinomycin D (7-AAD). CDDP-induced cell death at a low concentration (0.6 micro g/ml) was mainly due to apoptosis (annexin V+/7-AAD-), while a mixture of apoptosis and secondary necrosis (annexin V+/7-AAD+) was found at a high concentration (6 micro g/ml). DTIC at the concentrations used induced only apoptosis. CDDP-induced apoptosis and secondary necrosis were accompanied by activation of caspase-3 and modulation of Bcl-2 family members Bcl-2 and Bax. On Western blotting Bax was seen to be upregulated with concomitant downregulation of Bcl-2. Flow cytometry, which enables measurement of protein at the single-cell level, revealed that Bcl-2+/Bax- cells were decreased, with a slight concomitant rise in Bcl-2-/Bax+ cells on stimulation with CDDP. These findings suggest that the chemotherapeutic agents CDDP and DTIC induce apoptosis and/or secondary necrosis depending on dose, probably involving the modulation of Bcl-2 family proteins.
Melanoma Res 2003 Oct
PMID:Induction of apoptosis and/or necrosis following exposure to antitumour agents in a melanoma cell line, probably through modulation of Bcl-2 family proteins. 1451 87

The expression pattern of integrin-type cell adhesion receptors is often changed during malignant transformation. In the present work, we studied the prognostic significance of beta1 and alphav integrin chains for survival of patients with metastatic melanoma. The expression levels of beta1 integrin were also compared with those of Bcl-2, an anti-apoptotic protein, the presence of which is associated with treatment response and survival in melanoma. The expression of beta1 and alphav integrins in 68 melanoma metastases obtained from 55 patients treated with combined chemoimmunotherapy was studied by immunohistochemistry using anti-beta1 and anti-alphav antibodies. The patients were divided into two groups (using a cut-off point of >/= 81%) for beta1 integrin expression levels and into three categories (negative/low, median, high) for alphav integrin expression levels. All tumours were positive for beta1 integrin, and the tumours (n = 6) which had the highest alphav score were also strongly positive for beta1 (94%; P = 0.0055). Patients (n = 43) with 80% or less beta1 integrin-positive tumour cells in their samples had a median disease-free survival (DFS) of 17.0 months, and patients (n = 12) with 81% or more beta1 integrin-positive tumour cells had a DFS of only 5.7 months (P = 0.0001). Patients (n = 32) with low alphav integrin expression levels had shorter DFS (median 12.3 months; P = 0.0146) than patients (n = 20) with median expression levels (median 16.7 months; P = 0.0146). However, three patients who had a very strong alphav expression in their tumours had a median DFS of only 1.8 months (P = 0.0146). Median level expression of beta1 integrin was associated with the presence of Bcl-2 in tumour cells (P = 0.0033). Our results suggest that beta1 and alphav integrin chains are independently expressed in metastatic melanoma and may have an effect on the metastatic potential of melanoma cells.
Melanoma Res 2004 Feb
PMID:Integrin chains beta1 and alphav as prognostic factors in human metastatic melanoma. 1509 Nov 91

Melanoma cells are relatively resistant to Apo2L/TRAIL (TNF-related apoptosis-inducing ligand). We postulated that resistance might result from higher expression of inhibitors of apoptosis including Bcl-2, FLIP (FLICE-like inhibitory protein) or IAPs such as XIAP (X-linked inhibitor of apoptosis) or survivin. Compared to scrambled or mismatch controls, targeting individual inhibitors with siRNA (si-Bcl-2, si-XIAP, si-FLIP or si-Surv), followed by Apo2L/TRAIL resulted in marked increase in apoptosis in melanoma cells. Compared to Bcl-2 or FLIP, siRNAs against XIAP and survivin were most potent in sensitizing melanoma cells. A similar substantial increase in apoptosis was seen in renal carcinoma cells (SKRC-45, Caki-2), following the inhibition of either XIAP or survivin by siRNAs. Apo2L/TRAIL treatment in IAP-targeted cells resulted in cleavage of Bid, activation of caspase-9 and cleavage of PARP (poly ADP-ribose polymerase). Thus, Apo2L/TRAIL resistance can be overcome by interfering with expression of inhibitors of apoptosis regulating both extrinsic (death receptor) or intrinsic (mitochondrial) pathways of apoptosis in melanoma cells.
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PMID:Downregulation of Bcl-2, FLIP or IAPs (XIAP and survivin) by siRNAs sensitizes resistant melanoma cells to Apo2L/TRAIL-induced apoptosis. 1511 63

The First International Symposium on Melanoma and Other Cutaneous Malignancies, held in New York City on 23-25 April 2004, brought together researchers and clinicians from all over the world to discuss recent advances in the prevention, treatment and diagnosis of melanoma and other cutaneous malignancies. Discussion topics included primary and secondary prevention; advances in surgical therapy, including sentinel and elective lymph node dissection; the biology and pathogenesis of melanoma, including pathways of drug resistance; genomic analysis of melanoma, serum and tumour cell markers; with point and counterpoint sessions debating therapeutic controversies. The role of vaccines in the management of melanoma was discussed, including cell vaccines, dendritic cell-based vaccination and present research to improve the generation of melanoma vaccine-specific immunity. Adjuvant immunotherapy with high-dose IFN-alpha and an ongoing trial with biochemotherapy were debated. In addition, the role of chemotherapy and novel targeted agents in metastatic melanoma were discussed. Among the emerging agents and therapeutic targets presented were Bcl-2 antisense therapy, RAF kinases, heat-shock proteins, thalidomide and newer immunomodulatory drugs, cytotoxic T lymphocyte antigen-4 antibody and topical imiquimod. The symposium also provided an overview of existing and emerging agents and modalities in the management of patients with cutaneous T cell lymphomas, ocular melanoma and melanoma involving brain metastases. Sessions also included case-based learning and devoted ample time to providing 'how to' information for practising physicians.
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PMID:First International Symposium on Melanoma and Other Cutaneous Malignancies. 1533 20

Neuroectodermal tumors are highly malignant and increasingly common tumors. Because the cure rate of these neoplasias by conventional treatment is very low, new therapeutic approaches are needed. Entrapping high concentrations of cytotoxic drugs and/or oligonucleotides within stabilized liposomal formulations represents an emerging modality of antitumor treatment. Here, we tested the in vitro and in vivo antitumor effects of a novel antisense oligodeoxynucleotide (asODN) liposomal formulation, the coated cationic liposomes (CCL), by targeting the c-myc and the c-myb oncogenes on melanoma and neuroblastoma, respectively, through the use of a monoclonal antibody against the disialoganglioside GD2, selectively expressed by neuroectoderma-derived tumors. Our methods produced GD2-targeted liposomes that stably entrapped 90 percent of added asODNs. These liposomes showed selective binding for GD2-positive tumor cells in vitro. Neuroblastoma cells treated with free myb-as or nontargeted CCL-myb-as showed the same level of c-myb protein expression as control cells. In contrast, c-myb protein expression of cells treated with aGD2-CCL-myb-as was inhibited by approximately 70 percent. Melanoma and neuroblastoma cell proliferation was inhibited to a greater extent by GD2-targeted liposomes containing c-myc or c-myb asODNs than by nontargeted liposomes or free asODNs. Mice bearing established subcutaneous human melanoma xenografts treated with aGD2-CCL-myc-as exhibited significantly reduced tumor growth and increased survival. The mechanism for the antitumor effects appears to be downregulation of the expression of the c-myc protein, induction of p53, and inhibition of Bcl-2 proteins, leading to extensive tumor cell apoptosis. In contrast, the increased life span obtained in a neuroblastoma pseudometastatic mouse model with the liposomal c-myb asODNs seems to be due to a synergistic mechanism: specific targeting to neuroblastoma cancer cells, downmodulation of c-myb protein expression, and stimulation of the innate immune system. These results suggest that inhibition of c-myc or c-myb proto-oncogenes by GD2-targeted antisense therapy could provide an effective approach for the treatment of neuroectodermal tumors in an adjuvant setting.
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PMID:Targeted delivery of oncogene-selective antisense oligonucleotides in neuroectodermal tumors: therapeutic implications. 1565 Feb 35


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