Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genistein, a naturally occurring isoflavone found chiefly in soybeans, has been reported to be a potent antitumor agent. Genistein is presumed to exert multiple effects related to the inhibition of cancer growth. Metastatic melanoma is a chemotherapy-refractory neoplasm. The present study was designed to explore the possible activity of genistein to inhibit the aberrant proliferation and to induce apoptosis of human malignant melanoma cells in cooperation with cisplatin treatment. Five human melanoma cell lines were utilized for these experiments. Genistein at physiologic concentrations (20 microM) did not induce apoptosis by itself but did enhance cisplatin-induced apoptosis in all five human melanoma cell lines tested. The enhanced susceptibility among the cell lines was diverse. Changes in the expression of two anti-apoptotic proteins, bcl-2 and bcl-xL, and one pro-apoptotic protein, apoptotic protease activating factor-1 (Apaf-1), were examined. Genistein alone or cisplatin alone generally did not alter bcl-2 expression or bcl-xL expression, but slightly increased Apaf-1 in some cell lines. The combined treatment with genistein and cisplatin significantly reduced bcl-2 and bcl-xL protein and increased Apaf-1 protein expression. These data suggest that genistein therapy may enhance the chemosensitivity of melanoma patients.
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PMID:Genistein enhances the cisplatin-induced inhibition of cell growth and apoptosis in human malignant melanoma cells. 1295 Jul 22

TR3 was originally recognized for its role in the regulation of cell survival and differentiation, however, it was recently found to be a potent pro-apoptotic protein. In order to characterize the role of TR3 in melanoma cell apoptosis, we studied expression of TR3 in melanoma cell lines and tissues, its subcellular distribution and function during apoptosis using various expression and RNA interference vectors. We found that TR3 was constitutively expressed in both cultured melanoma cells and melanoma tissues. TR3 expression was significantly decreased in advanced melanomas comparing to benign nevi. Over-expression of wild type TR3 or mutant TR3 lacking the DNA binding domain resulted in massive apoptosis in melanoma cells, whereas stable knockdown of TR3 using RNA interference resulted in melanoma cell resistance to apoptosis induced by chemotherapeutic agents ATRA and cisplatin. We further demonstrated that apoptosis in melanoma cells was mediated, at least partially, through TR3 mitochondrial translocation but not alteration in TR3 expression levels. Our results suggest that TR3 is an important apoptosis inducing factor in melanoma cells. Decreased expression of TR3 in metastatic melanoma cells may contribute to their reduced apoptotic potential and increased resistance to chemotherapy.
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PMID:Nuclear orphan receptor TR3/Nur77 mediates melanoma cell apoptosis. 1729 6

Targeting specific metabolic pathways has emerged for cancer therapeutics. For melanoma, metabolic studies have solely focused on high glucose uptake. By contrast, little is known regarding addiction to glutamine. Using five melanoma lines and two normal cell types, addition of aminooxyacetate (AOA), an inhibitor of glutamate-dependent transaminase regulating glutaminolytic pathway, two lines underwent low levels of apoptosis (>30%), while the other three lines were resistant, as were normal cells to AOA. However, three resistant lines (but not normal cells), became sensitized to undergoing apoptosis when TRAIL was combined with AOA. TRAIL by itself had minimal effects on all cell lines and normal cells, and did not augment AOA-induced killing in the two sensitive melanoma lines. AOA plus TRAIL induced a caspase-dependent apoptotic response. AOA did not influence TRAIL DR4 or DR5 cell surface death receptor levels, but AOA enhanced pro-apoptotic protein levels of Noxa, while reducing pro-survival protein Mcl-1. To verify AOA was targeting glutamine pathway, depletion of glutamine produced similar results, because absence of glutamine sensitized three melanoma lines, but not fibroblasts to killing by TRAIL. Glutamine depletion also led to Noxa induction. These results indicate some lines are addicted to glutamine, and treatment with AOA or glutamine depletion sensitizes melanoma to TRAIL-mediated killing, while sparing normal cells. Future studies are indicated to translate these discoveries to metastatic melanoma as there is currently no treatment available to prolong survival.
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PMID:Targeting glutamine metabolism sensitizes melanoma cells to TRAIL-induced death. 2059 41

Metastatic melanoma has poor prognosis and is refractory to most conventional chemotherapies. The alkylating agent temozolomide (TMZ) is commonly used in treating melanoma but has a disappointing response rate. Agents that can act cooperatively with TMZ and improve its efficacy are thus highly sought after. The BH3 mimetic ABT-737, which can induce apoptosis by targeting pro-survival Bcl-2 family members, has been found to enhance the efficacy of many conventional chemotherapeutic agents in multiple cancers. We found that combining TMZ and ABT-737 induced strong synergistic apoptosis in multiple human melanoma cell lines. When the drugs were used in combination in a mouse xenograft model, they drastically reduced tumor growth at concentrations where each individual drug had no significant effect. We found that TMZ treatment elevated p53 levels, and that the pro-apoptotic protein Noxa was elevated in TMZ/ABT-737 treated cells. Experiments with shRNA demonstrated that the synergistic effect of TMZ and ABT-737 was largely dependent on Noxa. Experiments with nutlin-3, a p53 inducer, demonstrated that p53 induction was sufficient for synergistic cell death with ABT-737 in a Noxa-dependent fashion. However, p53 was not necessary for TMZ/ABT-737 synergy as demonstrated by a p53-null line, indicating that TMZ and ABT-737 together induce Noxa in a p53-independent fashion. These results demonstrate that targeting anti-apoptotic Bcl-2 members is a promising method for treating metastatic melanoma, and that clinical trials with TMZ and Bcl-2 inhibitors are warranted.
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PMID:The combination of BH3-mimetic ABT-737 with the alkylating agent temozolomide induces strong synergistic killing of melanoma cells independent of p53. 2189 76