Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis protease-activating factor-1 (Apaf-1), which plays a central role in the formation of the apoptosome, is absent or poorly expressed (because of a transcriptional silencing by methylation) in a substantial percentage of metastatic melanomas and melanoma cell lines, which are unable to activate caspase-9 and execute the mitochondrial pathway of apoptosis. We studied cisplatin-induced apoptosis of the Apaf-1-positive human metastatic Me665/2/21 melanoma cells. Our results indicate that caspase-7 is already processed in still-adhering cells and such activation, contrary to the common view, precedes caspase-3 processing. As expected by the cytochrome c release into the cytosol, caspase-9 is processed to active forms (p37 and p35), along with a yet-unidentified p28. Interestingly, we also demonstrate a remarkable loss of Apaf-1 protein, along with the appearance of a related immunoreactive fragment of approximate, equals 26 kDa; such proteolytic degradation proves to be a caspase-3/-7-mediated event. Our data also indicate that the inhibition afforded by ac-DEVD-CHO on several components (i.e., caspase-3/-7 and caspase-9 activities), and Apaf-1 proteolytic degradation, does not significantly abrogate either the apoptotic morphology or the cleavage of canonical targets, such as poly(ADP-ribose) polymerase (PARP) and lamin B. These results suggest that caspase-3 and caspase-7 are dispensable for the execution of apoptosis and, in our cellular model, the point of no return could be out of the mitochondrial cascade.
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PMID:Cisplatin-induced apoptosis in melanoma cells: role of caspase-3 and caspase-7 in Apaf-1 proteolytic cleavage and in execution of the degradative phases. 1503 20

Histone deacetylase (HDAC) inhibitors have attracted much interest because of their ability to arrest cell growth, induce cell differentiation, and in some cases, induce apoptosis of cancer cells. In the present study, we have examined a new HDAC inhibitor, suberic bishydroxamate (SBHA), for its effect on a panel of human melanoma cell lines. We report that it induces varying degrees of apoptosis in the melanoma lines but not in melanocytes and fibroblasts. Induction of apoptosis was caspase dependent and was associated with induction of changes in mitochondrial membrane permeability, which could be inhibited by overexpression of Bcl-2. The changes in mitochondria were independent of caspase activation and were associated with changes in conformation of Bax. SBHA down-regulated several key antiapoptotic proteins including X-linked inhibitor of apoptosis and the Bcl-2 family proteins, Bcl-XL and Mcl-1. In contrast, it induced up-regulation of the Bcl-2 family proapoptotic proteins, Bim, Bax, and Bak. In addition, SBHA induced relocation of the protein Bim to mitochondria and its association with Bcl-2. De novo protein synthesis was required for initiation of apoptosis in that the protein synthesis inhibitor, cycloheximide, inhibited SBHA-induced conformational changes in Bax as well as changes in mitochondrial membrane permeability and activation of caspase-3. These results suggest that SBHA induces apoptosis by changing the balance between proapoptotic and antiapoptotic proteins in melanoma cells. The protein Bim may be a key initiator of apoptosis in cells treated with SBHA.
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PMID:The histone deacetylase inhibitor suberic bishydroxamate regulates the expression of multiple apoptotic mediators and induces mitochondria-dependent apoptosis of melanoma cells. 1507 86

Previously, we demonstrated that a plant steroid, diosgenin, altered cell cycle distribution and induced apoptosis in the human osteosarcoma 1547 cell line. The objective of this study was to investigate if the antiproliferative effect of diosgenin was similar for different human cancer cell lines such as laryngocarcinoma HEp-2 and melanoma M4Beu cells. Moreover, this work essentially focused on the mitochondrial pathway. We found that diosgenin had an important and similar antiproliferative effect on different types of cancer cells. In addition, our new results show that diosgenin-induced apoptosis is caspase-3 dependent with a fall of mitochondrial membrane potential, nuclear localization of AIF and poly (ADP-ribose) polymerase cleavage. Diosgenin treatment also induces p53 activation and cell cycle arrest in the different cell lines studied.
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PMID:Induction of antiproliferative effect by diosgenin through activation of p53, release of apoptosis-inducing factor (AIF) and modulation of caspase-3 activity in different human cancer cells. 1522 12

Two sesquiterpenoids, mansonone E (ME) and mansonone F (MF) were first isolated from the dried root bark of Ulmus pumila (shironire in Japanese), and their antiproliferative activities on human tumor cells were evaluated in vitro. ME had more potent cytotoxic effects on four tumor cell lines, human cervical cancer HeLa, human malignant melanoma A375-S2, human breast cancer MCF-7, and human histiocytic lymphoma U937, than those of MF. The results showed that ME induced oligonucleosomal fragmentation of DNA in HeLa cells and activated caspase-3, followed by the degradation of the inhibitor of caspase-activated DNase, decreased the expression of anti-apoptotic mitochondrial proteins Bcl-2 and Bcl-(XL), and increased that of proapoptotic Bax.
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PMID:Cytotoxic effects of mansonone E and F isolated from Ulmus pumila. 1525 34

Silymarin, a plant flavonoid from milk thistle (Silybum marianum [L.] GAERTNER) was first evaluated for its protective effect against UV irradiation-induced apoptosis in human malignant melanoma cells (A375-S2 cells). Treatment with silymarin 500 microM for 12 h significantly inhibited UV irradiation (2.4 J/cm(2), 5 min)-induced apoptosis in A375-S2 cells. Activities of caspase-9 and caspase-3 in UV-irradiated A375-S2 cells were effectively reduced by silymarin in a dose-dependent manner, while the expression of the inhibitor of caspase-activated DNase (ICAD), protein expression of Bcl-x(L) (Bcl-2 family member), and the activity of extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) were increased simultaneously. It is suggested that the inhibitory effect of silymarin is exerted by blockage of the caspase/ICAD pathway after increased expression of Bcl-x(L) protein and activation of the ERK/MAPK pathway.
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PMID:Silymarin prevents UV irradiation-induced A375-S2 cell apoptosis. 1525 35

Human melanoma is the most aggressive form of human skin cancer, and is notoriously resistant to any current modalities of cancer therapy. Here we show that lonidamine (LND), a mitochondria-targeting non-conventional chemotherapeutic agent, markedly induced apoptosis in radioresistant human malignant melanoma C32TG cells. Either LND of up to 250 microM or X-ray irradiation of up to 15 Gy alone induced only a few percent of the apoptosis when administrated separately. When the two agents were combined, the apoptosis prominently increased to 29.3 %. The apoptotic cells thus induced by the combination treatment showed chromatin condensation, a depletion in DeltaPsim, and an activation of caspase-3. A pan-caspase inhibitor Z-Asp-CH(2)DCB completely suppressed the apoptosis. The combination treatment also decreased Bcl-2 and Bad-phosphorylation. These results indicate that the mitochondria pathway of apoptosis would devise a new radiotherapy strategy for treating malignant melanoma.
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PMID:Apoptosis of human melanoma cells by a combination of lonidamine and radiation. 1530 59

Norcantharidin (NCTD) is the demethylated form of cantharidin, which is the active substance of mylabris. To examine the pathway of NCTD-induced A375-S2 cell death, 3-(4, 5-dimethylthiazol-2-yl)-2, 5-dipheyltetrazolium bromide (MTT) assay, photomicroscopical observation, DNA agarose gel electrophoresis, caspase activity assay and Western blot analysis were carried out. A375-S2 cells treated with NCTD exhibited several typical characteristics of apoptosis. The inhibitory effect of NCTD on human melanoma, A375-S2 cells, was partially reversed by the inhibitors of pan-caspase, caspase-3 and caspase-9. The activities of caspase-3 and -9 were significantly increased after treatment with NCTD at different time. The expression of inhibitor of caspase-activated DNase was decreased in a time-dependent manner, simultaneously, the ratio of Bcl-2/Bax or Bcl-xL/Bax was decreased and the expression ratio of proteins could be reversed by caspase-3 inhibitor. The expression of cytochrome c in cytosol was increased after NCTD treatment and caspase- 3 inhibitor had no significant effect on the up-regulation of cytochrom c. These results suggest that NCTD induced A375-S2 cell apoptosis and the activation of caspase and mitochondrial pathway were involved in the process of NCTD-induced A375-S2 cell apoptosis.
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PMID:Norcantharidin induces human melanoma A375-S2 cell apoptosis through mitochondrial and caspase pathways. 1530 48

Ketoconazole (KTZ) has been used as a second-line agent in hormone-refractory cancer therapy. Since transition metal complexes including those of Ru(III), show important anticancer activity with limited toxicity, we investigated the potential antitumor efficacy of Ru(II) complexed to KTZ or clotrimazole (CTZ) compared to Ru(II) alone or uncomplexed azoles. RuCl2(KTZ)2 exerted greater apoptosis- associated caspase-3 activation than RuCl2(CTZ)2, KTZ, CTZ or RuCl2(MeCN)4 against several human tumor cell monolayers. PARP cleavage and a decrease in S+G2 cells were evident after RuCl2(KTZ)2 treatment in genetically matched C8161 melanoma monolayers with unequal p53 functional status. Release of mitochondrial cytochrome c and Mn-SOD suggest mitochondria as a target of RuCl2(KTZ)2. Treatment of WM164 melanoma monolayers with 25 microM of cisplatin or RuCl2(KTZ)2 showed that the latter is more effective than cisplatin at inducing PARP fragmentation and proapoptotic Bak expression. Such results suggest that these Ru(II) and Pt(II) metal complexes are unequally effective and act through alternative signaling pathways. In studies with multicellular spheroids, which frequently are more resistant to cytotoxic anticancer drugs than monolayers, those from wt p53 C8161 melanoma underwent PARP fragmentation in response to RuCl2(KTZ)2. In contrast, spheroids of mut p53 A431 carcinoma overexpressing EGF receptor were resistant to either RuCl2(KTZ)2 or anti-EGF receptor C225 MAb. However, joint treatment with both agents restored growth arrest and apoptosis in these spheroids. In contrast to the antitumor action of cisplatin, which is known to be hampered by p53 dysfunction, we show that RuCl2(KTZ)2 is active irrespective of p53 functional status against several adherent tumor cells and synergizes with anti-EGF receptor C225 MAb to kill tumor spheroids resistant to either agent.
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PMID:Tumor apoptosis induced by ruthenium(II)-ketoconazole is enhanced in nonsusceptible carcinoma by monoclonal antibody to EGF receptor. 1538 61

The role of intracellular free zinc and its chelation by TPEN (N,N,N',N'- tetrakis(2-pyridylmethyl)ethylene-diamine) was studied in Bowes human melanoma cells. The content of free Zn pools was determined by fluorescent probe Zinquin. Depletion of zinc triggered apoptosis confirmed by cell blebbing, changes in mitochondrial transmembrane potential and GSH levels, caspase-3 activation and nuclear fragmentation. Apoptosis was only partially prevented by cyclosporin A or N-acetylcystein, suggesting various independent but likely interrelated mechanisms participating in this process.
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PMID:Depletion of endogenous zinc stores induces oxidative stress and cell death in human melanoma cells. 1544 56

Over the coming years, skin cancer could become a significant public health problem. Previous results indicate that ursolic acid (UA), a pentacyclic triterpene acid, has pleiotropic biologic activities such as antiinflammatory and antiproliferative activities on cancer cells. As UA represents a promising chemical entity for the protection of human skin, in agreement with tests done by the cosmetic industry, we investigated its effects on the M4Beu human melanoma cell line. In this report, we demonstrated for the first time that UA had a significant antiproliferative effect on M4Beu, associated with the induction of an apoptotic process, characterized by caspase-3 activation, the downstream central effector of apoptosis. We demonstrated that UA-induced apoptosis was dependent on the mitochondrial intrinsic pathway, as shown by transmembrane potential collapse (DeltaPsim) and by alteration of the Bax-Bcl-2 balance, with a concomitant increase in Bax expression and decrease in Bcl-2 expression. We also showed that UA-induced DeltaPsim was associated with apoptosis-inducing factor leakage from mitochondria. Taken together, our results suggest that UA-induced apoptosis on M4Beu cells is accomplished via triggering of mitochondrial pathway. In conclusion, UA could be an encouraging compound in the treatment or prevention of skin cancer and may represent a new promising anticancer agent in the treatment of melanoma.
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PMID:Ursolic acid induces apoptosis through mitochondrial intrinsic pathway and caspase-3 activation in M4Beu melanoma cells. 1552 87


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