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)

Resistance of malignant melanoma cells to Fas-mediated apoptosis is among the mechanisms by which they escape immune surveillance. However, the mechanisms contributing to their resistance are not completely understood, and it is still unclear whether antiapoptotic Bcl-2-related family proteins play a role in this resistance. In this study, we report that treatment of Fas-resistant melanoma cell lines with cycloheximide, a general inhibitor of de novo protein synthesis, sensitizes them to anti-Fas monoclonal antibody (mAb)-induced apoptosis. The cycloheximide-induced sensitization to Fas-induced apoptosis is associated with a rapid down-regulation of Mcl-1 protein levels, but not that of Bcl-2 or Bcl-xL. Targeting Mcl-1 in these melanoma cell lines with specific small interfering RNA was sufficient to sensitize them to both anti-Fas mAb-induced apoptosis and activation of caspase-9. Furthermore, ectopic expression of Mcl-1 in a Fas-sensitive melanoma cell line rescues the cells from Fas-mediated apoptosis. Our results further show that the expression of Mcl-1 in melanoma cells is regulated by the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) and not by phosphatidylinositol 3-kinase/AKT signaling pathway. Inhibition of ERK signaling with the mitogen-activated protein/ERK kinase-1 inhibitor or by expressing a dominant negative form of mitogen-activated protein/ERK kinase-1 also sensitizes resistant melanoma cells to anti-Fas mAb-induced apoptosis. Thus, our study identifies mitogen-activated protein kinase/ERK/Mcl-1 as an important survival signaling pathway in the resistance of melanoma cells to Fas-mediated apoptosis and suggests that its targeting may contribute to the elimination of melanoma tumors by the immune system.
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PMID:Down-regulation of mcl-1 by small interfering RNA sensitizes resistant melanoma cells to fas-mediated apoptosis. 1823 61

Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) is a novel cytokine displaying selective apoptosis-inducing activity in transformed cells without harming normal cells. The present studies focused on defining the mechanism(s) by which a GST-MDA-7 fusion protein inhibits cell survival of primary human glioma cells in vitro. GST-MDA-7 killed glioma cells with diverse genetic characteristics that correlated with inactivation of ERK1/2 and activation of JNK1-3. Activation of JNK1-3 was dependent on protein kinase R-like endoplasmic reticulum kinase (PERK), and GST-MDA-7 lethality was suppressed in PERK-/- cells. JNK1-3 signaling activated BAX, whereas inhibition of JNK1-3, deletion of BAX, or expression of dominant-negative caspase-9 suppressed lethality. GST-MDA-7 also promoted a PERK-, JNK-, and cathepsin B-dependent cleavage of BID; loss of BID function promoted survival. GST-MDA-7 suppressed BAD and BIM phosphorylation and heat shock protein 70 (HSP70) expression. GST-MDA-7 caused PERK-dependent vacuolization of LC3-expressing endosomes whose formation was suppressed by incubation with 3-methyladenine, expression of HSP70 or BiP/GRP78, or knockdown of ATG5 or Beclin-1 expression but not by inhibition of the JNK1-3 pathway. Knockdown of ATG5 or Beclin-1 expression or overexpression of HSP70 reduced GST-MDA-7 lethality. Our data show that GST-MDA-7 induces an endoplasmic reticulum stress response that is causal in the activation of multiple proapoptotic pathways, which converge on the mitochondrion and highlight the complexity of signaling pathways altered by mda-7/IL-24 in glioma cells that ultimately culminate in decreased tumor cell survival.
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PMID:Caspase-, cathepsin-, and PERK-dependent regulation of MDA-7/IL-24-induced cell killing in primary human glioma cells. 1828 15

Hydroquinone, an activator of caspase-9 activity via reactive oxygen species, and farnesol, a post-translational down-regulator of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity suppress the growth of murine 816 melanoma cells. Our previous studies have shown that farnesyl-O-acetylhydroquinone has a markedly greater growth-suppressive activity than that predicted by the responses to the parent compounds. Perillyl alcohol, a modulator of small G-protein activity, and biphenyl compounds, activators of Fas-mediated death pathways, suppress B16 growth. A similar synergistic increase in the potency of each compound when ether-linked to acetylhydroquinone is reported. Perillyl-O-acetylhydroquinone, biphenylethyl-O-acetylhydroquinone and biphenylpropyl-O-acetylhydroquinone had dose-dependent impacts on the proliferation of B16 cells with 50% inhibitory concentration (IC50) values of 8.0, 4.2 and 1.4 micromol/L, respectively. The growth-suppression effected by biphenylpropyl-O-acetylhydroquinone was accompanied by a dose-dependent arrest at the G1/S interface of the cell cycle, an impact greater than that previously reported for farnesyl-O-acetylhydroquinone (IC50 = 2.5 micromol/L). These new hydroquinone derivatives may have potential in cancer chemoprevention and/or therapy.
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PMID:Biphenylalkylacetylhydroquinone ethers suppress the proliferation of murine B16 melanoma cells. 1850 48

The unresponsiveness of metastatic melanoma to conventional chemotherapeutic and biological agents is largely due to the development of resistance to apoptosis. Pyrimethamine belongs to the group of antifolate drugs, and in addition to antiprotozoan effects, it exerts a strong proapoptotic activity, which we recently characterized in human T lymphocytes. However, no data regarding pyrimethamine anticancer activity are available thus far. To this end, we examined the in vitro effects of pyrimethamine on apoptosis, cell cycle distribution, and cell proliferation of human metastatic melanoma cell lines. The in vivo antitumor potential of pyrimethamine was evaluated in a severe combined immunodeficiency (SCID) mouse xenotransplantation model. Our data indicate that pyrimethamine, when used at a clinically relevant concentration, induced apoptosis in metastatic melanoma cells via the activation of the cathepsin B and the caspase cascade (i.e., caspase-8 and caspase-9) and subsequent mitochondrial depolarization. This occurred independently from CD95/Fas engagement. Moreover, pyrimethamine induced a marked inhibition of cell growth and an S-phase cell cycle arrest. Results obtained in SCID mice, injected s.c. with metastatic melanoma cells and treated with pyrimethamine, indicated a significant inhibitory effect on tumor growth. In conclusion, our results suggest that pyrimethamine-induced apoptosis may be considered as a multifaceted process, in which different inducers or regulators of apoptosis are simultaneously implicated, thus permitting death defects of melanoma cells to be bypassed or overcome. On these bases, we hypothesize that pyrimethamine could represent an interesting candidate for the treatment of metastatic melanoma.
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PMID:Pyrimethamine induces apoptosis of melanoma cells via a caspase and cathepsin double-edged mechanism. 1859 30

Methylene blue (MB) is a widely studied agent currently under investigation for its properties relating to photodynamic therapy (PDT). Recent studies have demonstrated that MB exhibits profound phototoxicity affecting a variety of tumor cell lines. However, the mechanistic explanation for methylene-blue-mediated photodynamic therapy (MB-PDT) in the context of melanoma therapy is still obscure. In the present study, B16F1 melanoma cells were treated by MB-PDT under different conditions, and thereafter subjected to cell viability detection assays. MB-PDT could induce intense apoptotic cell death through a series of steps beginning with the photochemical generation of reactive oxygen species that activate the caspase-9/caspase-3 apoptosis pathway. Blocking activation of caspase-3 and induction of oxidative stress by caspase inhibitor and by glutathione, respectively, markedly reduced apoptotic cell death in vitro. Importantly, proteomics study defining altered protein expression in treated cells suggests the involvement of several mitochondrial proteins playing important roles in electron transfer chain, implying mitochondrial dysfunction during the treatment. Furthermore, a transplantable mouse melanoma model was utilized to estimate the effectiveness of MB-PDT in vivo. The treated mice displayed decreased tumor size and prolonged survival days, which was associated with enhanced apoptotic cell death. These results, offering solid evidence of the induction of mitochondria-related apoptosis in tumor cells, reveal new aspects of MB-PDT having potential to be a palliative treatment of melanoma.
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PMID:Apoptosis induced by methylene-blue-mediated photodynamic therapy in melanomas and the involvement of mitochondrial dysfunction revealed by proteomics. 1901 62

Concanavalin A (Con A), a mannose/glucose-binding legume lectin, can induce cancer cell death through a mitochondria-mediated autophagic pathway; however, the precise mechanisms by which it mediates cell death are still only rudimentarily understood. In the present study, Con A possesses a remarkable antiproliferative effect on human melanoma A375 cells. Also, there is a link between the antiproliferative activity of Con A and its sugar-binding activity. Subsequently, Con A can induce human melanoma A375 cell apoptosis in a caspase-dependent manner. In addition, the treatment with Con A can cause mitochondrial transmembrane potential collapse, leading to cytochrome c release and caspase-9-caspase-3 activation. In conclusion, we demonstrate that there may be a close correlation between the antiproliferative activity of Con A and its sugar-binding activity. More importantly, we report for the first time that Con A can induce human melanoma A375 cell death in a caspase-dependent manner as well as via a mitochondrial apoptotic pathway.
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PMID:Induction of apoptosis by Concanavalin A and its molecular mechanisms in cancer cells. 1920 54

To investigate the possibility that tumor cells undergoing linearly patterned programmed cell necrosis (LPPCN) establish a spatial foundation for vasculogenic mimicry (VM) and to reveal that hypoxia influences LPPCN formation as well as Endo G and DNase 1 expression, 78 C57 mice were divided evenly into two groups and engrafted with B16 melanoma. Starting 9 days after inoculation, subgroups of mice were killed every 2 days. LPPCN and the tumor blood supply vessel types were counted and Endo G and DNase 1 mRNA expression were measured. Additionally, 124 cases of human melanoma samples were collected to assess the clinical significance of LPPCN and VM. The data revealed that regions of LPPCN were positive for caspase-3, caspase-9 and Bax, and negative for TUNEL staining. Electron microscopy images indicated that these cells took on the morphologic changes of necrosis. There was more DNase I mRNA expression in the hypoxic group than in the control group (P<0.05) in vitro, and the expression of Endo G mRNA in the hypoxic groups was significantly higher than that in the control groups both in vitro and in vivo (P<0.05). VM and LPPCN cell numbers in the ischemic group were higher than those in the control group in the early stage of tumor growth. Finally, the survival time for patients whose samples showed LPPCN and VM was significantly shorter than that of patients with one or neither of those factors. We speculated that under hypoxic conditions, some melanoma cells might undergo LPPCN, thus providing a spatial foundation for VM channel formation.
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PMID:Hypoxia influences linearly patterned programmed cell necrosis and tumor blood supply patterns formation in melanoma. 1929 5

Cytotoxicity and apoptosis induced by etoposide were studied during 72 hr in human melanoma cells. Etoposide initiated DNA-damage signaling via ATM kinase and activated p53 pathway and caspase-2. In response to treatment with etoposide, mitochondria of melanoma cells first increased their abundance and activity, and at later treatment intervals their dynamic behavior and functions became suppressed. Observed mitochondrial perturbation was not preceded by membrane potential loss but cytochrome c release was observed together with a rise in caspase-9 and caspase-3 activities. The pharmacological inhibition of relevant induced targets proved the importance of ATM and caspase-2 in etoposide-mediated cytotoxicity and apoptosis.
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PMID:Cytotoxicity and mitochondrial apoptosis induced by etoposide in melanoma cells. 1948 5

The antineoplastic properties of gallium are well documented. Owing to their robust accumulation of gallium, melanoma cells should be amenable to gallium-based anticancer drugs. With the aim of improving the disappointingly low activity of inorganic gallium salts, we have developed the orally bioavailable gallium complex KP46 [tris(8-quinolinolato)gallium(III)] that had already been successfully studied in a phase I clinical trial. To assess its therapeutic potential in malignant melanoma, its antiproliferative effects were investigated in series of human cell lines and primary explanted melanoma samples by means of the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and the Human Tumor Cloning Assay, respectively. When compared with other cell lines, the majority of melanoma cells rank among the KP46-sensitive cell lines (50% inhibitory concentration values: 0.8-3.7 micromol/l). Clinically achievable concentrations of KP46 proved to be highly effective in melanoma cells from primary explants of cutaneous and lymph node metastases. Colony growth was inhibited in 10 of 10 specimens by 5 micromol/l KP46 (corresponding to the steady-state plasma concentration measured earlier in a study patient) and in four of 10 specimens by 0.5 micromol/l KP46. In-vitro potency of KP46 is higher than that of dacarbazine or fotemustine and comparable with that of cisplatin. The effects induced by KP46 in melanoma cell lines involve cell-cycle perturbations (S-phase arrest) and apoptosis (activation of caspase-9, PARP [poly(ADP-ribose) polymerase] cleavage, formation of apoptotic bodies). No effects on DNA secondary structure could be observed in an electrophoretic mobility shift assay using double-stranded plasmid DNA. Thus, further studies on the therapeutic applicability of KP46 in malignant melanoma are warranted.
Melanoma Res 2009 Oct
PMID:The gallium complex KP46 exerts strong activity against primary explanted melanoma cells and induces apoptosis in melanoma cell lines. 1958 67

This study was conducted to examine the polyamine transporter (PAT) recognization and antitumor effects of anthracenymethyl homospermidine (ANTMHspd) and its apoptotic mechanism in B16 melanoma cells. ANTMHspd promoted a dose-dependent apoptosis in B16 melanoma cells and the apoptosis was associated with the excellent PAT recognization, externalization of cell membrane phosphatidylserine and the disruption of mitochondria, these processes were correlated with up-regulation of polyamine oxidase, an increase in intracellular reactive oxygen species (ROS) production and oxidative stress. In addition, reduction of MMP, release of cytochrome c, up-regulation of Bax protein expression, down-regulation of Bcl-2 protein expression, and activation of caspase-3, caspase-9 were also observed in B16 cells after treatment with ANTMHspd. Furthermore, N-acetylcysteine obviously antagonized ANTMHspd-induced apoptosis. Importantly, ANTMHspd was found to be better tolerated and revealed potent antitumor effect on inhibiting tumor growth in situ and suppressing pulmonary metastasis in xenograft mice model. These data demonstrate that ANTMHspd is an excellent PAT recognization and potent antitumor agent.
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PMID:Polyamine transporter recognization and antitumor effects of anthracenymethyl homospermidine. 1959 33


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