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)

Pseudolaric acid B is a major compound found in the bark of Pseudolarix kaempferi Gordon. In our study, pseudolaric acid B inhibited growth of human melanoma cells, A375-S2 in a time- and dose-dependent manner. A375-S2 cells treated with pseudolaric acid B showed typical characteristics of apoptosis including morphologic changes, DNA fragmentation, sub-diploid peak in flow cytometry, cleavage of poly-ADP ribose polymerase (PARP) and degradation of inhibitor of caspase-activated DNase (ICAD). P53 protein expression was upregulated while cells were arrested at the G2/M phase of the cell cycle. There was a decrease in the expression of anti-apoptotic Bcl-2 and Bcl-xL proteins, whereas pro-apoptotic Bax was increased. The two classical caspase substrates, PARP and ICAD, were both decreased in a time-dependent manner, indicating the activation of downstream caspases.
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PMID:Pseudolaric acid B induces apoptosis through p53 and Bax/Bcl-2 pathways in human melanoma A375-S2 cells. 1574 11

The family of the poly(adenosine diphosphate-ribose) polymerase (PARP) proteins is directly involved in genomic stability, DNA repair, and apoptosis by DNA damage. In this study, we evaluated the role of PARP-1 in melanoma and its prognostic importance. We studied by immunohistochemistry and Western blot analysis PARP-1 expression in a selected series of 80 primary melanoma of the head and neck region. The results were correlated with tumor thickness and patient's outcome. A follow-up of at least 3 years was available. Fifteen cases of benign melanocytic nevi were used as controls. Normal melanocytes showed only scattered, focal nuclear positivity and were considered as negative for PARP-1 expression by immunohistochemistry (score, 0). Thirty cases of melanoma (37.5%) showed nuclear expression of PARP-1 in both radial and vertical growth phases. Western blot analysis showed the presence of a high signal for full-length PARP-1 only in the cases with high immunohistochemical (nuclear) expression of protein (score, ++/+++) in both radial and vertical growth phase. A significant correlation was present between PARP-1 expression in vertical growth phase and the thickness of tumor lesion (P = .014); all but one tumor measuring less than 0.75 mm showed no or low PARP-1 expression. No correlation was found between PARP-1 expression in radial growth phase and tumor thickness (P = .38, data not shown). These data suggest that PARP-1 overexpression is a potential novel molecular marker of aggressive cutaneous malignant melanoma and a direct correlation between PARP-1-mediated inhibition of the apoptosis and biologic behavior of cutaneous malignant melanoma.
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PMID:Poly(adenosine diphosphate-ribose) polymerase 1 expression in malignant melanomas from photoexposed areas of the head and neck region. 1608 40

Matrix metalloproteinases, like MMP-2 and MMP-9 gelatinases, show multiple functions as extracellular/cell-surface enzymes, and are broadly recognised for their matrix-degrading ability and involvement in cell motility. Given that adherent cells have reduced attachment during migration and also detach from their substratum during apoptosis, we now investigated whether extracellular matrix-bound gelatinases and intracellular MMP-2 and MMP-9 are modified with progression of death-inducing stimuli. This report shows that melanoma cells undergoing death in response to 2-acetyl furanonaphtoquinone (FNQ) as evidenced by greater Annexin V binding, increased cytosolic expression of pro-MMP-2 and intracellular activation of particulate MMP-9. These changes were associated with early activation of a substrate-attached 40 kDa gelatinase reciprocal with changes in extracellular matrix-bound activated MMP-2. A subsequent activation of secreted MMP-9 and induction of apoptosis-associated fragmentation of poly ADP-Ribose polymerase (PARP) correlated with cell detachment. Our data suggests that intracellularly activated gelatinases may cleave survival-associated substrates other than gelatin that share the Gly-Leu/Iso-Pro like collagen-binding acetylcholinesterase, thereby linking them to apoptosis associated with cell detachment.
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PMID:Invasion-associated MMP-2 and MMP-9 are up-regulated intracellularly in concert with apoptosis linked to melanoma cell detachment. 1617 Jun 65

Disruption of poly(ADP-ribose) polymerase (PARP) pathways by inhibitors of PARP catalytic domain has been shown to increase the anti-tumour activity of temozolomide (TMZ). Since PARP is inhibited by poly(ADP)ribosylation, herein we tested whether inhibition of poly(ADP-ribose) glycohydrolase (PARG) might enhance TMZ efficacy. The PARG inhibitor N-bis-(3-phenyl-propyl)9-oxo-fluorene-2,7-diamide (GPI 16552) was administered in combination with TMZ to mice injected subcutaneously or intracranially with B16 melanoma cells. The ability of treatment to reduce melanoma metastatic spreading and invasion of the extracellular matrix was also tested. The results indicated that combined treatment with GPI 16552 and TMZ significantly reduced melanoma growth, increased life-span of mice bearing tumour at the CNS site, and decreased the ability of melanoma cells to form lung metastases and to invade the extracellular matrix. In conclusion, PARG inhibition represents an alternative strategy to enhance TMZ efficacy against melanoma in peripheral as well as at CNS site.
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PMID:Poly(ADP-ribose) glycohydrolase inhibitor as chemosensitiser of malignant melanoma for temozolomide. 1628 62

G3139, an 18-mer phosphorothioate antisense oligonucleotide targeted to the initiation codon region of the Bcl-2 mRNA, can induce caspase-dependent apoptosis via the intrinsic mitochondrial pathway in 518A2 and other melanoma cells. G3139-mediated apoptosis appears to be independent of its ability to down-regulate the expression of Bcl-2 protein, because the release of mitochondrial cytochrome c precedes in time the down-regulation of Bcl-2 protein expression. In this study, we demonstrate the ability of G3139 and other phosphorothioate oligonucleotides to bind directly to mitochondria isolated from 518A2 cells. Furthermore, we show that this interaction leads to the release of cytochrome c in the absence of a mitochondrial membrane permeability transition. Our data further demonstrate that there is an interaction between G3139 and VDAC, a protein that can facilitate the physiologic exchange of ATP and ADP across the outer mitochondrial membrane. Evidence from the electrophysiologic evaluation of VDAC channels reconstituted into phospholipid membranes demonstrates that G3139 is capable of producing greatly diminished channel conductance, indicating a closed state of the VDAC. This effect is oligomer length-dependent, and the ability of phosphorothioate homopolymers of thymidine of variable lengths to cause the release of cytochrome c from isolated mitochondria of 518A2 melanoma cells can be correlated with their ability to interact with VDAC. Because it has been suggested that the closure of VDAC leads to the opening of another outer mitochondrial membrane channel through which cytochrome c can transit, thus initiating apoptosis, it appears that VDAC may be an important pharmacologic target of G3139.
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PMID:A pharmacologic target of G3139 in melanoma cells may be the mitochondrial VDAC. 1664 53

To study the molecular mechanism of the disintegrin eristostatin, cellular functional studies were performed using ten recombinant alanine mutants. ADP-induced platelet aggregation revealed critical contributions of seven residues within the 'RGD loop' (R24, R27, G28, N31) and C-terminus (W47, N48, G49) of this disintegrin. Using an in vitro scratch wound healing assay, four human melanoma cell lines yielded similar results when exposed to wildtype eristostatin. All eristostatin-treated cells healed less of the wounded area than control conditions. This phenomenon was reproduced when using fibronectin as the matrix. C8161 cells showed significant delay in wound closure with the N-terminal mutant P4A but not with R24A or G28A. Evidence from our laboratory and others suggests neither alpha IIb, alpha 4 nor alpha 5 integrins are directly involved in eristostatin's interactions. Eristostatin did not affect the number of melanoma cells in culture after 24 h or the development of apoptosis. However, phosphorylation studies performed after these melanoma cells were exposed to eristostatin revealed changes in several tyrosine phosphorylated molecules.
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PMID:Scratching below the surface: wound healing and alanine mutagenesis provide unique insights into interactions between eristostatin, platelets and melanoma cells. 1670 21

The Arg-Gly-Asp (RGD) tripeptide unit is a cell-cell and cell-extracellular matrix recognition sequence of some integrins that is found within several extracellular matrix glycoproteins and dendroaspin, a disintegrin-like venom protein isolated from the snake venom of the Dendroaspis jamsonii. In the present study, the RGD motif in dendroaspin was substituted by Lys-Gly-Asp (KGD), His-Gly-Asp (HGD), Gln-Gly-Asp (QGD) and Ala-Gly-Asp (AGD) denoted as KGD-den, HGD-den, QGD-den and AGD-den, respectively. Each of the mutants exhibited activity as inhibitor of ADP-induced platelet aggregation with IC50 values of 0.26, 2.5, 6, and 17 microM for KGD-den, HGD-den, QGD-den, and AGD-den, respectively, as compared with RGD-den (IC50 = 0.18 microM). Interestingly, HGD-den was approx. two-fold more potent and a more selective inhibitor than either the KGD-den or QGD-den counterpart at blocking A375-SM human melanoma cell adhesion to fibrinogen (beta3-mediated). KGD-den, HGD-den, and QGD-den were preferentially antagonists of A375-SM human melanoma cell adhesion to fibrinogen rather than to fibronectin (alpha5beta1-, beta3-mediated). Both HGD-den and KGD-den were equipotent as inhibitors of human erythroleukaemia (HEL) cell adhesion to fibrinogen (IC50 = 0.15 microM) and also preferential inhibitors of HEL cell adhesion to fibrinogen (beta3 and beta1-mediated) rather than to fibronectin. These findings show that the presence of the arginine within the RGD motif of dendroaspin is not obligatory and substitution of this residue can modulate inhibitory potency and integrin binding selectivity.
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PMID:The effect of the single substitution of arginine within the RGD tripeptide motif of a modified neurotoxin dendroaspin on its activity of platelet aggregation and cell adhesion. 1679 16

The molecular chaperone heat shock protein 90 (HSP90) has emerged as an exciting molecular target for cancer therapy. It operates as part of a multichaperone complex and is essential for the conformation, stability, and function of several key oncogenic client proteins such as mutant p53, ERBB2, B-RAF, C-RAF, and CDK4. The HSP90-based chaperone machine is driven by the hydrolysis of ATP and ADP/ATP nucleotide exchange. Many of the inhibitors of HSP90 interrupt the intrinsic ATPase activity, causing degradation of the client proteins via the ubiquitin-proteasome pathway. The first-in-class HSP90 inhibitor in clinical trials is the geldanamycin analog, 17-allylamino, 17-demethoxygeldanamycin (17-AAG). The results that have emerged from these trials have been encouraging, with stable disease observed in two melanoma patients. Pharmacodynamic endpoints, such as induction of HSP70 and downregulation of C-RAF and CDK4 in peripheral blood mononuclear cells and tumor biopsies from treated patients, provided evidence of HSP90 inhibition at well-tolerated doses. The toxicity of 17-AAG has been mild. Several preclinical studies have shown that 17-AAG may enhance the efficacy of a variety of chemotherapeutic agents. Phase II clinical trials in various cancers have been initiated as well as Phase I trials of combined therapy with 17-AAG. However, there are several limitations with 17-AAG such as solubility, stability, and hepatotoxicity. Thus, it is not surprising that new HSP90 agents are under development against this novel target for cancer therapy and several show promise.
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PMID:Inhibitors of the HSP90 molecular chaperone: current status. 1686 Jun 62

The PTEN/Akt signal pathway plays an important role in tumorigenesis. Mutations or deletions of PTEN have been observed in up to 60% of melanoma cell lines, resulting in PI3K/Akt activation. The Forkhead family of transcription factors induce apoptosis in their unphosphorylated forms and were recently reported to be a substrate of Akt kinase. In the present study, an adenovirus expressing a triple mutant (TM) of FKHRL1, which cannot be phosphorylated by Akt, was assessed for its ability to induce apoptosis in melanoma cells. Marked overexpression of FKHRL1/TM was evident in the SK-MEL-2 cell line 24 hours after infection with Ad-FKHRL1/TM by Western blot analysis. The expression of FKHRL1/ TM was moderately delayed in SK-MEL-28 cells. Overexpression of FKHRL1/TM can efficiently inhibit melanoma cell growth and result in rapid loss of cell viability. Cell cycle analysis showed overexpression of FKHRL1/TM in both melanoma cell lines resulted in development of a Sub-G1 population, indicating apoptosis by Ad-FKHRL1/TM infection. Apoptosis was confirmed by morphologic inspection, poly-ADP-ribosepolymerase (PARP) cleavage assay, and annexin V-PE analysis. After Ad-FKHRL1/TM infection, the expression of Bax and Bak did not differ markedly, whereas Mcl-1 and Bcl-x(L) levels decreased markedly. Involvement of caspase 3 and 6 in FKHRL1/TM-mediated apoptosis was demonstrated by cleavage of caspase 3/CPP32 and PARP as well as fragmentation of the caspase 6 substrate lamin B in SK-MEL-2 cells as early as 24 hours after Ad-FKHRL1/ TM infection, but those events were delayed 72 hours in SK-MEL-28. In addition, we found that p27(kip1) was cleaved in SK-MEL-2 cells at 24 hours after treatment with Ad-FKHRL1/TM. This cleavage was observed in SK-MEL-28 cells until 72 hours after infection with Ad-FKHRL1/TM. Our data suggest that adenovirus expressing a FKHRL1 triple mutant could be a useful vector for gene therapy of cancers resistant to chemotherapy and radiotherapy induced by hyperactivity of PI3K/Akt.
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PMID:Adenovirus-mediated gene transfer of FKHRL1 triple mutant efficiently induces apoptosis in melanoma cells. 1686 5

G3139, an antisense Bcl-2 phosphorothioate oligodeoxyribonucleotide, induces apoptosis in melanoma and other cancer cells. This apoptosis happens before and in the absence of the downregulation of Bcl-2 and thus seems to be Bcl-2-independent. Binding of G3139 to mitochondria and its ability to close voltage-dependent anion-selective channel (VDAC) have led to the hypothesis that G3139 acts, in part, by interacting with VDAC channels in the mitochondrial outer membrane (21). In this study, we demonstrate that G3139 is able to reduce the mitochondrial outer membrane permeability to ADP by a factor of 6 or 7 with a K(i) between 0.2 and 0.5 microM. Because VDAC is responsible for this permeability, this result strengthens the aforesaid hypothesis. Other mitochondrial respiration components are not affected by [G3139] up to 1 microM. Higher levels begin to inhibit respiration rates, decrease light scattering and increase uncoupled respiration. These results agree with accumulating evidence that VDAC closure favors cytochrome c release. The speed of this effect (within 10 min) places it early in the apoptotic cascade with cytochrome c release occurring at later times. Other phosphorothioate oligonucleotides are also able to induce VDAC closure, and there is some length dependence. The phosphorothioate linkages are required to induce the reduction of outer membrane permeability. At levels below 1 microM, phosphorothioate oligonucleotides are the first specific tools to restrict mitochondrial outer membrane permeability.
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PMID:Phosphorothioate oligonucleotides reduce mitochondrial outer membrane permeability to ADP. 1713 95


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