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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

UV solar radiation is the major environmental risk factor for malignant melanoma. A great effort is currently posed on the search of new compounds able to prevent or reduce UV-mediated cell damage. Ferulic acid is a natural compound recently included in the formulation of solar protecting dermatological products. The purpose of the present work was to assess whether its ethyl ester derivative, FAEE, could protect skin melanocytes from UV-induced oxidative stress and cell damage. Experiments on human melanocytes irradiated with UVB showed that FAEE treatment reduced the generation of ROS, with a net decrease of protein oxidation. FAEE treatment was accompanied by an induction of HSP70 and heme oxygenase, by a marked suppression of PARP activation and a significant suppression of apoptosis. Moreover FAEE prevented iNOS induction, thus suppressing the secondary generation of NO-derived oxidizing agents. FAEE may represent a potentially effective pharmacological approach to reduce UV radiation-induced skin damage.
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PMID:Protective effect of ferulic acid ethyl ester against oxidative stress mediated by UVB irradiation in human epidermal melanocytes. 1927 91

Recently, we reported that UVB-activated indole-3-acetic acid (IAA) induces the apoptosis of G361 human melanoma cells. In the present study, we used IAA and visible light combinations to treat B16F10 melanoma-implanted nude mice using an experimental intense pulsed light (IPL) therapy model. We first investigated whether activated IAA by horseradish peroxidase (HRP) or UVB causes apoptosis of B16F10 melanoma cells. IAA/HRP or IAA/UVB combination lead to apoptosis of B16F10 cells, as reported in other cell lines. Interestingly, IAA alone was not cytotoxic. These findings suggested the potential use of IAA in the treatment of melanoma. For the future clinical use, we also tested whether visible light has the same effects like UVB and found that visible light also activates IAA to produce free radicals and that IAA/visible light decreased cell viability significantly. Based on these results, IAA/IPL combination was tried whether it can induce apoptosis in vivo status. TUNEL staining showed that IAA/IPL treatment induced apoptosis of tumor cells. In addition, the expressions of p53, Fas, and PARP were upregulated in the IAA/IPL-treated group than in untreated control, demonstrating that IAA/IPL treatment caused apoptosis in melanoma-implanted nude mice. In conclusion, we showed that IAA/IPL induces melanoma regression in B16F10 melanoma-implanted nude mice. These results suggest the potential use of IAA/IPL in the treatment of malignant melanoma.
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PMID:Tumor apoptosis by indole-3-acetic acid/light in B16F10 melanoma-implanted nude mice. 1930 Oct 20

Malignant melanomas are generally drug resistant and have a very poor prognosis. We have studied the effects of a chemical conjugate of pseudomonas exotoxin A (PE) and the antibody 9.2.27, which recognizes the high molecular weight melanoma associated antigen (HMW-MAA) expressed in most malignant melanomas and melanoma cell lines. We demonstrate that the 9.2.27PE immunotoxin (IT) induces cell death in malignant melanoma cells through protein synthesis inhibition followed by some morphological and biochemical features of apoptosis, like rounding up of cells, chromatin condensation and inactivation of PARP. Unlike previous results with the 425.3PE IT in breast cancer cells, we detected no depolarization of the mitochondrial membrane after 9.2.27PE IT treatment. This is likely due to the lack of strong activation of caspase-8 and caspase-3. The lack of depolarization suggests that cytochrome c, a molecule that triggers activation of caspase-3, was retained within the mitochondria. In addition, the protein level of the antiapoptotic Bcl-2 did not decrease in contrast to other antiapoptotic molecules belonging to the inhibitor of apoptosis and the Bcl-2 family. This suggests that Bcl-2 may play a role in maintaining the mitochondrial membrane integrity in the 9.2.27PE-treated cells. Nevertheless, 9.2.27PE IT efficiently killed malignant melanoma cells that can be ascribed to inhibition of protein synthesis followed by some morphological and biochemical features of apoptosis.
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PMID:The melanoma specific 9.2.27PE immunotoxin efficiently kills melanoma cells in vitro. 1935 Jun 33

Altered redox homeostasis involved in the control of cancer cell survival and proliferative signaling represents a chemical vulnerability that can be targeted by prooxidant redox intervention. Here, we demonstrate that the redox dye 2,6-dichlorophenolindophenol (DCPIP) may serve as a prooxidant chemotherapeutic targeting human melanoma cells in vitro and in vivo. DCPIP-apoptogenicity observed in the human melanoma cell lines A375 and G361 was inversely correlated with NAD(P)H:quinone oxidoreductase (NQO1) expression levels. In A375 cells displaying low NQO1 activity, DCPIP induced apoptosis with procaspase-3 and PARP cleavage, whereas G361 cells expressing high levels of enzymatically active NQO1 were resistant to DCPIP-cytotoxicity. Genetic (siRNA) or pharmacological (dicoumarol) antagonism of NQO1 strongly sensitized G361 cells to DCPIP apoptogenic activity. DCPIP-cytotoxicity was associated with the induction of oxidative stress and rapid depletion of glutathione in A375 and NQO1-modulated G361 cells. Expression array analysis revealed a DCPIP-induced stress response in A375 cells with massive upregulation of genes encoding Hsp70B' (HSPA6), Hsp70 (HSPA1A), heme oxygenase-1 (HMOX1), and early growth response protein 1 (EGR1) further confirmed by immunodetection. Systemic administration of DCPIP displayed significant antimelanoma activity in the A375 murine xenograft model. These findings suggest feasibility of targeting tumors that display low NQO1 enzymatic activity using DCPIP.
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PMID:Antimelanoma activity of the redox dye DCPIP (2,6-dichlorophenolindophenol) is antagonized by NQO1. 1939 13

Constitutive ERK activation, superoxide dismutases (SOD) and p53 mutations are implicated in modulating tumor apoptotic response. We now investigated whether human melanoma survival in response to sodium nitroprusside (SNP) is modulated by: (a) stable introduction of a DN-mutant p53; (b) pharmacologically inhibiting ERK activation with UO126; (c) addition of exogenous SOD. Nitroprusside releases nitric oxide (NO) when intact, or acts in a NO-independent manner via iron and residual cyanide after light exposure (lex-SNP). When tested at 300 microM in 72 h treatments by cytometric live-dead assays, intact SNP caused a 50% lethality versus a 30% lethality induced by lex-SNP. No protection from SNP toxicity was seen when inhibiting the PI3-kinase pathway with LY294002 or c-Jun NH(2) kinase signaling with SP600125. However, pretreatment with UO126 protected from SNP-mediated cell death including counteracting apoptosis-associated Bax expression and PARP cleavage, plus reversing loss of Cu,Zn-SOD. Moreover, addition of exogenous SOD also protected cells from SNP toxicity. In spite of the greater earlier effects of intact SNP, cells treated with single doses of either intact or lex-SNP, revealed about a 90% mortality in longer 120 h treatments, and these were also counteracted by UO126 or exogenous SOD. This report is the first to show that: constitutive ERK activation characteristic of cancer cells, increases a nitroprusside-induced apoptosis modulated by SOD.
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PMID:ERK activation increases nitroprusside induced apoptosis in human melanoma cells irrespective of p53 status: role of superoxide dismutases. 1939 58

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

Small molecule inhibitors of PARP-1 have been pursued by various organizations as potential therapeutic agents either capable of sensitizing cytotoxic treatments or acting as stand-alone agents to combat cancer. As one of the strategies to expand our portfolio of PARP-1 inhibitors, we pursued unsaturated heterocycles to replace the saturated cyclic amine derivatives appended to the benzimidazole core. Not only did a variety of these new generation compounds maintain high enzymatic potency, many of them also displayed robust cellular activity. For example, the enzymatic IC(50) and cellular EC(50) values were as low as 1 nM or below. Compounds 24 (EC(50) = 3.7 nM) and 44 (EC(50) = 7.8 nM), featuring an oxadiazole and a pyridine moiety, respectively, demonstrated balanced potency and PK profiles. In addition, these two molecules exhibited potent oral in vivo efficacy in potentiating the cytotoxic agent temozolomide in a B16F10 murine melanoma model.
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PMID:Synthesis and evaluation of a new generation of orally efficacious benzimidazole-based poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors as anticancer agents. 1988 60

The capability of PARP activity inhibitors to prevent DNA damage recovery suggested the use of these drugs as chemo- and radio-sensitisers for cancer therapy. Our research, carried out on cultured human M14 melanoma cells, was aimed to examine if PJ-34, a potent PARP activity inhibitor of second generation, was per se able to affect the viability of these cancer cells without any DNA damaging agents. Using time-lapse videomicroscopy, we evidenced that 10 microM PJ-34 treatment induced severe mitotic defects leading to dramatic reduction of cell proliferation and to cell death. PJ-34 cytotoxic effect was further confirmed by analysis of cell viability and clonogenic assay. Absence of canonic apoptosis markers allowed us to exclude this kind of cell death. No single and/or double stranded DNA damage was evidenced. Immunofluorescence analysis showed an aberrant mitotic scenario in several cells and subsequent multinucleation suggesting an atypical way for cells to die: the mitotic catastrophe. The detection of aberrant accumulation of polymerised actin inside the nucleolus was noteworthy. Taken together, our results demonstrate that, targeting PARP activity by PJ-34, cancer cell survival is affected independently of DNA damage repair. Two findings are remarkable: (a) cisplatin concentration can be reduced by three quarters if it is followed by treatment with 10 microM PJ-34 for 24 h to obtain the same cytotoxic effect; (b) effects dependent on PJ-34 treatment are reversible. Our data suggest that, to reduce the harm done to non-tumour cells during chemotherapy with cisplatin, the latter could be coupled with PJ-34 treatment.
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PMID:Inhibition of PARP activity by PJ-34 leads to growth impairment and cell death associated with aberrant mitotic pattern and nucleolar actin accumulation in M14 melanoma cell line. 1989 Aug 34

Ultraviolet (UV) radiation is a major risk factor for the development of melanoma. Recent studies have reported that the intake of citrate-containing juices may reduce the risk of cancer. Thus, we investigated the effects of citrate on UVB-irradiated B16 murine melanoma cells. B16 cells had more evident apoptotic features with the combination of citrate/UVB than by citrate or UVB alone; cell death of HaCaT human keratinocytes was not observed with citrate/UVB. Western blot analysis demonstrated that citrate/UVB led to phosphorylation of the stress signaling proteins, such as c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). Furthermore, citrate/UVB caused activation of caspase-9/-3 as well as cleavage of poly(ADP-ribose) polymerase (PARP). Correspondingly, cell cycle analysis showed that citrate/UVB clearly increased the sub-G0/G1 phase, which indicated apoptotic cell death of B16 cells. Therefore, our study has demonstrated that sub-lethal doses of citrate enhanced the apoptotic cell death of melanoma cells under UVB irradiation. From these results, we suggest that citrate might reduce the risk of developing melanoma induced by UVB.
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PMID:Enhanced effects of citrate on UVB-induced apoptosis of B16 melanoma cells. 2009 42

Magnolol inhibited proliferation of human malignant melanoma A375-S2 cells. The drug induced oligonucleosomal fragmentation of DNA in A375-S2 cells and increased caspase-3, 8, 9 activities followed by the degradation of caspase-3 substrates, inhibitor of caspase dependent DNase (ICAD) and poly-(ADP-ribose) polymerase (PARP). Pan-caspase inhibitor (z-VADfmk), caspase-3 inhibitor (z-DEVD-fmk), capase-8 inhibitor (z-IETD-fmk), caspase-9 inhibitor (z-LEHD-fmk) and caspase-10 inhibitor (z-AEVD-fmk) inhibited magnolol-induced A375-S2 cell apoptosis. The level of anti-apoptotic mitochondrial protein Bcl-2 was up-regulated while the level of pro-apoptotic protein Bax was down-regulated. Taken together, our results indicate that magnolol induces apoptosis by activation of both mitochondrial and death receptor pathways in A375-S2 cells.
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PMID:Magnolol induces apoptosis via activation of both mitochondrial and death receptor pathways in A375-S2 cells. 2016 9


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