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

We have previously confirmed the in vitro activity of cisplatin and carboplatin against human melanoma cell lines. Both drugs are important components in the chemotherapy used in our service for advanced metastatic melanoma. In this communication we report the in vitro activity of oxaliplatin against human melanoma cell lines in comparison with cisplatin and carboplatin. Oxaliplatin was found to be active against C32 and G361 cell lines with IC50 values of 49.48 and 9.07 microM (1 h exposure), 9.47 and 1.30 microM (4 h exposure), and 0.98 and 0.14 microM (24 h exposure), respectively. The cytotoxic activity of oxaliplatin in this in vitro system appears to be significantly superior to that of carboplatin. Its activity becomes comparatively closer to that of cisplatin as exposure time increases. Indeed at a 24 h exposure oxaliplatin appears to be significantly more active than cisplatin against the G361 cell line (p=0.0343). Oxaliplatin merits evaluation in the clinic both as a single agent and in combination with other drugs active against melanoma.
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PMID:Oxaliplatin is active in vitro against human melanoma cell lines: comparison with cisplatin and carboplatin. 1114 94

Metastatic melanoma monotherapies with drugs such as dacarbazine, cisplatin or paclitaxel (PXT) are associated with significant toxicity and low efficacy rates. These facts reinforce the need for development of novel agents or combinatory strategies. Cl-IB-MECA is a small molecule, orally bioavailable, well tolerated and currently under clinical trials as an anticancer agent. Our aim was to investigate a possible combinatory therapeutic strategy using PXT and Cl-IB-MECA on human C32 melanoma cells and its underlying mechanisms. Cytotoxicity was evaluated using MTT reduction, lactate dehydrogenase leakage and neutral red uptake assays, for different concentrations and combinations of both agents, at 24 and 48 h. Apoptosis was also assessed using fluorescence microscopy and through the evaluation of caspases 8, 9, and 3 activities. We demonstrated, for the first time, that combination of PXT and Cl-IB-MECA significantly increases cytotoxicity for clinically relevant concentrations. This combination seems to act synergistically in disrupting membrane integrity, but also causing lysosomal and mitochondrial dysfunction. When using the lowest PTX concentration (10 ng/mL), co-incubation with CI-IB-MECA (micromolar concentrations) potentiated overall cytotoxic effects and morphological signs of apoptosis. All combinations studied enhanced caspase 8, 9, and 3 activities, suggesting the involvement of both intrinsic and extrinsic apoptotic pathways. The possibility that cytotoxicity elicited by Cl-IB-MECA, alone or in combination with PXT, involves adenosine receptor activation was discarded and results confirmed that oxidative stress is only involved in cytotoxicity after treatment with PXT, alone. Being melanoma a very apoptosis-resistance cancer, this combination seems to hold promise as a new therapeutic strategy for melanoma.
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PMID:Potentiation of cytotoxicity of paclitaxel in combination with Cl-IB-MECA in human C32 metastatic melanoma cells: A new possible therapeutic strategy for melanoma. 2403 53

Although vemurafenib has been shown to improve the overall survival of patients with metastatic melanoma harboring the BRAF V600E mutation, its efficacy is often hampered by drug resistance acquired within a relatively short period through several distinct mechanisms. In the present study, we investigated the effect of fluvastatin as a possible strategy to overcome such acquired resistance using a cultured cell line model. We established vemurafenib-resistant (VR) cells from three BRAF (V600E)-mutated melanoma lines (C32, HMY-1, and SK-MEL-28) and evaluated the mechanism of acquired resistance of VR cells by water-soluble tetrazolium salts assay, western blot, real-time quantitative PCR, and immunofluorescent microscopy. The efficacy of the combination of growth inhibitory effect of vemurafenib and fluvastatin on respective parental and VR cells were assessed by calculating combination index and western blot. IC50 values of three VR cells were ~5-100-fold higher than those for the respective parental cells. The VR cells derived from HMY-1 and SK-MEL-28 showed constitutive activation of AKT kinase, and the specific AKT inhibitor MK-2208 or the PI3K inhibitor wortmannin increased the cellular sensitivity to vemurafenib. Intriguingly, application of a statin-related drug, fluvastatin, also resulted in a synergistic increase of sensitivity to vemurafenib in the VR cells (combination index: 0.73-0.86) probably by alleviating constitutive AKT activation, whereas the same treatment did not notably alter the vemurafenib sensitivity of the parental cells. Our results suggest the possible usefulness of statin-related drugs for overcoming vemurafenib resistance acquired through constitutive activation of the PI3K-AKT axis.
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PMID:Fluvastatin exerts an antitumor effect in vemurafenib-resistant melanoma cells. 3092 Apr 1