Abstract
The increasing incidence of melanoma makes this cancer an important public health problem. Therapeutic resistance is still a major obstacle to the therapy of patients with metastatic melanomas. The aim of this study was to develop the melanoma cell line resistant to DNA-alkylating agents and to elucidate the mechanisms involved in acquired drug resistance. We established a unique melanoma subline Mel MeR resistant to DNA-alkylating drug aranoza by continuous stepwise selection of the Mel Me/WT cell line with increasing concentrations of this drug. Mel MeR cells were also cross-resistant to streptozotocin or cisplatin. Here, we show that aranoza-resistant melanoma cells modulate the ABC transporter activity, upregulate the expression of PRAME, adopt a vascular-related phenotype and engage in vasculogenic mimicry. LCS1269, a vasculogenic mimicry low-molecular-weight inhibitor, reverses the sensitivity of resistant melanoma cells to DNA-damaging agents. In this study, we provide experimental evidence that LCS1269 might be considered as a new potential anticancer agent capable of overcoming multidrug resistance for DNA-damaging agents in melanoma.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Antigens, Neoplasm / genetics
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Antineoplastic Agents, Alkylating / pharmacology*
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Apoptosis / drug effects
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CD24 Antigen / metabolism
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Carbazoles / pharmacology*
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Cell Line, Tumor*
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Drug Resistance, Neoplasm* / genetics
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Endoglin / metabolism
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Fluorescent Dyes / metabolism
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Gene Expression / drug effects
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Glycosides / pharmacology*
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Humans
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Hyaluronan Receptors / metabolism
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Intercellular Adhesion Molecule-1 / metabolism
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Male
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Melanoma / blood supply
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Melanoma / drug therapy*
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Melanoma / genetics
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Melanoma / metabolism*
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Methylnitrosourea / analogs & derivatives*
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Methylnitrosourea / pharmacology
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Middle Aged
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Neoplasm Proteins / genetics
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Neoplastic Stem Cells / metabolism
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Neovascularization, Pathologic / prevention & control*
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Nuclear Proteins / genetics
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Phenotype
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Phosphoprotein Phosphatases / genetics
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Proto-Oncogene Proteins c-kit / metabolism
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Rhodamine 123 / metabolism
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Tetraspanin 30 / metabolism
Substances
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ABCB5 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Antigens, Neoplasm
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Antineoplastic Agents, Alkylating
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CD24 Antigen
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CD24 protein, human
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CD44 protein, human
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CD63 protein, human
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Carbazoles
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ENG protein, human
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Endoglin
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Fluorescent Dyes
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GAGE1 protein, human
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Glycosides
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Hyaluronan Receptors
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LCS1269
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Neoplasm Proteins
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Nuclear Proteins
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PRAME protein, human
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Tetraspanin 30
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aranoza
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Intercellular Adhesion Molecule-1
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Rhodamine 123
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Methylnitrosourea
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Proto-Oncogene Proteins c-kit
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CTDSP1 protein, human
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Phosphoprotein Phosphatases