Abstract
Glioblastoma is a deadly cancer with intrinsic chemoresistance. Understanding this property will aid in therapy. Glucosylceramide synthase (GCS) is associated with resistance and poor outcome; little is known about glioblastomas. In glioblastoma cells, temozolomide and paclitaxel induce ceramide increase, which in turn promotes cytotoxicity. In drug-resistant cells, both drugs are unable to accumulate ceramide, increased expression and activity of GCS is present, and its inhibitors hinder resistance. Resistant cells exhibit cross-resistance, despite differing in marker expression, and cytotoxic mechanism. These findings suggest that GCS protects glioblastoma cells against autophagic and apoptotic death, and contributes to cell survival under chemotherapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents, Alkylating / pharmacology
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Antineoplastic Agents, Phytogenic / pharmacology
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Apoptosis / drug effects*
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Autophagy / drug effects*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival
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Central Nervous System Neoplasms / drug therapy
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Central Nervous System Neoplasms / metabolism
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Ceramides / metabolism
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Dacarbazine / analogs & derivatives*
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Dacarbazine / pharmacology
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Drug Resistance, Neoplasm / physiology
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Glioblastoma / drug therapy*
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Glioblastoma / metabolism
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Glucosyltransferases / metabolism*
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Humans
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Paclitaxel / pharmacology*
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Temozolomide
Substances
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Antineoplastic Agents
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Antineoplastic Agents, Alkylating
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Antineoplastic Agents, Phytogenic
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Ceramides
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Dacarbazine
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Glucosyltransferases
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ceramide glucosyltransferase
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Paclitaxel
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Temozolomide