1. Triptolide synergistically enhances temozolomide-induced apoptosis and potentiates inhibition of NF-κB signaling in glioma initiating cells.
- Author
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Sai K, Li WY, Chen YS, Wang J, Guan S, Yang QY, Guo CC, Mou YG, Li WP, and Chen ZP
- Subjects
- Animals, Apoptosis genetics, Cell Line, Tumor, Cell Transformation, Neoplastic drug effects, Cell Transformation, Neoplastic genetics, Dacarbazine pharmacology, Dacarbazine therapeutic use, Disease Models, Animal, Diterpenes therapeutic use, Drug Synergism, Epoxy Compounds pharmacology, Epoxy Compounds therapeutic use, Glioma drug therapy, Humans, Mice, NF-kappa B genetics, Neoplasm Transplantation, Phenanthrenes therapeutic use, Proto-Oncogene Proteins c-bcl-2 metabolism, Signal Transduction genetics, Stimulation, Chemical, Temozolomide, Transcription, Genetic drug effects, X-Linked Inhibitor of Apoptosis Protein metabolism, Antineoplastic Agents, Alkylating pharmacology, Apoptosis drug effects, Dacarbazine analogs & derivatives, Diterpenes pharmacology, Glioma genetics, Glioma pathology, NF-kappa B physiology, Phenanthrenes pharmacology, Signal Transduction drug effects
- Abstract
Glioblastoma multiforme (GBM) is a lethal solid cancer in adults. Temozolomide (TMZ) is a first-line chemotherapeutic agent but the efficacy is limited by intrinsic and acquired resistance in GBM. Triptolide (TPL), a derivative from traditional Chinese medicine, demonstrated anti-tumor activity. In this study, we explored the interaction of TPL and TMZ in glioma-initiating cells (GICs) and the potential mechanism. A GIC line (GIC-1) was successfully established. Cell viability of GIC-1 after treatment was measured using a CCK-8 assay. The interaction between TPL and TMZ was calculated from Chou-Talalay equations and isobologram. Self-renewal was evaluated with tumor sphere formation assay. Apoptosis was assessed with flow cytometry and western blot. Luciferase assay was employed to measure NF-κB transcriptional activity. The expression of NF-κB downstream genes, NF-κB nuclear translocalization and phoshorylation of IκBα and p65 were evaluated using western blot. We found that GIC-1 cells were resistant to TMZ, with the expected IC50 of 705.7 μmol/L. Co-treatment with TPL yielded a more than three-fold dose reduction of TMZ. TPL significantly increased the percentage of apoptotic cells and suppressed the tumor sphere formation when combined with TMZ. Phosphorylation of IκBα and p65 coupled with NF-κB nuclear translocalization were notably inhibited after a combined treatment. Co-incubation synergistically repressed NF-κB transcriptional activity and downstream gene expression. TPL sensitizes GICs to TMZ by synergistically enhancing apoptosis, which is likely resulting from the augmented repression of NF-κB signaling. TPL is therefore a potential chemosensitizer in the treatment of GBM.
- Published
- 2014
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