Calanquinone A induces anti-glioblastoma activity through glutathione-involved DNA damage and AMPK activation
Journal
European Journal of Pharmacology
Journal Volume
730
Journal Issue
1
Pages
90-101
Date Issued
2014
Author(s)
Abstract
Glioblastoma, a highly malignant glioma, is resistant to both radiation and chemotherapy and is an intractable problem in clinical treatment. New therapeutic approaches are in urgent need. Calanquinone A, an herbal constituent, displayed anti-proliferative activity against glioblastoma cells, including A172, T98 and U87. Flow cytometric analysis showed an S phase arrest and a subsequent apoptosis to calanquinone A action. Further identification demonstrated a rapid increase of γH2A.X formation at S phase. The data together with comet tail formation and Chk1 activation indicated DNA damage response. N-acetyl cysteine (an antioxidant and a glutathione precursor) and exogenously applied glutathione, but not trolox (an antioxidant), completely abolished calanquinone A-induced effects. Immunofluorescence assay revealed that calanquinone A decreased the intracellular glutathione levels in both A172 and T98 cells. However, calanquinone A, by itself, did not conjugate glutathione. The data suggested that the decrease of cellular glutathione predominantly contributed to the anticancer mechanism. Furthermore, calanquinone A induced the activation of AMP-activated protein kinase (AMPK) and the inhibition of p70S6K activity. Rhodamine efflux assay showed that calanquinone A did not block efflux activity, indicating that calanquinone A was not a P-glycoprotein substrate. In summary, the data suggest that calanquinone A displays anti-glioblastoma activity through a decrease of cellular glutathione levels that subsequently induces DNA damage stress and AMPK activation, leading to cell cycle arrest at S-phase and apoptotic cell death. Furthermore, calanquinone A does not serve as a P-glycoprotein substrate, suggesting a potential for further development in anti-glioblastoma therapy. ? 2014 Elsevier B.V. All rights reserved.
SDGs
Other Subjects
acetylcysteine; calanquinone A; checkpoint kinase 1; etoposide; glutathione; herbaceous agent; histone H2AX; hydroxymethylglutaryl coenzyme A reductase kinase; multidrug resistance protein; rhodamine; S6 kinase; trolox C; unclassified drug; antineoplastic agent; calanquinone A; glutathione; hydroxymethylglutaryl coenzyme A reductase kinase; quinone derivative; S6 kinase; antineoplastic activity; antiproliferative activity; apoptosis; article; cancer cell; cancer chemotherapy; cell line; controlled study; DNA damage; drug targeting; enzyme activation; enzyme activity; flow cytometry; glioblastoma; human; human cell; immunofluorescence test; priority journal; S phase cell cycle checkpoint; cell proliferation; drug effects; enzyme activation; glioblastoma; intracellular space; metabolism; pathology; tumor cell line; AMP-Activated Protein Kinases; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; DNA Damage; Enzyme Activation; Glioblastoma; Glutathione; Humans; Intracellular Space; Quinones; Ribosomal Protein S6 Kinases, 70-kDa; S Phase Cell Cycle Checkpoints
Type
journal article