title: The cytotoxic effect of β-elemene against malignant glioma is enhanced by base-excision repair inhibitor methoxyamine.
abstract: This study investigated the effects of β-elemene + methoxyamine, a DNA base-excision repair inhibitor, on the inhibition of glioma growth. We treated C6 and SHG44 glioma cells with β-elemene and methoxyamine individually or in combinations, and subsequently analyzed cellular survivals by MTT assay. Comet assay, γ-H2AX focus formation assay and Western-blot were performed to investigate whether the observed cytotoxicity was associates with DNA damages. Finally, a xenograft tumor model was established in nude mice with C6 cells to analyze in vivo tumor inhibition effects of β-elemene, which was followed by determination of the expression of anti-apoptotic protein Bcl-2 via immunohistochemistry staining. Results showed that β-elemene could significantly inhibit the growth of glioma cells in a dose- and time-dependent manner. The combination of methoxyamine with β-elemene could result in a greater extent of DNA injuries in vitro. Furthermore, in vivo tumors exhibited a marked shrinkage in volume in β-elemene + methoxyamine treatment group. Immunohistochemistry analysis of the tumor tissues showed a distinctive decrease in Bcl-2 staining in β-elemene (56 %) and β-elemene + methoxyamine (36 %) groups when compared with the negative control (77 %). In conclusion, β-elemene exhibits a significant cytotoxic effect against glioma cells both in vitro and in vivo, which is likely to be mediated by its potential to damage tumor cell DNA and activate apoptotic pathway. Such growth inhibition effect of β-elemene could be potentiated by methoxyamine co-administration. Therefore, a combination of the two agents as a novel chemotherapeutic option for glioma merits further investigations.
authors.affiliation: Department of Neurosurgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Zhu
authors.forename: Jue
authors.initials: J
authors.lastname: Hu
authors.forename: Fang
authors.initials: F
authors.lastname: Shen
authors.forename: Hong
authors.initials: H
authors.lastname: Shen
authors.forename: Weiguo
authors.initials: W
authors.lastname: Liu
authors.forename: Jianmin
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects* / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D005260:Female; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D006898:Hydroxylamines / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D012717:Sesquiterpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D006898:Hydroxylamines; D012717:Sesquiterpenes; C445979:beta-elemene; C005214:methoxyamine