title: Hypericin-induced apoptosis of human malignant glioma cells is light-dependent, independent of bcl-2 expression, and does not require wild-type p53.
abstract: Hypericin and tamoxifen are experimental agents for the adjuvant chemotherapy of malignant glioma. We report that hypericin and tamoxifen induce apoptosis of 7 human malignant glioma cell lines in a concentration- and time-dependent manner. Illumination is essential for the cytotoxicity of hypericin but not tamoxifen. Apoptosis is unaffected by inhibitors of RNA and protein synthesis or free radical scavengers, does not require wild-type p53 activity, and occurs in glioma cells expressing high levels of bcl-2. There is no correlation between hypericin and tamoxifen-induced cytotoxicity and inhibition of protein kinase C (PKC). Ectopic expression of a murine bcl-2 transgene provides modest protection from tamoxifen but does not affect hypericin toxicity. Hypericin and tamoxifen do not modulate glioma cell killing induced by tumor necrosis factor-alpha (TNF-alpha) or CD95 ligand. Both drugs augment the acute cytotoxicity of various cancer chemotherapy drugs but fail to shift their EC50 values in modified colony formation assays. These data do not provide further supportive evidence how to enhance the limited efficacy of tamoxifen treatment for human malignant glioma. However, hypericin is a promising agent for the treatment of malignant glioma if local photodynamic activation of hypericin in the glioma tissue can be achieved.
authors.affiliation: Department of Neurology, University of Tübingen, School of Medicine, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Weller
authors.forename: M
authors.initials: M
authors.lastname: Trepel
authors.forename: C
authors.initials: C
authors.lastname: Grimmel
authors.forename: M
authors.initials: M
authors.lastname: Schabet
authors.forename: D
authors.initials: D
authors.lastname: Bremen
authors.forename: S
authors.initials: S
authors.lastname: Krajewski
authors.forename: J C
authors.initials: JC
authors.lastname: Reed
mesh_terms: D000873:Anthracenes; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D004351:Drug Resistance; D005910:Glioma / Q000473:pathology*; D006801:Humans; D008027:Light; D009281:Naphthalenes / Q000494:pharmacology; D010569:Perylene / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000528:radiation effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D012313:RNA / Q000037:antagonists & inhibitors; D013629:Tamoxifen / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D051028:bcl-2-Associated X Protein; D019014:fas Receptor / Q000502:physiology
chemical_list: D000873:Anthracenes; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D009281:Naphthalenes; D011500:Protein Synthesis Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D013629:Tamoxifen; D010569:Perylene; D012313:RNA; C004965:hypericin; D011493:Protein Kinase C; C058819:calphostin C