HYPERICIN-INDUCED APOPTOSIS OF HUMAN-MALIGNANT GLIOMA-CELLS IS LIGHT-DEPENDENT, INDEPENDENT OF BCL-2 EXPRESSION, AND DOES NOT REQUIRE WILD-TYPE P53

Hypericin and tamoxifen are experimental agents for the adjuvant chemo therapy of malignant glioma. We report that hypericin and tamoxifen in duce apoptosis of 7 human malignant glioma cell lines in a concentrati on-and time-dependent manner. Illumination is essential for the cytoto xicity of hypericin but not tamoxifen. Apoptosis is unaffected by inhi bitors of RNA and protein synthesis or free radical scavengers, does n ot require wild-type p53 activity, and occurs in glioma cells expressi ng high levels of bcl-2. There is no correlation between hypericin and tamoxifen-induced cytotoxicity and inhibition of protein kinase C (PK C). Ectopic expression of a murine bcl-2 transgene provides modest pro tection from tamoxifen,but does not affect hypericin toxicity. Hyperic in and tamoxifen do not modulate glioma cell killing induced by tumor necrosis factor-alpha (TNF-alpha) or CD95 ligand. Both drugs augment t he acute cytotoxicity of various cancer chemotherapy drugs but fail to shift their EC50 values in modified colony formation assays. These da ta do not provide further supportive evidence how to enhance the limit ed 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 ca n be achieved.