BACKGROUND: Human glioblastoma is a deadly brain cancer that continues to defy all current therapeutic strategies. The authors induced apoptosis in human glioblastoma T98G and U87MG cells after treatment with apigenin, (−)‐epigallocatechin, (−)‐epigallocatechin‐3‐gallate (EGCG), and genistein, which did not induce apoptosis in human normal astrocytes.METHODS: Induction of apoptosis was examined using Wright staining and ApopTag assay. Production of reactive oxygen species (ROS) and increase in intracellular free Ca²⁺ were measured by fluorescent probes. Analysis of mRNA and Western blotting indicated increases in expression and activities of the stress kinases and cysteine proteases for apoptosis. JC‐1 showed changes in mitochondrial membrane potential (ΔΨ_m), and use of specific inhibitors confirmed activation of kinases and proteases in apoptosis.RESULTS: Treatment of glioblastoma cells with apigenin, (−)‐epigallocatechin, EGCG, or genistein triggered ROS production that induced apoptosis with phosphorylation of p38 mitogen‐activated protein kinase (MAPK) and activation of the redox‐sensitive c‐Jun N‐terminal kinase 1 pathway. Pretreatment of cells with ascorbic acid attenuated ROS production and p38 MAPK phosphorylation. Increases in intracellular free Ca²⁺ and activation of caspase‐4 indicated involvement of endoplasmic reticulum stress in apoptosis. Other events in apoptosis included overexpression of Bax, loss of ΔΨ_m, mitochondrial release of cytochrome c and Smac into the cytosol, down‐regulation of baculoviral inhibitor‐of‐apoptosis repeat‐containing proteins, and activation of calpain, caspase‐9, and caspase‐3. (−)‐Epigallocatechin and EGCG also induced caspase‐8 activity. Apigenin, (−)‐epigallocatechin, EGCG, and genistein did not induce apoptosis in human normal astrocytes.CONCLUSIONS: Results strongly suggest that flavonoids are potential therapeutic agents for induction of apoptosis in human glioblastoma cells. Cancer 2010. © 2010 American Cancer Society.