Bisindolylmaleimide IX Induces Reversible and Time-Dependent Tumor Necrosis Factor Receptor Family-Mediated Caspase Activation and Cell Death.
We have previously shown that Bisindolylmaleimide (Bis) IX is localized in mitochondria but also acts as an inhibitor of transcription and facilitates tumor necrosis factor receptor family-mediated apoptosis. In this study, we found that Bis IX is freely distributed both within cells and extracellular medium and acts as a reversible apoptosis-inducing agent. Bis IX was found to induce time-dependent apoptosis in combination with TNF-a, TRAIL, and anti-Fas Ab. Using human prostatic carcinoma cell lines DU145 and LNCaP that are resistant to treatment with TNF family death-inducing ligands, we have shown that different, albeit still unidentified, inhibitory factors are responsible for the resistance to TRAIL-, Fas-, and TNF-a-mediated apoptosis. Our data also suggest that the turnover of apoptosis suppressor factors is much faster in DU145 compared to LNCaP. Lastly, we have found that Bis IX can override the apoptosis-inhibitory effects of Bcl-2 overexpression. In conclusion, Bis IX could be used as a drug to facilitate apoptosis of cancer cells that are resistant to treatment with death-inducing ligands as well as a valuable tool to discern the factors that mediate resistance to different death-inducing ligands.
Rokhlin
Oskar W
OW
Department of Pathology, The University of Iowa Iowa City, Iowa 52242, USA. oskar-rokhlin@uiowa.edu
Cohen
Michael B
MB
D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D015152:Blotting, Northern; D020169:Caspases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D008301:Maleimides / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D013997:Time Factors; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D007211:Indoles; D008024:Ligands; D008301:Maleimides; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; C467001:bisindolylmaleimide IX; D019014:fas Receptor; D020169:Caspases