1. RNA synthesis block by 5, 6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) triggers p53-dependent apoptosis in human colon carcinoma cells.
- Author
-
te Poele RH, Okorokov AL, and Joel SP
- Subjects
- Adenocarcinoma pathology, Cell Survival drug effects, Clone Cells, Colonic Neoplasms pathology, Humans, Tumor Cells, Cultured, Adenocarcinoma metabolism, Apoptosis drug effects, Colonic Neoplasms metabolism, Dichlororibofuranosylbenzimidazole toxicity, Nucleic Acid Synthesis Inhibitors toxicity, RNA antagonists & inhibitors, RNA biosynthesis, Tumor Suppressor Protein p53 physiology
- Abstract
Most modern chemo- and radiotherapy treatments of human cancers use the DNA damage pathway, which induces a p53 response leading to either G1 arrest or apoptosis. However, such treatments can induce mutations and translocations leading to secondary malignancies or recurrent disease, which often have a poor prognosis because of resistance to therapy. Here we report that 5, 6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB), an inhibitor of CDK7 TFIIH-associated kinase, CKI and CKII kinases, blocking RNA polymerase II in the early elongation stage, triggers p53-dependent apoptosis in human colon adenocarcinoma cells in a transcription independent manner. The fact that DRB kills tumour-derived cells without employment of DNA damage gives rise to the possibility of the development of a new alternative chemotherapeutic treatment of tumours expressing wild type p53, with a decreased risk of therapy-related, secondary malignancies.
- Published
- 1999
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