RNA synthesis block by 5, 6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) triggers p53-dependent apoptosis in human colon carcinoma cells.
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.
te Poele
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RH
Barry Reed Oncology Laboratory, ICRF Department of Medical Oncology, St Bartholomew's Hospital, West Smithfield, London EC1A 7BE, UK.
Okorokov
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AL
Joel
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SP
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D004004:Dichlororibofuranosylbenzimidazole / Q000633:toxicity*; D006801:Humans; D019384:Nucleic Acid Synthesis Inhibitors / Q000633:toxicity*; D012313:RNA / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D019384:Nucleic Acid Synthesis Inhibitors; D016159:Tumor Suppressor Protein p53; D004004:Dichlororibofuranosylbenzimidazole; D012313:RNA