The cell killing activity of antitumor camptothecins is due to collisions between drug-trapped Topoisomerase I (Top1) and DNA replication forks, leading to irreversible DNA double-strand breaks and apoptosis. In addition, recent evidences demonstrated that camptothecins have specific transcription-dependent effects that are independent from DNA breaks at replication forks. Here, we focus on the latter drug effects, discussing the influence of Top1 and camptothecins on RNA polymerase II regulation by cyclin-dependent kinases, co-transcriptional regulation of mRNA maturation, and activation of novel antisense RNAs at the human HIF-1α gene locus. The new findings suggest that specific transcription-dependent effects of the drug can contribute to the antitumor activity of camptothecins and upcoming non-camptothecin Top1-targeted drugs. The complete understanding of specific regulatory mechanisms altered by camptothecins may lead to the definition of useful novel targets for human tumor therapy.
Capranico G, Baranello L, Bertozzi D, Marinello J (2012). Transcriptional Stress by Camptothecin: Mechanisms and Implications for the Drug Antitumor Activity. NEW YORK : Humana Press - Springer Science [10.1007/978-1-4614-0323-4_14].
Transcriptional Stress by Camptothecin: Mechanisms and Implications for the Drug Antitumor Activity
CAPRANICO, GIOVANNI;MARINELLO, JESSICA
2012
Abstract
The cell killing activity of antitumor camptothecins is due to collisions between drug-trapped Topoisomerase I (Top1) and DNA replication forks, leading to irreversible DNA double-strand breaks and apoptosis. In addition, recent evidences demonstrated that camptothecins have specific transcription-dependent effects that are independent from DNA breaks at replication forks. Here, we focus on the latter drug effects, discussing the influence of Top1 and camptothecins on RNA polymerase II regulation by cyclin-dependent kinases, co-transcriptional regulation of mRNA maturation, and activation of novel antisense RNAs at the human HIF-1α gene locus. The new findings suggest that specific transcription-dependent effects of the drug can contribute to the antitumor activity of camptothecins and upcoming non-camptothecin Top1-targeted drugs. The complete understanding of specific regulatory mechanisms altered by camptothecins may lead to the definition of useful novel targets for human tumor therapy.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
