An Efficient Mammalian Transfer RNA Target for Bleomycin

Abstract

The antitumor antibiotic bleomycin has long been believed to exert its therapeutic effects at the level of DNA cleavage. Recently, evidence has been presented to suggest that RNA cleavage may also be important and that one or more transfer RNAs may be involved. To define those tRNAs that may represent important loci for the action of bleomycin, we have fractionated chicken liver tRNAs and identified those isoacceptors most susceptible to oxidative cleavage by Fe(II).BLM. Two chicken liver tRNAs, tRNA3Lys and tRNAPhe, were found to be cleaved with exceptional facility by Fe(II).BLM, and both were cleaved predominantly at U66. The cleavage of tRNA3Lys was shown to be minimally affected by physiological concentrations of Mg2+. Chicken liver tRNA3Lys is identical in sequence with human tRNA3Lys. These findings support a possible role for a critical tRNA such as tRNA3Lys in the mechanism by which bleomycin mediates its antitumor activity.

Dynamics of Bleomycin Interaction with a Strongly Bound Hairpin DNA Substrate, and Implications for Cleavage of the Bound DNA

“…3 The antitumor activity of bleomycin is believed to derive from its ability to degrade DNA, 4 and possibly also RNA. 4d,5 DNA cleavage has been especially well characterized, and the mechanism of degradation and derived products have been described in some detail. 6 …”

Combined action of binase and bleomycin toward human lung adenocarcinoma cells

“…Блеомицин помимо деструкции ДНК вызывает фрагментацию тРНК, при этом вторая реакция является более специфичной [10]. Механизм его действия на уровне РНК отчасти сходен с таковым для цитотоксической онконазы, которая проявляет свои противоопухолевые свойства, ингибируя синтез белка за счёт деградации одной или нескольких тРНК; предполагают, что оба противоопухолевых препарата специфически расщепляют тРНК Lys и тРНК Phe [19,20]. Для биназы каталитическая активность также является важным фактором проявления противоопухолевого действия [21][22][23].…”

Natural Products as Anticancer Agents

“…Bleomycin was originally thought to act through DNA cleavage, because it cleaves both DNA and RNA in an oxidative, sequence-selective, metal-dependent fashion in the presence of oxygen. Recent studies, however, suggest that an alternative mechanism of action may be inhibition of t-RNA from experiments reported recently by the Hecht group (73). Bleomycins are used clinically in combination therapy for the treatment of squamous cell carcinomas and malignant lymphomas.…”