Natural and engineered ribonucleases as potential cancer therapeutics

Abstract

By reason of their cytotoxicity, ribonucleases (RNases) are potential anti-tumor drugs. Particularly members from the RNase A and RNase T1 superfamilies have shown promising results. Among these enzymes, Onconase, an RNase from the Northern Leopard frog, is furthest along in clinical trials. A general model for the mechanism of the cytotoxic action of RNases includes the interaction of the enzyme with the cellular membrane, internalization, translocation to the cytosol, and degradation of ribonucleic acid. The interplay of these processes as well as the role of the thermodynamic and proteolytic stability, the catalytic activity, and the capability of the RNase to evade the intracellular RNase inhibitor has not yet been fully elucidated. This paper discusses the various approaches to exploit RNases as cytotoxic agents.

A nucleic acid-hydrolyzing antibody penetrates into cells via caveolae-mediated endocytosis, localizes in the cytosol and exhibits cytotoxicity

“…1C). Thus, we hypothesized that cytotoxicity exerted by cytosolic 3D8 scFv was due to its ability to hydrolyze cytosolic RNAs, since many DNA-hydrolyzing Abs can also hydrolyze RNA [33] and some ribonucleases (RNases) give rise to cell toxicity when they are internalized into the cytosol [19,34].…”

“…Small interfering RNA (siRNA) oligonucleotides were synthesized at Bioneer Co. (Daejeon, Korea). The mRNA sequences targeted by caveolin-1, clathrin, and dynamin-2 siRNA were 5 -AGA CGA GCU GAG CGA GAA GCA -3 [18,19], 5 -AAC CUG CGG UCU GGA GUC AAC -3 [20], and 5 -GUG GAC CUG GUU AUC CAG GAG CUA A -3 [21] respectively. An unrelated (scramble) siRNA with sequence of 5 -CCU ACG CCA CCA AUU UCG U -3 was employed as a control.…”

Antitumor activity of apoptotic nuclease TBN1 from L. esculentum.

“…Nucleolytic enzymes like ribonucleases (RNases) belong, as mild toxins, to potential alternatives to non-mutagenic antitumor drugs and chemotherapeutics. In the past, exclusively animal RNases were studied in this respect [5,6,7,8,9]. Among the enzymes of practical significance, onconase, an RNase from the Northern Leopard frog, is currently undergoing phase III clinical trials for the treatment of malignant mesothelioma [10].…”

“…Among the enzymes of practical significance, onconase, an RNase from the Northern Leopard frog, is currently undergoing phase III clinical trials for the treatment of malignant mesothelioma [10]. Onconase and its variants have been found to reduce the tumor size in animals and to enhance the cytotoxic efficacy of chemotherapeutics [8]. Together with anticarcinogenic properties, some cytotoxic side effects of RNases of human and animal origin including bovine seminal ribonuclease (BS-RNase) and onconase have been reported [8,11].…”

“…Onconase and its variants have been found to reduce the tumor size in animals and to enhance the cytotoxic efficacy of chemotherapeutics [8]. Together with anticarcinogenic properties, some cytotoxic side effects of RNases of human and animal origin including bovine seminal ribonuclease (BS-RNase) and onconase have been reported [8,11]. In this respect, it is of interest to analyze nucleolytic enzymes of plant origin for their potential antitumorigenic effects and biological activities.…”