Ribonucleases as potential modalities in anticancer therapy

Abstract

Antitumor ribonucleases are small (10–28 kDa) basic proteins. They were found among members of both, ribonuclease A and T1 superfamilies. Their cytotoxic properties are conferred by enzymatic activity, i.e., the ability to catalyze cleavages of phosphodiester bonds in RNA. They bind to negatively charged cell membrane, enter cells by endocytosis and translocate to cytosol where they evade mammalian protein ribonuclease inhibitor and degrade RNA. Here, we discuss structures, functions and mechanisms of antitumor activity of several cytotoxic ribonucleases with particular emphasis to the amphibian Onconase, the only enzyme of this class that reached clinical trials. Onconase is the smallest, very stable, less catalytically efficient and more cytotoxic than most RNase A homologues. Its cytostatic, cytotoxic and anticancer effects were extensively studied. It targets tRNA, rRNA, mRNA as well as the non-coding RNA (microRNAs). Numerous cancer lines are sensitive to Onconase; their treatment with 10 – 100 nM enzyme leads to suppression of cell cycle progression, predominantly through G1, followed by apoptosis or cell senescence. Onconase also has anticancer properties in animal models. Many effects of this enzyme are consistent with the microRNAs, one of its critical targets. Onconase sensitizes cells to a variety of anticancer modalities and this property is of particular interest, suggesting its application as an adjunct to chemotherapy or radiotherapy in treatment of different tumors. Cytotoxic RNases as exemplified by Onconase represent a new class of antitumor agents, with an entirely different mechanism of action than the drugs currently used in the clinic. Further studies on animal models including human tumors grafted on severe combined immunodefficient (SCID) mice and clinical trials are needed to explore clinical potential of cytotoxic RNases.

Ribonuclease binase inhibits primary tumor growth and metastases via apoptosis induction in tumor cells

“…[1][2][3][4][5] The antitumor activity was shown for BS-RNase from bovine seminal, [6][7][8][9] onconase from oocytes of Rana pipiens, [10][11][12] bovine pancreatic RNase A, 13 cSBL and jSBL RNases from Rana catesbeiana and Rana japonica, 14 microbial RNases [15][16][17] and conjugates of RNases with various molecules. [18][19][20] One of the properties that are important for potential therapeutic application of RNases is their ability to induce cancer cell death by apoptosis.…”

Surface-Dependent Differences in the Adsorption of Pancreatic and Microbial Ribonucleases Visualized by Atomic Force Microscopy

“…These properties allow the use of muscovite in the study of adsorption of RNAse as a structural analogue of the surface of tumor cells that have a higher negative charge compared with the surface of normal cells 28 . This model is especially relevant for the cationic RNAses, having the ability to selectively act on cells, including tumor ones 13 .…”

“…Active study of the effect of electrostatic properties of RNAses on their cytotoxicity has made a significant contribution to the understanding of the mechanism of interaction of molecules of RNAses to the surface of tumor cells. In particular, the selectivity of the action of RNAses could be explained from the position of the electrostatic interaction of cationic RNAses to the negatively charged surface of tumor cells, which contain increased amounts of anionic phospholipids in the outer monolayer of the membrane 13 . However, the selectivity of the action of RNAses on cells cannot be mediated only by their electrostatic properties 14 .…”

Onconase induces autophagy sensitizing pancreatic cancer cells to gemcitabine and activates Akt/mTOR pathway in a ROS-dependent manner

“…Such a capacity confers to ONC a high cytotoxic activity against several human cancer cell types, such as glioma cells [7] or lymphoma B cells [8]. Notably, ONC is currently used in Phase II and Phase IIIb clinical trials as therapy against non-small cell lung cancer and against unresectable malignant mesothelioma, respectively [9]. In addition to its anticancer properties, ONC is known to assume relevant roles as an anti-viral enzyme which inhibits HIV-1 virion production within viable replicating cells by degrading viral RNA and tRNALys [10,11].…”