Strengths and Challenges of Secretory Ribonucleases as AntiTumor Agents

Abstract

Approaches to develop effective drugs to kill cancer cells are mainly focused either on the improvement of the currently used chemotherapeutics or on the development of targeted therapies aimed at the selective destruction of cancer cells by steering specific molecules and/or enhancing the immune response. The former strategy is limited by its genotoxicity and severe side effects, while the second one is not always effective due to tumor cell heterogeneity and variability of targets in cancer cells. Between these two strategies, several approaches target different types of RNA in tumor cells. RNA degradation alters gene expression at different levels inducing cell death. However, unlike DNA targeting, it is a pleotropic but a non-genotoxic process. Among the ways to destroy RNA, we find the use of ribonucleases with antitumor properties. In the last few years, there has been a significant progress in the understanding of the mechanism by which these enzymes kill cancer cells and in the development of more effective variants. All the approaches seek to maintain the requirements of the ribonucleases to be specifically cytotoxic for tumor cells. These requirements start with the competence of the enzymes to interact with the cell membrane, a process that is critical for their internalization and selectivity for tumor cells and continue with the downstream effects mainly relying on changes in the RNA molecular profile, which are not only due to the ribonucleolytic activity of these enzymes. Although the great improvements achieved in the antitumor activity by designing new ribonuclease variants, some drawbacks still need to be addressed. In the present review, we will focus on the known mechanisms used by ribonucleases to kill cancer cells and on recent strategies to solve the shortcomings that they show as antitumor agents, mainly their pharmacokinetics.

Anticancer Activity of Reconstituted Ribonuclease S‐Decorated Artificial Viral Capsid

“…Ribonuclease (RNase) [1] is an enzyme that degrades ribonucleic acid into oligonucleotides and mononucleotides, which is attracting attention as an enzyme preparation that exhibits anticancer activity by administering into cancer cells. [2][3][4][5][6][7][8][9][10][11][12][13][14][15] When RNase is administered to cancer cells, it exhibits anticancer effects by degrading intracellular ribonucleic acid, inducing apoptosis by caspases, proteolytic enzymes involved in programmed cell death, and regulating DNA transcription, and cytokine production. [16,17] Since cancer cells have specific ligands for RNase on their surface, RNases selectively accumulate into cancer cells.…”

The role of human ribonuclease A family in health and diseases: A systematic review

“…Mature RNases are secretory proteins that share the specific elements of the sequence signature ( Figure 1 A), a kidney-shaped tertiary structure stabilized by disulfide bonds, and a catalytic center comprising two histidine residues and one lysine residue ( Figure 1 B) ( Cuchillo et al., 2011 ). As enzymes, these proteins mainly digest single-stranded RNA substrates, such as tRNA, rRNA, or mRNA, by catalyzing the trans-phosphorylation and hydrolysis of the phosphodiester bond ( Castro et al., 2021 ; Cuchillo et al., 2011 ; Raines, 1998 ). However, their ribonucleolytic activity varies in magnitude.…”

“…Furthermore, RNase 2, 3, 5, and 7 participate in regulating allergies or immune diseases of the skin, the respiratory system, and the gut ( Lu et al., 2018 ). In tumors, RNase 5 has been shown to promote tumor growth and metastasis ( Sheng and Xu, 2016 ); however, RNase 1 is considered as candidate therapy for tumors ( Castro et al., 2021 ). In neurological disorders, RNase 2 and 3 are considered risk factors because of their potential neurotoxicity ( Singh and Batra, 2011 ), whereas RNase 4 and 5 are found as neuroprotective factors ( Li et al., 2013 ; Sebastià et al., 2009 ).…”

Structural and Functional Differences between Homologous Bacterial Ribonucleases

“…Catalyzing the degradation of RNA polymers, RNases indirectly participate in many cellular processes such as gene expression, cell growth and differentiation, and immune response [4][5][6]. The ability of RNases to inhibit the growth of tumor cells and the reproduction of viruses in infected cells was also shown [7,8]. The application of RNases as antitumor and antiviral agents implies their penetration into mammalian cells which contain a cytosolic RNase inhibitor (RI).…”