Improving the specific antitumor efficacy of ONC by fusion with N-terminal domain of transferrin

Qi, Jianying; Ye, Xianlong; Bai, Haijing; Xu, Chi

doi:10.1080/09168451.2018.1456318

Cited by 4 publications

(3 citation statements)

References 33 publications

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“…Following target of oncological treatment became the transferrin receptor (TfR), which is overexpressed in numerously cancers. Connection onconase and TfR-targeting antibody was performed to increase efficacy RNAse [76]. This assumption was confirmed in trial with TfR rich cancer cells (HepG2 and Hela).…”

Section: Targeted Therapeutic Rnases (Immunornases)mentioning

confidence: 80%

Ribonucleases and Immunoribonucleases as Potential Modalities of Anticancer Therapy

Kowalik¹,

Witkowska²,

Smolewski³

2020

DDA

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A novel approach of antitumor treatment, that involves targeting RNA either using specific antisense oligonucleotides or cytostatic/cytotoxic ribonucleases (RNases), is being promoted. Among recently described cytotoxic RNases, amphibian RNases, including ranpirnase (onconase; ONC) and Amphinase (rAmph), are promising anticancer agents. They manifest strong antitumor effects and act synergistically with several cytostatics. Recently, rapidly developed proteins by engineering of RNases, displayed cytotoxic activity against several types of malignant cells. Most recent data show the role of microRNAs in mediating tumor progression, opening a new field of possible molecular targets for RNases. This review summarizes the current status of those RNases and immunoRNases as promising novel anticancer therapeutics.

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Section: Targeted Therapeutic Rnases (Immunornases)mentioning

confidence: 80%

Ribonucleases and Immunoribonucleases as Potential Modalities of Anticancer Therapy

Kowalik¹,

Witkowska²,

Smolewski³

2020

DDA

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“…Moreover, toxicity against head–neck EGFR-expressing tumor cells was registered upon conjugating ONC with a dengue virus-derived peptide [ 130 ]. Moreover, ONC fusion with the transferrin N-terminal domain gained activity against HepG2 and Hela cells [ 131 ], while fusion with the scorpion-derived chlorotoxin made ONC potently active against U251 and SHG-44 glioma cells [ 132 ]. A similar approach was also applied with diabodies, i.e., noncovalent dimers of ONC conjugated with dimeric antibody fragments (scFv) derived from variable regions of their heavy and light chains [ 45 ].…”

Section: Rnases and Rna Processing As Tumor And Viral Infection Manag...mentioning

confidence: 99%

Role of the Ribonuclease ONCONASE in miRNA Biogenesis and tRNA Processing: Focus on Cancer and Viral Infections

Menegazzi

Gotte

2022

IJMS

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The majority of transcribed RNAs do not codify for proteins, nevertheless they display crucial regulatory functions by affecting the cellular protein expression profile. MicroRNAs (miRNAs) and transfer RNA-derived small RNAs (tsRNAs) are effectors of interfering mechanisms, so that their biogenesis is a tightly regulated process. Onconase (ONC) is an amphibian ribonuclease known for cytotoxicity against tumors and antiviral activity. Additionally, ONC administration in patients resulted in clinical effectiveness and in a well-tolerated feature, at least for lung carcinoma and malignant mesothelioma. Moreover, the ONC therapeutic effects are actually potentiated by cotreatment with many conventional antitumor drugs. This review not only aims to describe the ONC activity occurring either in different tumors or in viral infections but also to analyze the molecular mechanisms underlying ONC pleiotropic and cellular-specific effects. In cancer, data suggest that ONC affects malignant phenotypes by generating tRNA fragments and miRNAs able to downregulate oncogenes expression and upregulate tumor-suppressor proteins. In cells infected by viruses, ONC hampers viral spread by digesting the primer tRNAs necessary for viral DNA replication. In this scenario, new therapeutic tools might be developed by exploiting the action of ONC-elicited RNA derivatives.

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“…The protein-fusion technique has been applied also to ONC to conjugate and express it with many diverse adducts (Figures 1I,J), such as various antibody fragments, human serum albumin, dengue virus-derived peptide, and more recently with the N-terminal domain of transferrin (177, 216, 218, 219, 221, 230). All these adducts displayed augmented cytotoxicity in vitro against many cancer cells, and in some cases also in mice (177, 218).…”

Section: Rnase Oligomerization: a Strategy To Obtain Stable And More mentioning

confidence: 99%

Biological Activities of Secretory RNases: Focus on Their Oligomerization to Design Antitumor Drugs

Gotte

Menegazzi

2019

Front. Immunol.

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Ribonucleases (RNases) are a large number of enzymes gathered into different bacterial or eukaryotic superfamilies. Bovine pancreatic RNase A, bovine seminal BS-RNase, human pancreatic RNase 1, angiogenin (RNase 5), and amphibian onconase belong to the pancreatic type superfamily, while binase and barnase are in the bacterial RNase N1/T1 family. In physiological conditions, most RNases secreted in the extracellular space counteract the undesired effects of extracellular RNAs and become protective against infections. Instead, if they enter the cell, RNases can digest intracellular RNAs, becoming cytotoxic and having advantageous effects against malignant cells. Their biological activities have been investigated either in vitro, toward a number of different cancer cell lines, or in some cases in vivo to test their potential therapeutic use. However, immunogenicity or other undesired effects have sometimes been associated with their action. Nevertheless, the use of RNases in therapy remains an appealing strategy against some still incurable tumors, such as mesothelioma, melanoma, or pancreatic cancer. The RNase inhibitor (RI) present inside almost all cells is the most efficacious sentry to counteract the ribonucleolytic action against intracellular RNAs because it forms a tight, irreversible and enzymatically inactive complex with many monomeric RNases. Therefore, dimerization or multimerization could represent a useful strategy for RNases to exert a remarkable cytotoxic activity by evading the interaction with RI by steric hindrance. Indeed, the majority of the mentioned RNases can hetero-dimerize with antibody derivatives, or even homo-dimerize or multimerize, spontaneously or artificially. This can occur through weak interactions or upon introducing covalent bonds. Immuno-RNases, in particular, are fusion proteins representing promising drugs by combining high target specificity with easy delivery in tumors. The results concerning the biological features of many RNases reported in the literature are described and discussed in this review. Furthermore, the activities displayed by some RNases forming oligomeric complexes, the mechanisms driving toward these supramolecular structures, and the biological rebounds connected are analyzed. These aspects are offered with the perspective to suggest possible efficacious therapeutic applications for RNases oligomeric derivatives that could contemporarily lack, or strongly reduce, immunogenicity and other undesired side-effects.

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Improving the specific antitumor efficacy of ONC by fusion with N-terminal domain of transferrin

Cited by 4 publications

References 33 publications

Ribonucleases and Immunoribonucleases as Potential Modalities of Anticancer Therapy

Ribonucleases and Immunoribonucleases as Potential Modalities of Anticancer Therapy

Role of the Ribonuclease ONCONASE in miRNA Biogenesis and tRNA Processing: Focus on Cancer and Viral Infections

Biological Activities of Secretory RNases: Focus on Their Oligomerization to Design Antitumor Drugs

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