Comprehensive comparison of the cytotoxic activities of onconase and bovine seminal ribonuclease

Matoušek, J.; Souček, J; Slavík, Tomáš; Tománek, M.; Lee, J.Eugene; Raines, Ronald T.

doi:10.1016/j.cca.2003.10.005

Cited by 35 publications

(41 citation statements)

References 62 publications

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“…In our experiments, a lower toxicity of TBN1 nuclease to embryonic cells was observed in comparison with BS-RNase and onconase [11]. These results are promising for further studies of this and other plant nucleases given their possible lower side effects.…”

Section: Apoptotic Nuclease Tbn1 As a Perspective Anticarcinogenic Agsupporting

confidence: 63%

“…As can be judged from these results, the TBN1 embryotoxicity was lower compared to those observed with all the other enzymes examined (Table 2). In all the events, the embryotoxic activity of TBN1 nuclease was also not as strong as that of onconase that we described earlier [11].…”

Section: Antitumorigenic Activity and Embryotoxicity Of Tbn1 In Compamentioning

confidence: 45%

“…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.…”

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confidence: 99%

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Antitumor activity of apoptotic nuclease TBN1 from L. esculentum.

Matoušek

Podzimek²,

Poučková³

et al. 2010

neo

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Nuclease from tomato (TBN1) was produced by in planta biotechnology purified and tested for its anticarcinogenic properties. The nuclease was cytostatic after its intratumoral administration to nude mice bearing human melanoma or prostate carcinoma or after tumor targeting by TBN1 administration intravenously as conjugate with polyethylene glycol (PEG). Inhibitory effects of TBN1 on tumor growth were comparable to effects of bovine seminal RNase (BS-RNase), but the inhibition was reached at about ten times lower protein concentration. Simultaneously, TBN1 exhibited a lower degree of embryotoxicity compared to BS-RNAse and other nucleases. TBN1 showed significant stability in vivo, because it was readily detected after its administration intratumorally or intravenously by the fluorescence methods. Intravenous administration of TBN1-PEG caused significant inhibition of tumor proliferation without obvious degenerative changes, while direct administration of TBN1 into melanoma tumors led to rapid tumor tissue degeneration. The fact can be essential for the mode of TBN1 biological action that mature nuclease is a small (36 kDa) thermostable glycoprotein that has ability to destroy human 28S, 18S, 7S and 5.8S RNA, circular RNAs, double-stranded RNA in vitro and shows DNase and 3'nucleotidase activities.

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Section: Apoptotic Nuclease Tbn1 As a Perspective Anticarcinogenic Agsupporting

confidence: 63%

Section: Antitumorigenic Activity and Embryotoxicity Of Tbn1 In Compamentioning

confidence: 45%

mentioning

confidence: 99%

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Antitumor activity of apoptotic nuclease TBN1 from L. esculentum.

Matoušek

Podzimek²,

Poučková³

et al. 2010

neo

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“…56 A chemotherapeutic agent based on a human ribonuclease have multiple advantages over ONC, including enhanced catalytic activity, 17 decreased renal toxicity, 57,58 and decreased immunogenicity. 59 To endow ribonucleases that are not naturally cytotoxic with cytotoxic activity requires the consideration of multiple biochemical attributes, including ribonucleolytic activity, cationic charge, conformational stability, and (especially) RI evasion. 29,17…”

Section: Rnase 1 As a Chemotherapeutic Agentmentioning

confidence: 99%

Inhibition of Human Pancreatic Ribonuclease by the Human Ribonuclease Inhibitor Protein

Johnson

McCoy

Bingman

et al. 2007

Journal of Molecular Biology

135

201

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The ribonuclease inhibitor protein (RI) binds to members of the bovine pancreatic ribonuclease (RNase A) superfamily with an affinity in the femtomolar range. Here, we report on structural and energetic aspects of the interaction between human RI (hRI) and human pancreatic ribonuclease (RNase 1). The structure of the crystalline hRI·RNase 1 complex was determined at a resolution of 1.95 Å, revealing the formation of 19 intermolecular hydrogen bonds involving 13 residues of RNase 1. In contrast, only 9 such hydrogen bonds are apparent in the structure of the complex between porcine RI and RNase A. hRI, which is anionic, also appears to use its horseshoe-shaped structure to engender long-range Coulombic interactions with RNase 1, which is cationic. In accordance with the structural data, the hRI·RNase 1 complex was found to be extremely stable (t ½ = 81 days; K d = 2.9 × 10 -16 M). Site-directed mutagenesis experiments enabled the identification of two cationic residues in RNase 1-Arg39 and Arg91-that are especially important for both the formation and stability of the complex, and are thus termed "electrostatic targeting residues". Disturbing the electrostatic attraction between hRI and RNase 1 yielded a variant of RNase 1 that maintained ribonucleolytic activity and conformational stability but had a 2.8 × 10 3 -fold lower association rate for complex formation and 5.9 × 10 9 -fold lower affinity for hRI. This variant of RNase 1, which exhibits the largest decrease in RI affinity of any engineered ribonuclease, is also toxic to human erythroleukemia cells. Together, these results provide new insight into an unusual and important protein-protein interaction, and could expedite the development of human ribonucleases as chemotherapeutic agents.

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“…In humans, eosinophil-derived neurotoxin and eosinophil cationic protein (6) exert neurotoxicity as well as antiparasitic activity (7). Bovine seminal ribonuclease (BS-RNase) has been found to induce apoptosis of human thyroid carcinoma cell lines (8,9). Onconase (ONC) from Rana pipiens is cytotoxic (10) and cytostatic to several tumor lines and is currently in phase III clinical trials for the treatment of malignant mesothelioma (8,11,12).…”

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confidence: 99%

The Importance of Dynamic Effects on the Enzyme Activity

Merlino

Mazzarella

Carannante

et al. 2005

Journal of Biological Chemistry

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Onconase (ONC), a member of the RNase A superfamily extracted from oocytes of Rana pipiens, is an effective cancer killer. It is currently used in treatment of various forms of cancer. ONC antitumor properties depend on its ribonucleolytic activity that is low in comparison with other members of the superfamily. The most damaging side effect from Onconase treatment is renal toxicity, which seems to be caused by the unusual stability of the enzyme. Therefore, mutants with reduced thermal stability and/or increased catalytic activity may have significant implications for human cancer chemotherapy. In this context, we have determined the crystal structures of two Onconase mutants (M23L-ONC and C87S,des103-104-ONC) and performed molecular dynamic simulations of ONC and C87S,des103-104-ONC with the aim of explaining on structural grounds the modifications of the activity and thermal stability of the mutants. The results also provide the molecular bases to explain the lower catalytic activity of Onconase compared with RNase A and the unusually high thermal stability of the amphibian enzyme.Ribonucleases are widely found in living organisms and have been proposed to function in RNA metabolism and gene expression (1). Several ribonucleases have been isolated from organs of various animals and have been well characterized. Bovine pancreatic ribonuclease (RNase A) 1 is the most studied member of the family (2). It has been used as a model for the study of the fundamental aspects of protein structure and function (2, 3). Several members of the RNase A superfamily exhibit additional biological functions in connection with their intrinsic ribonucleolytic activities (4, 5). In humans, eosinophil-derived neurotoxin and eosinophil cationic protein (6) exert neurotoxicity as well as antiparasitic activity (7). Bovine seminal ribonuclease (BS-RNase) has been found to induce apoptosis of human thyroid carcinoma cell lines (8, 9). Onconase (ONC) from Rana pipiens is cytotoxic (10) and cytostatic to several tumor lines and is currently in phase III clinical trials for the treatment of malignant mesothelioma (8,11,12). ONC shares 30% of identity with the sequence of RNase A, and its three-dimensional structure exhibits a highly conserved ribonuclease-like topology (13), which comprises a characteristic V-shaped ␤-sheet motif surrounded by three ␣-helices. Differences are mainly localized in the loop regions, which are significantly shorter in ONC, and at the C terminus where a disulfide bond, unique to amphibian ribonucleases, tethers the C-terminal residue Cys 104 to Cys 87 located in one strand of the ␤-sheet (13). Another distinct property of ONC is the presence of an N-terminal pyroglutamate (Pyr 1 ), which folds back against the N-terminal helix (13). The overall active site architecture closely resembles that of RNase A and includes His 10 , Lys 31 , and His 97 , which form the catalytic triad corresponding to His 12 , Lys 41 , and His 119 , respectively, of the pancreatic enzyme. Despite this similarity and the activating effe...

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Comprehensive comparison of the cytotoxic activities of onconase and bovine seminal ribonuclease

Cited by 35 publications

References 62 publications

Antitumor activity of apoptotic nuclease TBN1 from L. esculentum.

Antitumor activity of apoptotic nuclease TBN1 from L. esculentum.

Inhibition of Human Pancreatic Ribonuclease by the Human Ribonuclease Inhibitor Protein

The Importance of Dynamic Effects on the Enzyme Activity

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