Antitumor Ribonucleases

Investigating the effects of double mutation C30A/C75A on onconase structure: Studies at atomic resolution

“…The observed Lys31 movement supports the hypothesis that the decrease in catalytic efficiency of dmONC relative to wild type enzyme results from the rearrangement of Lys31 position. The dependence of ONC catalytic efficiency from small shifts of Lys31 position was also reported by Merlino et al…”

“…ONC structure is highly packed and consists of two β‐sheets and three α‐helices; helices H2 and H3 shield from water the two β‐sheets that form the characteristic V‐shaped motif defining two lobes (named V 1 and V 2 in analogy to RNase A structure) in the middle of which helix H1 is positioned (Figure ). Furthermore, native ONC has pyroglutamic residue that blocks the N‐terminus and is essential for obtaining the fully active enzyme . In the course of an investigation on the determinants of onconase cytotoxicity we produced an ONC double mutant, C30A/C75A, (dmONC) in which Cys30 and Cys75 forming one of the four disulfide bridges were replaced by alanines.…”

Approaches to Endow Ribonucleases with Antitumor Activity: Lessons Learned from the Native Cytotoxic Ribonucleases

“…ONC reached phases II/IIIb for treatment of malignant pleural mesothelioma [21] although it presents renal toxicity that is reversed when the treatment is discontinued [32]. It exhibits selective cytostatic and cytotoxic activities against many tumor models both in vitro and in vivo [22,33] and presents synergy, proved also in vivo and in vitro, with a significant number of compounds [34]. ONC induces apoptosis or in some cases autophagy previously to apoptosis [35,36].…”

“…It has been described that ONC up-or downregulates genes that code for proteins involved in cell cycle control or transcription factors that are also responsible for its cytotoxicity [43]. Although from the literature the apoptotic effects seem to be cell-type dependent [34], recently it has been found that the activating transcription factor 3 (ATF3) controls ONC-induced apoptosis in a cell-type independent manner (Vert et al, submitted). Other tumoricidal amphibian RNases are Amphinase (Amph), also isolated from oocytes of R. pipiens [44] and the sialic acid-binding lectins (leczymes) found in Rana catesbeiana (RC-RNase) and Rana japonica (RJ-RNase) oocytes [45,46].…”

A Sweet Delivery for a Really Bitter Pill: Globo H and RNase 1

“…The result is the induction of apoptosis in the relevant cells. 1 In this issue, Raines and collaborators report Globo H hexasaccharide as a newly identified ligand of cytotoxic RNase. 2 This finding represents a first in the identification of specific cell surface ligand/receptor pairs for RNase and presents a potential mechanism for its membrane transport.…”