The role of electrostatic interactions in the antitumor activity of dimeric RNases.
The cytotoxic action of some ribonucleases homologous to bovine pancreatic RNase A, the superfamily prototype, has interested and intrigued investigators. Their ribonucleolytic activity is essential for their cytotoxic action, and their target RNA is in the cytosol. It has been proposed that the cytosolic RNase inhibitor (cRI) plays a major role in determining the ability of an RNase to be cytotoxic. However, to interact with cRI RNases must reach the cytosol, and cross intracellular membranes. To investigate the interactions of cytotoxic RNases with membranes, cytotoxic dimeric RNases resistant, or considered to be resistant to cRI, were assayed for their effects on negatively charged membranes. Furthermore, we analyzed the electrostatic interaction energy of the RNases complexed in silico with a model membrane. The results of this study suggest that close correlations can be recognized between the cytotoxic action of a dimeric RNase and its ability to complex and destabilize negatively charged membranes.
Notomista
Eugenio
E
Dipartimento di Biologia Strutturale e Funzionale, Università di Napoli Federico II, Napoli, Italy.
Mancheño
José Miguel
JM
Crescenzi
Orlando
O
Di Donato
Alberto
A
Gavilanes
José
J
D'Alessio
Giuseppe
G
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D003198:Computer Simulation; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D007425:Intracellular Membranes / Q000737:chemistry / Q000378:metabolism; D008560:Membrane Fluidity / Q000187:drug effects*; D012260:Ribonucleases / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D055672:Static Electricity
D000970:Antineoplastic Agents; D012260:Ribonucleases