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The successful application of exogenous ribonucleases of different origin to suppress tumor growth allows one to consider them as perspective therapeutics for treatment of oncological diseases. An important aspect of the success of an anti-cancer drug is low hepatotoxicity, which will reduce, if not eliminate entirely the undesirable side effects of treatment. Previously we have shown that ribonuclease from Bacillus intermedius (binase) exhibits high antitumor and antimetastatic activity in tumor models of different histological origin. In this work we studied hepatotoxic action of binase using mouse tumor model of Lewis lung carcinoma. Binase at doses of 0.1-1 mg/kg which produced effective suppression of tumor growth and metastasis, showed positive effect on the liver of tumor-bearing mice expressed in a significant reduction in the volume of destructive changes in the liver parenchyma and return to the normal level of the liver regenerative potential impaired due to endogenous intoxication and tumor burden., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Exogenous ribonucleases are known to inhibit tumor growth via apoptosis induction in tumor cells, allowing to consider them as promising anticancer drugs for clinical application. In this work the antitumor potential of binase was evaluated in vivo and the mechanism of cytotoxic effect of binase on tumor cells was comprehensively studied in vitro. We investigated tumoricidal activity of binase using three murine tumor models of Lewis lung carcinoma (LLC), lymphosarcoma RLS 40 and melanoma B-16. We show for the first time that intraperitoneal injection of binase at a dose range 0.1-5 mg/kg results in retardation of primary tumor growth up to 45% in LLC and RLS 40 and inhibits metastasis up to 50% in LLC and RLS 40 and up to 70% in B-16 melanoma. Binase does not exhibit overall toxic effect and displays a general systemic and immunomodulatory effects. Treatment of RLS 40-bearing animals with binase together with polychemotherapy revealed that binase decreases the hepatotoxicity of polychemotherapy while maintaining its antitumor effect. It was demonstrated that the cytotoxic effect of binase is realized via the induction of the intrinsic and extrinsic apoptotic pathways. Activation of intrinsic apoptotic pathway is manifested by a drop of mitochondrial potential, increase in calcium concentration and inhibition of respiratory activity. Subsequent synthesis of TNF-α in the cells under the action of binase triggers extrinsic apoptotic pathway through the binding of TNF with cell-death receptors and activation of caspase 8. Thus binase is a potential anticancer therapeutics inducing apoptosis in cancer cells.