Ribonuclease binase inhibits primary tumor growth and metastases via apoptosis induction in tumor cells

• Published in: Cell cycle (Georgetown, Tex.) Tex.), 2013-07, Vol.12 (13), p.2120-2131
• Main Authors: Mironova, Nadezhda, Petrushanko, Irina, Patutina, Olga, Sen'kova, Aexandra V., Simonenko, Olga, Mitkevich, Vladimir, Markov, Oleg, Zenkova, Marina, Makarov, Alexander A.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Antineoplastic Agents - toxicity; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; apoptotic pathways; Carcinoma, Lewis Lung - drug therapy; Carcinoma, Lewis Lung - secondary; Cell Line, Tumor; Cell Proliferation; Cyclophosphamide - pharmacology; Cyclophosphamide - therapeutic use; Cytokines - blood; cytotoxicity; Doxorubicin - pharmacology; Doxorubicin - therapeutic use; Drug Screening Assays, Antitumor; Endoribonucleases - administration & dosage; Endoribonucleases - pharmacology; Endoribonucleases - toxicity; Injections, Intramuscular; Injections, Intraperitoneal; Liver - drug effects; Liver - pathology; Lymphoma, Non-Hodgkin - blood; Lymphoma, Non-Hodgkin - drug therapy; Melanoma, Experimental - drug therapy; Melanoma, Experimental - secondary; Membrane Potential, Mitochondrial - drug effects; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; murine tumor model; Neoplasm Transplantation; Prednisone - pharmacology; Prednisone - therapeutic use; Reactive Oxygen Species - metabolism; RNase; Tumor Burden - drug effects; tumoricidal activity; Vincristine - pharmacology; Vincristine - therapeutic use
• ISSN: 1538-4101; 1551-4005
• DOI: 10.4161/cc.25164

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.