Marine alkaloid Monanchocidin a overcomes drug resistance by induction of autophagy and lysosomal membrane permeabilization

Abstract

// Sergey A. Dyshlovoy 1,2,3 , Jessica Hauschild 1 , Kerstin Amann 4 , Ksenia M. Tabakmakher 2 , Simone Venz 5,6 , Reinhard Walther 5 , Alla G. Guzii 2 , Tatiana N. Makarieva 2 , Larisa K. Shubina 2 , Sergey N. Fedorov 2 , Valentin A. Stonik 2 , Carsten Bokemeyer 1 , Stefan Balabanov 1,7 , Friedemann Honecker 1,8,* and Gunhild v. Amsberg 1,* 1 Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 2 Laboratory of Marine Natural Products Chemistry, G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-East Branch, Russian Academy of Sciences, Vladivostok, Russian Federation 3 School of Natural Sciences, Far East Federal University, Vladivostok, Russian Federation 4 Nephropathology Department, University Medical Center Erlangen, Erlangen, Germany 5 Department of Medical Biochemistry and Molecular Biology, University of Greifswald, Greifswald, Germany 6 Interfacultary Institute of Genetics and Functional Genomics, Department of Functional Genomics, University of Greifswald, Greifswald, Germany 7 Division of Hematology, University Hospital Zurich, Zurich, Switzerland 8 Tumor and Breast Center ZeTuP St. Gallen, St. Gallen, Switzerland * These authors have contributed equally to this work Correspondence to: Sergey A. Dyshlovoy, email: // Keywords : Monanchocidin A, autophagy, lysosomal membrane permeabilization, germ cell tumor cells, cisplatin resistance Received : March 13, 2015 Accepted : May 02, 2015 Published : May 19, 2015 Abstract Monanchocidin A (MonA) is a novel alkaloid recently isolated from the marine sponge Monanchora pulchra . The compound reveals cytotoxic activity in genitourinary cancers including cisplatin-sensitive and -resistant germ cell tumor (GCT) cell lines, hormone-sensitive and castration-resistant prostate carcinoma cell lines and different bladder carcinoma cell lines. In contrast, non-malignant cells were significantly less sensitive. MonA is highly synergistic with cisplatin in GCT cells. Induction of autophagy at lower and lysosomal membrane permeabilization (LMP) at higher concentrations were identified as the dominating modes of action. Cytotoxicity and protein degradation could be inhibited by 3-methyladenine, an inhibitor of autophagy. LMP was confirmed by loss of acridine orange staining of lysosoms and by release of cathepsin B. In conclusion, MonA exerts cytotoxiс activity by mechanisms different from “classical” apoptosis, and could be a promising new compound to overcome resistance to standard therapies in genitourinary malignancies.