title: New small molecules targeting apoptosis and cell viability in osteosarcoma.
abstract: Despite the option of multimodal therapy in the treatment strategies of osteosarcoma (OS), the most common primary malignant bone tumor, the standard therapy has not changed over the last decades and still involves multidrug chemotherapy and radical surgery. Although successfully applied in many patients a large number of patients eventually develop recurrent or metastatic disease in which current therapeutic regimens often lack efficacy. Thus, new therapeutic strategies are urgently needed. In this study, we performed a phenotypic high-throughput screening campaign using a 25,000 small-molecule diversity library to identify new small molecules selectively targeting osteosarcoma cells. We could identify two new small molecules that specifically reduced cell viability in OS cell lines U2OS and HOS, but affected neither hepatocellular carcinoma cell line (HepG2) nor primary human osteoblasts (hOB). In addition, the two compounds induced caspase 3 and 7 activity in the U2OS cell line. Compared to conventional drugs generally used in OS treatment such as doxorubicin, we indeed observed a greater sensitivity of OS cell viability to the newly identified compounds compared to doxorubicin and staurosporine. The p53-negative OS cell line Saos-2 almost completely lacked sensitivity to compound treatment that could indicate a role of p53 in the drug response. Taken together, our data show potential implications for designing more efficient therapies in OS.
authors.affiliation: Clinical Cooperation Group Osteosarcoma, Institute of Radiation Biology, Helmholtz Zentrum München-National Research Centre for Environmental Health, Neuherberg, Germany; Department of Pediatrics and Children´s Cancer Research Center, Technische Universität München, Munich, Germany.
authors.forename: Doris
authors.initials: D
authors.lastname: Maugg
authors.affiliation: Assay Development and Screening Platform, Institute for Molecular Toxicology and Pharmacology, Helmholtz Zentrum München-National Research Centre for Environmental Health, Neuherberg, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Rothenaigner
authors.affiliation: Assay Development and Screening Platform, Institute for Molecular Toxicology and Pharmacology, Helmholtz Zentrum München-National Research Centre for Environmental Health, Neuherberg, Germany.
authors.forename: Kenji
authors.initials: K
authors.lastname: Schorpp
authors.affiliation: Lehrstuhl für Organische Chemie I and Catalysis Research Center (CRC), Technische Universität München, Garching, Germany; Institute of Structural Biology, Helmholtz Zentrum München-National Research Centre for Environmental Health, Neuherberg, Germany.
authors.forename: Harish Kumar
authors.initials: HK
authors.lastname: Potukuchi
authors.affiliation: Institute of Bioinformatics, University of Münster, Münster, Germany.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Korsching
authors.affiliation: Clinical Cooperation Group Osteosarcoma, Institute of Radiation Biology, Helmholtz Zentrum München-National Research Centre for Environmental Health, Neuherberg, Germany; Bone Tumor Reference Center at the Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Baumhoer
authors.affiliation: Assay Development and Screening Platform, Institute for Molecular Toxicology and Pharmacology, Helmholtz Zentrum München-National Research Centre for Environmental Health, Neuherberg, Germany.
authors.forename: Kamyar
authors.initials: K
authors.lastname: Hadian
authors.affiliation: Clinical Cooperation Group Osteosarcoma, Institute of Radiation Biology, Helmholtz Zentrum München-National Research Centre for Environmental Health, Neuherberg, Germany; Department of Pediatrics and Children´s Cancer Research Center, Technische Universität München, Munich, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Smida
authors.affiliation: Clinical Cooperation Group Osteosarcoma, Institute of Radiation Biology, Helmholtz Zentrum München-National Research Centre for Environmental Health, Neuherberg, Germany; Department of Pediatrics and Children´s Cancer Research Center, Technische Universität München, Munich, Germany; Department of Pediatric Oncology, Klinikum Kassel, Kassel, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Nathrath
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053179:Caspase 7 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D055808:Drug Discovery; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D057166:High-Throughput Screening Assays; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D019311:Staurosporine / Q000494:pharmacology; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D054852:Small Molecule Libraries; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D053148:Caspase 3; D053179:Caspase 7; D019311:Staurosporine