New small molecules targeting apoptosis and cell viability in osteosarcoma

Doris Maugg; Ina Rothenaigner; Kenji Schorpp; Harish Kumar Potukuchi; Eberhard Korsching; Daniel Baumhoer; Kamyar Hadian; Jan Smida; Michaela Nathrath

doi:10.1371/journal.pone.0129058

New small molecules targeting apoptosis and cell viability in osteosarcoma

PLoS One. 2015 Jun 3;10(6):e0129058. doi: 10.1371/journal.pone.0129058. eCollection 2015.

Authors

Doris Maugg¹, Ina Rothenaigner², Kenji Schorpp², Harish Kumar Potukuchi³, Eberhard Korsching⁴, Daniel Baumhoer⁵, Kamyar Hadian², Jan Smida¹, Michaela Nathrath⁶

Affiliations

¹ 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.
² Assay Development and Screening Platform, Institute for Molecular Toxicology and Pharmacology, Helmholtz Zentrum München-National Research Centre for Environmental Health, Neuherberg, Germany.
³ 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.
⁴ Institute of Bioinformatics, University of Münster, Münster, Germany.
⁵ 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.
⁶ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Caspase 3 / genetics
Caspase 3 / metabolism
Caspase 7 / genetics
Caspase 7 / metabolism
Cell Line, Tumor
Cell Survival / drug effects
Doxorubicin / pharmacology
Drug Discovery
Gene Expression Regulation, Neoplastic*
HEK293 Cells
Hep G2 Cells
Hepatocytes / drug effects
Hepatocytes / metabolism
Hepatocytes / pathology
High-Throughput Screening Assays
Humans
Mesenchymal Stem Cells / drug effects
Mesenchymal Stem Cells / metabolism
Mesenchymal Stem Cells / pathology
Organ Specificity
Osteoblasts / drug effects*
Osteoblasts / metabolism
Osteoblasts / pathology
Signal Transduction
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Staurosporine / pharmacology
Structure-Activity Relationship
Tumor Suppressor Protein p53 / deficiency
Tumor Suppressor Protein p53 / genetics*

Substances

Antineoplastic Agents
Small Molecule Libraries
Tumor Suppressor Protein p53
Doxorubicin
Caspase 3
Caspase 7
Staurosporine

Grants and funding

This work was funded by the Translational Sarcoma Research Network (TranSarNet) FKZ 01GM0870 to JS, MN, DM, and FKZ 01GM0869 to EK, and by the European TRANSCAN I consortium—PROspective VAlidation of Biomarkers in Ewing Sarcoma for personalized translational medicine FZK 01KT1310 to EK. All authors were supported by the Bundesministerium für Bildung und Forschung. Financial support to HKP from Helmholtz Zentrum München is gratefully acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.