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.
Highlights
Osteosarcoma (OS) is an orphan disease with an incidence of approximately 0.4 per 100,000 population per year [1]
The effects of compounds on cell viability were assessed in U2OS cells, a well-characterized OS cell line [25], using Celltiter Blue (CtB) assay (Fig 1, step 2)
To identify those compounds that selectively act on OS cells, compounds were counter-screened in different OS and non-OS control cells (Table 1) using again cell viability as read-out (Fig 1, step 3)
Summary
Osteosarcoma (OS) is an orphan disease with an incidence of approximately 0.4 per 100,000 population per year [1]. Several genetic alterations have been described to occur in OS at varying frequency, OS are generally characterized by highly complex karyotypes [3,4], at least in a subset of tumors resulting from chromothripsis [5]. Researchers have failed to identify an OS-specific mutation or a pathway. These circumstances may partly explain that therapy in OS has not significantly improved in the last three decades. The standard therapy involves multidrug chemotherapy (methotrexate, doxorubicin, cisplatin and ifosfamide) in combination with radical surgery [6]. This treatment yields positive outcomes in many patients with an overall 5-year survival rate of approximately 70%. The prognosis drastically worsens in patients with apparent metastatic spread or recurrent disease with overall survival rates generally below 20% [7]
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