Screening of a growth inhibitor library of sarcoma cell lines to identify potent anti-cancer drugs

Abstract

There is a need for novel drugs for sarcoma treatment. In the present study, to identify inhibitors with potential therapeutic utility in sarcomas, we screened the growth inhibitory effects of 361 inhibitors, including experimental reagents and anti-cancer drugs approved for use in non-sarcoma malignancies and those under clinical trials. The inhibitors were initially tested using 10 osteosarcoma cell lines. The half-maximal inhibitory concentration (IC50) of leptomycin B, actinomycin D, chetomin, and staurosporine was <100 nM in all the cell lines. As the promiscuous effects of staurosporine on kinases make it unsuitable for clinical applications, the other three inhibitors were tested in an additional 15 sarcoma cell lines derived from synovial sarcoma, fibrosarcoma, liposarcoma, rhabdomyosarcoma, malignant peripheral nerve sheath tumor, leiomyosarcoma, and Ewing’s sarcoma. The IC50 of leptomycin B and actinomycin D was <100 nM in all cell lines and that of chetomin was <100 nM in all but three synovial sarcoma cell lines. Although the clinical development of leptomycin B, a chromosomal region maintenance (CRM)1/exportin (XPO)1 inhibitor, was discontinued because of toxicity, a previous clinical trial revealed that other CRM1/XPO1 inhibitors, such as selinexor, have anti-tumor effects in sarcomas. Actinomycin D has proven clinical utility in the treatment of sarcomas. Chetomin disrupts the interaction of hypoxia-inducible factor-1 with the transcriptional coactivator p300 and its clinical utility has not been established in sarcomas. Chetomin exhibited growth inhibitory effects on sarcoma cells with different histological subtypes. Library screening is a powerful approach to detect the potential utility of anti-cancer drugs in sarcoma treatment.