Omacetaxine reduces c-Myc expression and demonstrates antitumor effects in osteosarcoma

Omacetaxine mepesuccinate (OMX), formerly known as homoharringtonine, is a protein translation inhibitor approved for use in human chronic myeloid leukemia. Recent studies suggest that OMX may be effective against other cancer types, and may be successful against protein targets that are otherwise difficult to inhibit by reducing their translation rates. Using canine, human, and mouse osteosarcoma (OS) cell lines, we investigated the antineoplastic effects of OMX against OS by evaluating growth inhibition, migration and invasion, apoptosis, expression of c-Myc, changes in gene expression, and in vivo efficacy. OMX induced dose-dependent growth inhibition and apoptosis of OS cells with IC50 values in the low nanomolar range. OMX also reduced migration and Matrigel invasion. Strikingly, levels of c-Myc protein were reduced in most canine, human, and mouse OS cell lines after OMX exposure, and Myc target RNA transcripts were also reduced with treatment. OMX significantly inhibited tumor growth in and metastasis in two separate orthotopic mouse OS models. OMX is a promising candidate for treatment of OS in both dogs and humans, and potentially other c-Myc-driven cancers. Overall design: RNA-seq profiling of DLM8 and Gracie cells with 6 hours of 50 nM omacetaxine exposure and untreated control cells.