Chondrosarcoma: Adjuvant Therapeutic Effects of the ASPH Small Molecule Inhibitor, SMI-1182, With Doxorubicin

Chondrosarcoma (CS) is the most common adult malignant bone tumor. Its poor prognosis is due to chemotherapy resistance and high rates of post-treatment recurrence. The finding that CSs express abundant Aspartyl-Asparaginyl-Β-Hydroxylase (ASPH), which drives invasive tumor growth via Notch pathway activation, provides a new opportunity for treatment in combination with standard Doxorubicin (DOX) chemotherapy. We hypothesized that the small-molecule inhibitor SMI-1182, which targets the catalytic domain of ASPH, could enhance the chemotherapeutic effects of DOX by further reducing CS cell viability, motility, and invasive growth. Human CS-1 and CDS11 conventional chondrosarcoma cell lines were treated with broad dose ranges of DOX, SMI-1182, or DOX+SMI-1182 to measure their separate and combined effects on cell viability, toxicity, motility, and invasive growth. Mechanistic studies included assessments of genes and proteins pertinent to ASPH expression and Notch signaling. Treatment with DOX or SMI-1182 caused dose-dependent CS-1 and CDS11 cell loss and cytotoxicity. SMI-1182, with or without DOX, significantly reduced directional motility and invasive growth relative to vehicle. Combined treatments with DOX and SM-1182 had synergistic cytotoxic and anti-invasive growth effects linked to reduced expression of ASPH immunoreactivity, Notch transcription factors, and insulin receptor substrate, type I, which positively regulates both ASPH and Notch. Dual treatment with DOX and SMI-1182 could potentially improve disease-free survival with CS by simultaneous targeting of multiple upstream mediators of aggressive malignant tumor behavior.