Chondrosarcoma: Multi-Targeting Therapeutic Effects of Doxorubicin, BEZ235, and the Small Molecule Aspartyl-Asparaginyl-β-hydroxylase Inhibitor SMI1182.

BACKGROUND/OBJECTIVES: Chondrosarcoma (CS), the most common malignant bone tumor in adults, exhibits a poor prognosis due to high rates of post-surgical recurrence and metastasis, and resistance to chemotherapy. CS's abundant expression of aspartyl-asparaginyl-β-hydroxylase (ASPH), which drives invasive tumor growth via Notch and PI3K/mTOR activation, opens opportunities for treatment in combination with standard Doxorubicin (DOX) chemotherapy. We hypothesized that the small molecule inhibitor SMI1182, which targets the catalytic domain of ASPH, and BEZ235, which targets PI3K/mTOR, could enhance the chemotherapeutic effects of DOX. Human CS1 (Grade 3) and CDS11 (Grade 2) conventional CS cell lines were treated with broad dose ranges of DOX, BEZ235, or SMI1182 as mono- or combination therapy to assess their anti-tumor effects on cell viability, toxicity, and motility. METHODS: Mechanistic studies included the analysis of ASPH expression, Notch signaling, and insulin/IGF/IRS pathway activation through mTOR. DOX, BEZ235, or SMI1182 treatments caused dose-dependent cell loss and cytotoxicity. RESULTS: SMI1182 and BEZ235, with or without DOX, significantly reduced directional motility. Combined treatments had additive cytotoxic effects linked to the reduced expression of ASPH, Notch transcription factors, and insulin receptor substrate type I, which positively regulates both ASPH and Notch. CONCLUSIONS: Triple-drug treatment with DOX, SMI1182, and BEZ235 could potentially improve disease-free survival with CS by the simultaneous targeting of multiple upstream mediators of aggressive malignant tumor cell behavior.