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.
背景/目的：软骨肉瘤（CS）作为成人最常见的恶性骨肿瘤，因术后高复发率、高转移率及对化疗的耐药性而预后不良。CS中天冬氨酰-天冬酰胺酰-β-羟化酶（ASPH）的高表达通过激活Notch和PI3K/mTOR通路驱动肿瘤侵袭性生长，这为联合标准阿霉素（DOX）化疗提供了潜在治疗策略。我们假设靶向ASPH催化结构域的小分子抑制剂SMI1182与靶向PI3K/mTOR的BEZ235可增强DOX的化疗效果。本研究采用人源CS1（3级）和CDS11（2级）传统CS细胞系，通过单药或联合给药方式给予不同浓度梯度的DOX、BEZ235或SMI1182，评估其对细胞活力、毒性和运动能力的抗肿瘤效应。方法：机制研究包括分析ASPH表达、Notch信号通路及通过mTOR激活的胰岛素/IGF/IRS通路。结果：DOX、BEZ235或SMI1182处理均引起剂量依赖性细胞损失和细胞毒性。SMI1182和BEZ235（无论是否联合DOX）均显著降低细胞定向运动能力。联合治疗产生叠加的细胞毒性效应，该效应与ASPH、Notch转录因子及可正向调控ASPH和Notch的胰岛素受体底物1型表达下调相关。结论：DOX、SMI1182和BEZ235的三联疗法通过同时靶向调控侵袭性恶性肿瘤细胞行为的多个上游介质，有望改善软骨肉瘤患者的无病生存期。
肿瘤(癌症)患者之家