Imatinib Mesylate Exerts Anti-Proliferative Effects on Osteosarcoma Cells and Inhibits the Tumour Growth in Immunocompetent Murine Models

Osteosarcoma is the most common primary malignant bone tumour characterized by osteoid production and/or osteolytic lesions of bone. A lack of response to chemotherapeutic treatments shows the importance of exploring new therapeutic methods. Imatinib mesylate (Gleevec, Novartis Pharma), a tyrosine kinase inhibitor, was originally developed for the treatment of chronic myeloid leukemia. Several studies revealed that imatinib mesylate inhibits osteoclast differentiation through the M-CSFR pathway and activates osteoblast differentiation through PDGFR pathway, two key cells involved in the vicious cycle controlling the tumour development. The present study investigated the in vitro effects of imatinib mesylate on the proliferation, apoptosis, cell cycle, and migration ability of five osteosarcoma cell lines (human: MG-63, HOS; rat: OSRGA; mice: MOS-J, POS-1). Imatinib mesylate was also assessed as a curative and preventive treatment in two syngenic osteosarcoma models: MOS-J (mixed osteoblastic/osteolytic osteosarcoma) and POS-1 (undifferentiated osteosarcoma). Imatinib mesylate exhibited a dose-dependent anti-proliferative effect in all cell lines studied. The drug induced a G0/G1 cell cycle arrest in most cell lines, except for POS-1 and HOS cells that were blocked in the S phase. In addition, imatinib mesylate induced cell death and strongly inhibited osteosarcoma cell migration. In the MOS-J osteosarcoma model, oral administration of imatinib mesylate significantly inhibited the tumour development in both preventive and curative approaches. A phospho-receptor tyrosine kinase array kit revealed that PDGFRα, among 7 other receptors (PDFGFRβ, Axl, RYK, EGFR, EphA2 and 10, IGF1R), appears as one of the main molecular targets for imatinib mesylate. In the light of the present study and the literature, it would be particularly interesting to revisit therapeutic evaluation of imatinib mesylate in osteosarcoma according to the tyrosine-kinase receptor status of patients.

骨肉瘤（Osteosarcoma）是最常见的原发性恶性骨肿瘤，以骨样组织生成和/或溶骨性骨病变为特征。化疗应答不足凸显了探索新型治疗手段的重要性。甲磺酸伊马替尼（Imatinib mesylate，商品名Gleevec，诺华制药）是一种酪氨酸激酶抑制剂，最初被开发用于慢性髓系白血病的治疗。多项研究表明，甲磺酸伊马替尼可通过M-CSFR通路抑制破骨细胞分化，并通过PDGFR通路激活成骨细胞分化，这两类关键细胞参与了调控肿瘤发生发展的恶性循环。本研究探究了甲磺酸伊马替尼对5种骨肉瘤细胞系（人源：MG-63、HOS；大鼠源：OSRGA；小鼠源：MOS-J、POS-1）的增殖、凋亡、细胞周期及迁移能力的体外影响。同时，本研究在两种同源骨肉瘤模型（MOS-J：混合性成骨/溶骨性骨肉瘤；POS-1：未分化型骨肉瘤）中评估了甲磺酸伊马替尼作为治疗性与预防性手段的效果。甲磺酸伊马替尼在所有受试细胞系中均表现出剂量依赖性的抗增殖效应。该药物可使大多数细胞系出现G0/G1期细胞周期阻滞，而POS-1与HOS细胞则被阻滞于S期。此外，甲磺酸伊马替尼可诱导细胞死亡，并显著抑制骨肉瘤细胞的迁移能力。在MOS-J骨肉瘤模型中，口服甲磺酸伊马替尼可在预防性与治疗性给药方案中均显著抑制肿瘤生长。磷酸化受体酪氨酸激酶阵列试剂盒检测显示，在另外7种受体（PDGFRβ、Axl、RYK、EGFR、EphA2、EphA10、IGF1R）中，PDGFRα是甲磺酸伊马替尼的主要分子靶点之一。结合本研究结果与现有文献，根据患者的酪氨酸激酶受体表达状态重新评估甲磺酸伊马替尼在骨肉瘤中的治疗价值，将极具研究意义。