Lian Zhen, Han Jinsong, Huang Lin, Wei Chengming, Fan Yongyong, Xu Jiake, Zhou Mengyu, Feng Haotian, Liu Qian, Chen Lingzi, Li Zhaoning, Cheng Haichun, Yuan Guixin, Lin Xixi, Song Fangming, Su Yiji, Wang Chao, Huang Guopeng, Qin An, Song Yunlong, Yao Guanfeng
Department of Orthopedics, The Second Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong, China.
Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai, China.
Carcinogenesis. 2019 Apr 29;40(2):e1-e13. doi: 10.1093/carcin/bgy036.
Osteosarcoma is the most frequent primary bone tumor in children and adolescents. The phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is an attractive anticancer target because it plays key roles in the regulation of cell growth, division and differentiation. In this study, we demonstrated high expression of PI3K/mTOR signaling pathway-related genes in patients with osteosarcoma. We thus investigated the effects of A005, a newly synthesized dual PI3K/mTOR inhibitor, on osteosarcoma cells and in a mouse xenograft tumor model. The results confirmed that A005 inhibited the proliferation, migration and invasion of human osteosarcoma cells. In addition, A005 also inhibited receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation and bone resorption in vitro. Therefore, A005 was further applied to a SaOS-2 osteosarcoma-induced mouse osteolysis model. A005 inhibited tumor growth and prevented osteosarcoma-associated osteolysis via modulation of the PI3K/AKT/mTOR pathway. Overall, our results showed that A005 inhibited osteoclastogenesis and prevented osteosarcoma-induced bone osteolysis by suppressing PI3K/AKT/mTOR signaling. These findings indicated that A005 may be a promising candidate drug for the treatment of human osteosarcoma.
骨肉瘤是儿童和青少年中最常见的原发性骨肿瘤。磷脂酰肌醇3激酶（PI3K）/雷帕霉素哺乳动物靶蛋白（mTOR）信号通路是一个有吸引力的抗癌靶点，因为它在细胞生长、分裂和分化的调节中起关键作用。在本研究中，我们证明了骨肉瘤患者中PI3K/mTOR信号通路相关基因的高表达。因此，我们研究了新合成的双PI3K/mTOR抑制剂A005对骨肉瘤细胞和小鼠异种移植肿瘤模型的影响。结果证实，A005抑制人骨肉瘤细胞的增殖、迁移和侵袭。此外，A005在体外还抑制核因子κB受体激活剂配体（RANKL）诱导的破骨细胞分化和骨吸收。因此，A005进一步应用于SaOS-2骨肉瘤诱导的小鼠骨溶解模型。A005通过调节PI3K/AKT/mTOR途径抑制肿瘤生长并预防骨肉瘤相关的骨溶解。总体而言，我们的结果表明，A005通过抑制PI3K/AKT/mTOR信号传导抑制破骨细胞生成并预防骨肉瘤诱导的骨溶解。这些发现表明，A005可能是治疗人类骨肉瘤的一种有前景的候选药物。
