Shandong Provincial Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 270021, China.
Key Lab of Cerebral Microcirculation in Universities of Shandong, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong 271000, China.
Biomed Pharmacother. 2020 Oct;130:110544. doi: 10.1016/j.biopha.2020.110544. Epub 2020 Jul 25.
Osteosarcoma is a highly invasive primary malignant bone tumor. PI3K/mTOR pathway plays a key role in tumor progression, and inhibition of PI3K/mTOR pathway represents a novel strategy in therapy of osteosarcoma. CCT128930 and VS5584 are both inhibitors of PI3K/mTOR, but the anticancer mechanism of CCT128930 or/and VS5584 against human osteosarcoma cells remains unclear. Herein, U2OS and MG63 human osteosarcoma cells were cultured, and the anticancer effects of CCT128930 alone and the combined effect of CCT128930 and VS5584 against human osteosarcoma cells were explored. The results showed that CCT128930 as PI3K/mTOR inhibitor effectively inhibited p-p70 and p-AKT expression and dose-dependently inhibited U2OS cells and MG63 human osteosarcoma cells growth. Further studies found that CCT128930 triggered significant G-1 phase arrest and apoptosis, as convinced by the dysfunction of p27, Cyclin B1, Cyclin D1 and Cdc2, and PARP cleavage and caspase-3 activation. Moreover, CCT128930 treatment obviously enhanced VS5584-induced growth inhibition and apoptosis in human osteosarcoma cells, followed by enhanced PARP cleavage and caspase-3 activation. Taken together, CCT128930 alone or combined treatment with CCT128930 and VS5584 both effectively inhibited human osteosarcoma cells growth by induction of G1-phase arrest and apoptosis through regulating PI3K/mTOR and MAPKs pathways.
骨肉瘤是一种高度侵袭性的原发性恶性骨肿瘤。PI3K/mTOR 通路在肿瘤进展中发挥关键作用，抑制 PI3K/mTOR 通路代表了骨肉瘤治疗的一种新策略。CCT128930 和 VS5584 均为 PI3K/mTOR 的抑制剂，但 CCT128930 或/和 VS5584 对人骨肉瘤细胞的抗癌机制尚不清楚。在此，培养 U2OS 和 MG63 人骨肉瘤细胞，探讨 CCT128930 单独以及 CCT128930 与 VS5584 联合对人骨肉瘤细胞的抗癌作用。结果表明，作为 PI3K/mTOR 抑制剂的 CCT128930 有效抑制了 p-p70 和 p-AKT 的表达，并呈剂量依赖性抑制 U2OS 细胞和 MG63 人骨肉瘤细胞的生长。进一步研究发现，CCT128930 触发了明显的 G1 期阻滞和细胞凋亡，这一点可以从 p27、Cyclin B1、Cyclin D1 和 Cdc2 的功能障碍以及 PARP 切割和 caspase-3 激活得到证明。此外，CCT128930 处理明显增强了 VS5584 诱导的人骨肉瘤细胞生长抑制和凋亡，随后增强了 PARP 切割和 caspase-3 激活。总之，CCT128930 单独或联合治疗均能有效抑制人骨肉瘤细胞生长，通过调节 PI3K/mTOR 和 MAPKs 通路诱导 G1 期阻滞和细胞凋亡。
