Cell Cycle ( IF 3.4 ) Pub Date : 2020-05-13 , DOI: 10.1080/15384101.2020.1762041 Gen Ba 1, 2 , Zhongyan Hua 1, 2 , Ning Xu 1, 2 , Simeng Zhang 1, 2 , Zhihui Liu 3 , Carol J Thiele 3 , Zhijie Li 1, 2
Osteosarcoma (OS) is the most common primary malignancy of bone that mostly affects children, adolescents, and young people. Despite advances have been made in multimodal therapy of OS, the long-term survival rate has reached a plateau, and the main obstacles are bad response to chemotherapy and gained chemoresistance. In this study, we tested the therapeutic effect of a newly reported drug, DMAMCL, on OS. Five human OS cell lines (143B, MNNG, MG63, Saos-2, U-2OS), and the mouse fibroblast cell line (NIH3T3) and human retinal epithelial cell (ARPE19) were used. The anti-tumor effect of DMAMCL was studied by MTS assay or IncuCyte-Zoom (in vitro), and Xenograft-mice-model (in vivo). Changes of cell cycle, apoptotic cells, caspase3/7 activities, and stemness after DMAMCL treatment were investigated. BAX siRNAs were used to knockdown the expression of BAX. Expressions of CyclinB1, CDC2, BCL-2 family, PARP, CD133, and Nanog were measured by Western Blotting. DMAMCL-induced dose-dependent OS cell death in vitro, and suppressed tumor growth and extended the survival of xenograft-bearing mice. DMAMCL-induced G2/M phase arrest in vitro, and apoptosis both in vitro and in vivo. Down-regulation of BAX expression attenuated the DMAMCL-induced OS cell death in vitro. We also found that DMAMCL inhibited the stemness in OS cells. These results indicated that DMAMCL possess therapeutic value in OS and may be a promising candidate for the new drug discovery for OS therapy.
中文翻译:
新型药物 DMAMCL 抑制骨肉瘤生长并降低骨肉瘤干细胞的干细胞。
骨肉瘤 (OS) 是最常见的原发性骨恶性肿瘤,主要影响儿童、青少年和年轻人。尽管OS的多模式治疗取得了进展,但长期生存率已达到平台期,主要障碍是对化疗反应不佳和获得化疗耐药。在这项研究中,我们测试了新报告的药物 DMAMCL 对 OS 的治疗效果。使用了五种人类 OS 细胞系 (143B、MNNG、MG63、Saos-2、U-2OS),以及小鼠成纤维细胞系 (NIH3T3) 和人类视网膜上皮细胞 (ARPE19)。通过MTS测定或IncuCyte-Zoom(体外)和异种移植小鼠模型(体内)研究了DMAMCL的抗肿瘤作用)。研究了 DMAMCL 处理后细胞周期、凋亡细胞、caspase3/7 活性和干性的变化。BAX siRNAs 用于敲低 BAX 的表达。通过蛋白质印迹法测量 CyclinB1、CDC2、BCL-2 家族、PARP、CD133 和 Nanog 的表达。DMAMCL在体外诱导剂量依赖性 OS 细胞死亡,抑制肿瘤生长并延长异种移植小鼠的存活。DMAMCL 诱导的体外G2/M 期阻滞,以及体外和体内细胞凋亡。BAX表达的下调衰减的DMAMCL诱导的OS的细胞死亡的体外. 我们还发现 DMAMCL 抑制了 OS 细胞的干性。这些结果表明 DMAMCL 在 OS 中具有治疗价值,可能是 OS 治疗新药发现的有希望的候选者。