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Novel agent DMAMCL suppresses osteosarcoma growth and decreases the stemness of osteosarcoma stem cell.
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
Affiliation  

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。

更新日期:2020-05-13
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