Cheng Hao-Wei, Chein Rong-Jie, Cheng Ting-Jen, Wu Pei-Shan, Wu Hsin-Yi, Hung Pei-Fang, Wang Chia-Jen, Hsu Yuan-Ling, Wong Jau-Min, Yuan Ang, Wong Chi-Huey, Yang Pan-Chyr, Pan Szu-Hua
Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan.
Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
Cancer Sci. 2018 Mar;109(3):832-842. doi: 10.1111/cas.13489. Epub 2018 Feb 6.
Lung cancer is the leading cause of cancer-related death worldwide. Thus, developing novel therapeutic agents has become critical for lung cancer treatment. In this study, compound AS7128 was selected from a 2-million entry chemical library screening and identified as a candidate drug against non-small cell lung cancer in vitro and in vivo. Further investigation indicated that AS7128 could induce cell apoptosis and cell cycle arrest, especially in the mitosis stage. In addition, we also found that iASPP, an oncogenic protein that functionally inhibits p53, might be associated with AS7128 through mass identification. Further exploration indicated that AS7128 treatment could restore the transactivation ability of p53 and, thus, increase the expressions of its downstream target genes, which are related to cell cycle arrest and apoptosis. This occurs through disruption of the interactions between p53 and iASPP in cells. Taken together, AS7128 could bind to iASPP, disrupt the interaction between iASPP and p53, and result in cell cycle arrest and apoptosis. These findings may provide new insight for using iASPP as a therapeutic target for non-small cell lung cancer treatment.
肺癌是全球癌症相关死亡的主要原因。因此，开发新型治疗药物对于肺癌治疗至关重要。在本研究中，化合物AS7128是从一个拥有200万种化合物的化学文库筛选中选出的，并在体外和体内被鉴定为一种抗非小细胞肺癌的候选药物。进一步研究表明，AS7128可诱导细胞凋亡和细胞周期停滞，尤其是在有丝分裂阶段。此外，我们还发现，iASPP是一种在功能上抑制p53的致癌蛋白，可能通过质谱鉴定与AS7128相关。进一步探索表明，AS7128处理可恢复p53的反式激活能力，从而增加其下游靶基因的表达，这些基因与细胞周期停滞和凋亡有关。这是通过破坏细胞中p53与iASPP之间的相互作用而发生的。综上所述，AS7128可与iASPP结合，破坏iASPP与p53之间的相互作用，并导致细胞周期停滞和凋亡。这些发现可能为将iASPP用作非小细胞肺癌治疗的治疗靶点提供新的见解。
