Wang Dongsheng, Peng Shifang, Amin A R M Ruhul, Rahman Mohammad Aminur, Nannapaneni Sreenivas, Liu Yuan, Shin Dong M, Saba Nabil F, Eichler Jack F, Chen Zhuo G
Department of Hematology and Medicinal Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, United States of America.
Department of Biostatistics and Bioinformatics, Biostatistics and Bioinformatics Shared Resource at WCI, NE, Atlanta, GA, United States of America.
PLoS One. 2016 Dec 29;11(12):e0168450. doi: 10.1371/journal.pone.0168450. eCollection 2016.
The anti-tumor effect of a chelating phen-based ligand 2,9-di-sec-butyl-1,10-phenanthroline (dsBPT) and its combination with cisplatin were examined in both lung and head and neck cancer cell lines and xenograft animal models in this study. The effects of this agent on cell cycle and apoptosis were investigated. Protein markers relevant to these mechanisms were also assessed. We found that the inhibitory effect of dsBPT on lung and head and neck cancer cell growth (IC50 ranged between 0.1-0.2 μM) was 10 times greater than that on normal epithelial cells. dsBPT alone induced autophagy, G1 cell cycle arrest, and apoptosis. Our in vivo studies indicated that dsBPT inhibited tumor growth in a dose-dependent manner in a head and neck cancer xenograft mouse model. The combination of dsBPT with cisplatin synergistically inhibited cancer cell growth with a combination index of 0.3. Moreover, the combination significantly reduced tumor volume as compared with the untreated control (p = 0.0017) in a head and neck cancer xenograft model. No organ related toxicities were observed in treated animals. Our data suggest that dsBPT is a novel and potent antitumor drug that warrants further preclinical and clinical development either as a single agent or in combination with known chemotherapy drugs such as cisplatin.
本研究在肺癌和头颈癌细胞系及异种移植动物模型中检测了螯合型菲基配体2,9-二仲丁基-1,10-菲咯啉（dsBPT）的抗肿瘤作用及其与顺铂联合使用的效果。研究了该药物对细胞周期和凋亡的影响。还评估了与这些机制相关的蛋白质标志物。我们发现，dsBPT对肺癌和头颈癌细胞生长的抑制作用（IC50在0.1 - 0.2 μM之间）比对正常上皮细胞的抑制作用大10倍。单独使用dsBPT可诱导自噬、G1期细胞周期阻滞和凋亡。我们的体内研究表明，在头颈癌异种移植小鼠模型中，dsBPT以剂量依赖性方式抑制肿瘤生长。dsBPT与顺铂联合使用可协同抑制癌细胞生长，联合指数为0.3。此外，在头颈癌异种移植模型中，与未治疗的对照组相比，联合使用显著减小了肿瘤体积（p = 0.0017）。在接受治疗的动物中未观察到与器官相关的毒性。我们的数据表明，dsBPT是一种新型强效抗肿瘤药物，作为单一药物或与顺铂等已知化疗药物联合使用，值得进一步进行临床前和临床开发。
