Cancer Cell and Molecular Biology Branch, Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, Republic of Korea.
J Cancer Res Clin Oncol. 2014 May;140(5):757-67. doi: 10.1007/s00432-014-1623-5. Epub 2014 Mar 8.
To test whether transglutaminase 2 (TGase 2) inhibitor GK921 alone reverses renal cell carcinoma (RCC) tumor growth. RCC is resistant to both radiation and chemotherapy, and the prognosis remains poor. Despite the recent therapeutic success of vascular endothelial growth factor inhibition in RCC, approximately one-third of RCC patients develop metastatic disease. The expression of TGase 2 is markedly increased in most RCC cell lines, as well as in clinical samples.
Previously, we introduced the quinoxaline derivative GK13 as a lead compound for TGase 2 inhibitor. The inhibitory effect of GK13 on TGase 2 was improved in GK921 (3-(phenylethynyl)-2-(2-(pyridin-2-yl)ethoxy)pyrido[3,2-b]pyrazine). GK921 efficacy was tested using sulforhodamine in vitro as well as a xenograft tumor models using ACHN and CAKI-1 RCC cells.
GK921 showed cytotoxicity to RCC (average GI50 in eight RCC cell lines: 0.905 μM). A single treatment with GK921 almost completely reduced tumor growth by stabilizing p53 in the ACHN and CAKI-1 preclinical xenograft tumor models.
TGase 2 inhibitor GK921 abrogates RCC growth in xenograft tumor models, suggesting the possibility of a new therapeutic approach to RCC.
检测转谷氨酰胺酶 2（TGase 2）抑制剂 GK921 是否能单独逆转肾细胞癌（RCC）肿瘤生长。RCC 对放化疗均有耐药性，且预后较差。尽管血管内皮生长因子抑制治疗在 RCC 方面最近取得了成功，但仍有约三分之一的 RCC 患者发展为转移性疾病。大多数 RCC 细胞系以及临床样本中，TGase 2 的表达显著增加。
我们之前引入了喹喔啉衍生物 GK13 作为 TGase 2 抑制剂的先导化合物。GK13 的抑制作用在 GK921（3-（苯乙炔基）-2-（2-（吡啶-2-基）乙氧基）吡啶并[3,2-b]吡嗪）中得到了改善。使用 Sulforhodamine 在体外以及 ACHN 和 CAKI-1 RCC 细胞的异种移植肿瘤模型中测试了 GK921 的疗效。
GK921 对 RCC 具有细胞毒性（八种 RCC 细胞系的平均 GI50：0.905 μM）。单次 GK921 处理几乎完全通过稳定 ACHN 和 CAKI-1 临床前异种移植肿瘤模型中的 p53 来减少肿瘤生长。
TGase 2 抑制剂 GK921 可在异种移植肿瘤模型中阻断 RCC 生长，这提示了一种治疗 RCC 的新方法的可能性。
