Togashi Keita, Okada Masashi, Suzuki Shuhei, Sanomachi Tomomi, Seino Shizuka, Yamamoto Masahiro, Yamashita Hidetoshi, Kitanaka Chifumi
Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan.
Department of Ophthalmology and Visual Sciences, Yamagata University School of Medicine, Yamagata, Japan.
Anticancer Res. 2020 Sep;40(9):4961-4968. doi: 10.21873/anticanres.14499.
BACKGROUND/AIM: Despite advances in treatment modalities, the visual prognosis of retinoblastoma still remains unsatisfactory, underscoring the need to develop novel therapeutic approaches.
The effect on the growth of six human retinoblastoma cell lines and a normal human fibroblast cell line of CEP1347, a small-molecule kinase inhibitor originally developed for the treatment of Parkinson's disease and therefore with a known safety profile in humans, was examined. The role of the P53 pathway in CEP1347-induced growth inhibition was also investigated.
CEP1347 selectively inhibited the growth of retinoblastoma cell lines expressing murine double minute 4 (MDM4), a P53 inhibitor. Furthermore, CEP1347 reduced the expression of MDM4 and activated the P53 pathway in MDM4-expressing retinoblastoma cells, which was required for the inhibition of their growth by CEP1347.
We propose CEP1347 as a promising candidate for the treatment of retinoblastomas, where functional inactivation of P53 as a result of MDM4 activation is reportedly common.
背景/目的：尽管治疗方式有所进步，但视网膜母细胞瘤的视觉预后仍然不尽人意，这凸显了开发新治疗方法的必要性。
研究了CEP1347（一种最初开发用于治疗帕金森病且在人体具有已知安全性的小分子激酶抑制剂）对六种人视网膜母细胞瘤细胞系和一种正常人成纤维细胞系生长的影响。还研究了P53通路在CEP1347诱导的生长抑制中的作用。
CEP1347选择性抑制表达小鼠双微体4（MDM4，一种P53抑制剂）的视网膜母细胞瘤细胞系的生长。此外，CEP1347降低了MDM4的表达，并激活了表达MDM4的视网膜母细胞瘤细胞中的P53通路，这是CEP1347抑制其生长所必需的。
我们提出CEP1347作为治疗视网膜母细胞瘤的有前景的候选药物，据报道在视网膜母细胞瘤中因MDM4激活导致P53功能失活很常见。
