Ariyasu Shinya, Sawa Akiko, Morita Akinori, Hanaya Kengo, Hoshi Misato, Takahashi Ippei, Wang Bing, Aoki Shin
Center for Technologies Against Cancer, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan.
Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan.
Bioorg Med Chem. 2014 Aug 1;22(15):3891-905. doi: 10.1016/j.bmc.2014.06.017. Epub 2014 Jun 18.
In radiation therapy, adverse side effects are often induced due to the excessive cell death that occurs in radiosensitive normal cells. The radiation-induced cell death of normal cells is caused, at least in part, by apoptosis, which undergoes via activation of p53 and increase in the p53 protein, a zinc-containing transcriptional factor, in response to cellular damage. Therefore, radioprotective drugs that can protect normal cells from radiation and thus suppress adverse side effects would be highly desirable. We report herein on the radioprotective activity of 8-hydroxyquinoline (8HQ) derivatives that were initially designed so as to interact with the Zn(2+) in p53. Indeed, the 5,7-bis(methylaminosulfonyl)-8HQ and 8-methoxyquinoline derivatives considerably protected MOLT-4 cells against γ-ray radiation (10 Gy), accompanied by a low cytotoxicity. However, mechanistic studies revealed that the interaction of these drugs with p53 is weak and the mechanism for inhibiting apoptosis appears to be different from that of previously reported radioprotectors such as bispicen, which inhibits apoptosis via the denaturation of p53 as well as by blocking both transcription-dependent and -independent apoptotic pathways.
在放射治疗中，由于放射敏感的正常细胞中发生过度的细胞死亡，常常会引发不良副作用。正常细胞的辐射诱导细胞死亡至少部分是由凋亡引起的，凋亡是通过p53的激活以及含锌转录因子p53蛋白的增加来进行的，以响应细胞损伤。因此，能够保护正常细胞免受辐射从而抑制不良副作用的放射防护药物将是非常理想的。我们在此报告最初设计用于与p53中的Zn(2+)相互作用的8-羟基喹啉（8HQ）衍生物的放射防护活性。事实上，5,7-双（甲氨基磺酰基）-8HQ和8-甲氧基喹啉衍生物能显著保护MOLT-4细胞免受γ射线辐射（10 Gy），且细胞毒性较低。然而，机制研究表明，这些药物与p53的相互作用较弱，抑制凋亡的机制似乎与先前报道的放射防护剂如双吡啶不同，双吡啶通过p53的变性以及阻断转录依赖性和非依赖性凋亡途径来抑制凋亡。
