Fundamental study on molecular chaperone cancer therapy

本研究的目的是开发一种新的癌症治疗方法，即基于化学伴侣（甘油）将突变型p53 （mp53）蛋白的构象改变为野生型p53 （wtp53）蛋白，并恢复wtp53的功能。转染wtp53后，p53缺失细胞的热敏性增强，热诱导的细胞凋亡增强。用温度敏感的mp53横切的人甲状腺癌细胞（8305c）在诱导wtp53的培养条件下显示出放射、热或cddp敏感性。与具有正常p53功能的对照细胞（SAS/neo）相比，经mp53横切的人水细胞癌（SAS/mp53）细胞对x射线或CDDP具有耐药性。而SAS/mp53细胞在有甘油存在的x射线或CDDP处理后，对x射线或CDDP变得敏感，而SAS/neo细胞则没有。x射线或CDDP诱导的凋亡在SAS/mp53细胞中被抑制，而x射线或CDDP联合甘油在SAS/mp53细胞中诱导有效的DNA断裂和凋亡小体。在甘油存在的情况下用CDDP处理裸鼠移植的SAS/mp53肿瘤，观察到其生长延迟。从这些结果来看，放射和化学疗法结合化学伴侣疗法可能会改善癌症治疗的结果。

The aim of this study is to develop new cancer therapy, which is based on a chemical chaperone (glycerol) to change conformation of mutant p53 (mp53) protein to wild-type p53 (wtp53) protein and restore the function of wtp53. Transfection with wtp53 to p53-null cells increased the thermo sensitivity and enhanced heat-induced apoptosis.Human annalistic thyroid carcinoma cells (8305c) transected with temperature sensitive mp53 showed radio-, heat- or CDDP-sensitivity under culture condition inducing wtp53. Human aqueous cell carcinoma (SAS/mp53) cells transected with mp53 were resistant to X-ray or CDDP compared with the control cells having normal function of p53 (SAS/neo). However, SAS/mp53 cells became sensitive to X-ray or CDDP after X-ray or CDDP treatment in the presence of glycerol, while that of SAS/neo cells did not. X-ray or CDDP-induced apoptosis was suppressed in SAS/mp53 cells, whereas X-ray or CDDP treatment combined with glycerol induced efficient DNA fragmentation and apoptotic bodies in SAS/mp53 cells. Growth delay was observed in SAS/mp53 tumors transplanted in nude mice when they were treated with CDDP in the presence of glycerol. From these results, radiation and chemical therapies combined chemical chaperone therapy might improve the outcome of cancer therapies.