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，它是基于一种化学伴侣(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。将wtp53基因导入p53阴性细胞，可提高细胞的热敏感性，促进热诱导的细胞凋亡。人甲状腺癌细胞(8305c)在培养条件下表现出放射、热或顺铂敏感性。与p53功能正常的对照细胞(SAS/neo)相比，mP53基因转导的人房水癌细胞(SAS/mP53)对X射线和顺铂具有较强的耐受性。然而，经X射线或顺铂加甘油处理后，SAS/mp53细胞对X射线或顺铂变得敏感，而SAS/neo细胞对X射线或顺铂不敏感。X射线或顺铂诱导的SAS/mp53细胞的凋亡被抑制，而X射线或顺铂联合甘油可诱导SAS/mp53细胞DNA断裂和凋亡小体。在裸鼠体内移植的SAS/mP53肿瘤细胞在加入甘油的情况下，用顺铂治疗后，肿瘤生长明显延迟。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.