Tsoutsou Pelagia, Annibaldi Alessandro, Viertl David, Ollivier Jonathan, Buchegger Franz, Vozenin Marie-Catherine, Bourhis Jean, Widmann Christian, Matzinger Oscar
Department of a Radiation Oncology, Lausanne University Hospital, Lausanne, Switzerland.
c Laboratoire de Radio-Oncologie, CHUV, Lausanne, Switzerland.
Radiat Res. 2017 May;187(5):562-569. doi: 10.1667/RR14509.1. Epub 2017 Mar 21.
The synthetic peptide TAT-RasGAP has been shown to potentiate the efficacy of anti-cancer drugs. In this study, we explored the action of TAT-RasGAP when combined with radiation by investigating its radiosensitizing activity in vitro and in vivo. To investigate the modulation of intrinsic radiosensitivity induced by TAT-RasGAP, clonogenic assays were performed using four human cancer cell lines, HCT116 p53 (ATCC: CCL-247), HCT116 p53, PANC-1 (ATCC: CRL-1469) and HeLa (ATCC: CCL-2), as well as one nontumor cell line, HaCaT (CLS: 300493). Next, to investigate tumor growth delay after irradiation, HCT116 cell lines were selected and xenografted onto nude mice that were then treated with TAT-RasGAP alone or in combination with radiation or cisplatin. Afterwards, cell cycle and death modulation were investigated by quantification of micronuclei and apoptosis-related protein array. TAT-RasGAP radiosensitized all four human carcinoma cell lines tested but displayed no effect on normal cells. It also displayed no effect when administered as monotherapy. This radiosensitizing effect was confirmed in vivo in both p53-positive and p53-negative HCT116 xenografts. TAT-RasGAP combined with radiation enhanced the number of cells in S phase and subsequently delayed cell death, but had almost no effect on major apoptosis-related proteins. TAT-RasGAP is a radiosensitizing agent that acts on carcinoma cells and its radiosensitizing effect might be mediated, at least in part, by the enhancement of mitotic cell death.
合成肽TAT-RasGAP已被证明可增强抗癌药物的疗效。在本研究中，我们通过研究其在体外和体内的放射增敏活性，探讨了TAT-RasGAP与辐射联合使用时的作用。为了研究TAT-RasGAP诱导的内在放射敏感性的调节，我们使用四种人类癌细胞系HCT116 p53（ATCC：CCL-247）、HCT116 p53、PANC-1（ATCC：CRL-1469）和HeLa（ATCC：CCL-2）以及一种非肿瘤细胞系HaCaT（CLS：300493）进行了克隆形成试验。接下来，为了研究照射后的肿瘤生长延迟情况，我们选择了HCT116细胞系并将其异种移植到裸鼠身上，然后单独用TAT-RasGAP或与辐射或顺铂联合治疗。之后，通过微核定量和凋亡相关蛋白阵列研究细胞周期和死亡调节。TAT-RasGAP使所有四种测试的人类癌细胞系放射增敏，但对正常细胞无影响。单独给药时也无作用。这种放射增敏作用在p53阳性和p53阴性的HCT116异种移植瘤体内均得到证实。TAT-RasGAP与辐射联合使用增加了S期细胞数量，随后延迟了细胞死亡，但对主要凋亡相关蛋白几乎没有影响。TAT-RasGAP是一种作用于癌细胞的放射增敏剂，其放射增敏作用可能至少部分是通过增强有丝分裂细胞死亡来介导的。
