A bidirectional effect of Rac1 inhibition-Protects radiation-induced intestinal injury while inhibits tumor.
AIMS
To investigate whether Rac1 inhibition can alleviate radiation-induced intestinal injury (RIII), meanwhile exist no protection on tumors.


MATERIALS AND METHODS
Rac1 inhibition was achieved by its specific inhibitor, NSC23766. Mice were pretreated with different intraperitoneal injections, which were normal saline for NS group (N = 9), and 2.5 mg/kg and 5 mg/kg of NSC23766 for Low-Dose group (N = 9) and High-Dose group (N = 9), respectively. After total body irritation (10Gy), small intestinal tissues were collected for Hematoxylin-Eosin (H&E) staining and Terminal-deoxynucleotidyl Transferase Mediated dUTP Nick End Labeling (TUNEL). Intestinal epithelial and tumor cell lines, namely MODE-k and CT-26, were used to further study the role of Rac1 inhibition on radiation damage. Flow cytometry was used to detect changes in reactive oxygen species production, cell cycles and mitochondrial membrane potential, the latter was also checked by fluorescence microscope. Changes of protein-expression associated with apoptosis and cell cycles were detected by Western blotting to explain the possible molecular mechanism.


KEY FINDINGS
Height of intestine villi and depth of crypt were higher (P < 0.01) and apoptosis ratio lower (P < 0.01) in High-Dose group compared with those in NS group. After radiation, Rac1 inhibition pre-treatment improved the vitality (P < 0.01) and reduced the apoptosis (P < 0.01) in MODE-k while yielded opposite results in CT-26, and reduced ROS production of MODE-k (P < 0.01) while had little effect on that of CT-26. Rac1 inhibition differently affected the cell cycles of normal cells and that of tumor cells.


SIGNIFICANCE
Inhibition of Rac1 could alleviate RIII, meanwhile assist the killing effect of radiation on tumor cells.
['An|Ni|N|', 'Liu|Tingting|T|', 'Zhu|Baoliang|B|', 'Yang|Yajie|Y|', 'Yan|Xiaodi|X|', 'Cao|Man|M|', 'Chen|Yuanyuan|Y|', 'Liu|Ruling|R|', 'Xia|Penglin|P|', 'Liu|Cong|C|', 'Du|Jicong|J|', 'Gao|Fu|F|', 'Yuan|Hongbin|H|', 'Liu|Hu|H|', 'Cai|Jianming|J|']
D000634:Aminoquinolines D000818:Animals D017209:Apoptosis D002453:Cell Cycle D004305:Dose-Response Relationship, Drug D007414:Intestinal Neoplasms D007422:Intestines D008297:Male D051379:Mice D008807:Mice, Inbred BALB C D009479:Neuropeptides D011743:Pyrimidines D011833:Radiation Injuries, Experimental D011837:Radiation-Protective Agents D017382:Reactive Oxygen Species D014916:Whole-Body Irradiation D020830:rac1 GTP-Binding Protein
Rac1 Radiation-induced intestinal injury Cyclin Radiation sensitivity Reactive oxygen species (ROS)