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Zhang H.,Peking Union Medical College | Zhang S.,Peking Union Medical College | He H.,Peking Union Medical College | Zhao W.,Peking Union Medical College | And 3 more authors.
Cancer Letters | Year: 2011

To increase the efficacy of currently used anti-cancer genotoxins, a combination use of different drugs is a potential new therapeutical tool. Here, we reported that a synthetic RasGAP-derived peptide 38GAP with RasGAP301-326 and TAT penetration sequences could enhance the effect of chemotherapeutic agent CDDP in human colon carcinoma HCT116 cells. Our results showed that 38GAP significantly increased the CDDP-induced apoptosis in HCT116 cells. This synergistic effect was associated with abrogation of CDDP-induced G2/M arrest by down-regulations of phospho-Cdc2 and p21, and inhibitions of phospho-AKT, phospho-ERK and NF-κB. In animal models, 38GAP combined with CDDP significantly suppressed CT26 tumor growth, while 38GAP alone showed slight inhibitory effect. Our data suggest that 38GAP in combination with chemotherapeutics will become a potential therapeutic strategy for colon cancers. © 2011 Elsevier Ireland Ltd.


PubMed | Wuhan KatyGen Pharmaceuticals Inc. and Peking Union Medical College
Type: Journal Article | Journal: Acta pharmaceutica Sinica. B | Year: 2015

To increase the efficacy of currently used anti-cancer genotoxins, one of the current efforts is to find agents that can sensitize cancer cells to genotoxins so that the efficacious doses of genotoxins can be lowered to reduce deleterious side-effects. In this study, we reported that a synthetic RasGAP-derived peptide GAP159 could enhance the effect of chemotherapeutic agent cisplatin (CDDP) in human colon carcinoma HCT116 cells. Our results showed that GAP159 significantly increased the CDDP-induced cytotoxicity and apoptosis in HCT116 cells. This synergistic effect was associated with the inhibitions of phospho-AKT, phospho-ERK and NF-B. In mouse colon tumor CT26 animal models, GAP159 combined with CDDP significantly suppressed CT26 tumor growth, and GAP159 alone showed slight inhibitory effect. Our data suggests that co-treatment of GAP159 and chemotherapeutics will become a potential therapeutic strategy for colon cancers.


Cui W.,University of Chinese Academy of Sciences | Wei Z.,University of Chinese Academy of Sciences | Chen Q.,University of Chinese Academy of Sciences | Cheng Y.,Tsinghua University | And 5 more authors.
Journal of Chemical Information and Modeling | Year: 2010

Herein, we report a successful application of molecular modeling techniques to design two novel peptides with cytotoxicity on tumor cells. First, the interactions between the nuclear transport factor 2 (NTF2)-like domain of G3BP and the SH3 domain of RasGAP were studied by a well-designed protocol, which combines homology modeling, protein/protein docking, molecular dynamics simulations, molecular mechanics/ generalized born surface area (MM/GBSA) free energy calculations, and MM/GBSA free energy decomposition analysis together. Then, based on the theoretical predictions, two novel peptides were designed and synthesized for biological assays, and they showed an obvious sensitizing effect on cis-platin. Furthermore, the deigned peptides had no significant effects on normal cells, while cis-platin did. Our results demonstrate that it is feasible to use the peptides to enhance the efficacy of clinical drugs and to kill cancer cells selectively. We believe that our work should be very useful for finding new therapies for cancers. © 2010 American Chemical Society.


Ji M.-Y.,Wuhan University | Tan S.-Y.,Wuhan University | Zhang J.,Wuhan University | Chen J.-H.,Wuhan KatyGen Pharmaceuticals Inc. | And 2 more authors.
Chinese Journal of New Drugs | Year: 2011

Objective: To investigate the in vitro inhibitory effect of an anticancer peptide (A38, obtained by a computer-aided drug design) alone and in combination with cisplatin on early apoptosis of SGC-7901 cells, human gastric cancer cell line. Methods: Cultured cells were exposed to various concentrations of A38 or cisplatin alone, or A38 in combination with cisplatin for 24, 48 and 72 h. The inhibition rate was determined by MTT assay. Cell apoptosis was analyzed by flow cytometry. Results: After treatment with A38 alone, cisplatin alone or A38 in combination with cisplatin, SGC-7901 cell growth was significantly increased as compared to control at various time-points and concentrations. Flow cytometry results showed a significant increase in early apoptosis rate at 24, 48 and 72 h as well. The combination was more effective for both cell growth and apoptosis (P<0.01). Conclusion: A38 can inhibit growth of the human gastric cell line SGC-7901 cells and induce cell early apoptosis. A synergistic effect is achieved when low concentration cisplatin is combined with A38, showing a more significant inhibition than high concentrations of A38 alone or cisplatin alone.


Chen Z.-Q.,Wuhan University | Tan S.-Y.,Wuhan University | Chen J.-H.,Wuhan KatyGen Pharmaceuticals Inc. | Zhang J.,Wuhan KatyGen Pharmaceuticals Inc. | Chen C.-H.,Wuhan KatyGen Pharmaceuticals Inc.
Chinese Journal of Cancer Prevention and Treatment | Year: 2011

OBJECTIVE: To observe the inhibition of specific polypeptide p166 plus cisplatin, designed by computer aided drug designing system, on xenotransplanted human colon tumors of in nude mice and its side effects, and to discuss the potential mechanism. METHODS: Models of xenotransplanted colon carcinoma in nude mice were established by human HCT 116 cell line. The nude mice were randomly divided into three groups: normal saline group, cisplatin group(1 mg/kg) and p166 plus cisplatin group(4 mg/kg, containing cisplatin 1 mg/kg), and then received intraperitonal injection per day for ten days. The tumor volume was measured for calculating the tumor inhibition rate. The mice were sacrificed 11 days later. The blood was taken for examining the hepatic and nephritic function. Then the tumor was carried out for histopathological examination. Expression of Bax, Bcl-2, Cyt C and Caspase-3 protein were detected by immunohistochemistry. RESULTS: p166 plus cisplatin had significant inhibitory effect on the xenotransplanted tumor, and cisplatin followed. The tumor inhibition rates were 56.98% and 41.96% respectively. The levels of BUN, Cr, ALT and AST in pl66 plus cisplatin group were lower than those in cisplatin group (Cr, ALT and AST, P<0.05). Compared with those in cisplatin group, in p166 plus cisplatin group, the expression of Bcl-2 was down-regulated, while Bcl-2, Cyt C and Caspase-3 were up-regulated. CONCLUSIONS: p166 plus cisplatin can remarkbaly inhibit the growth of xenotransplanted colon tumors in nude mice, as well as reduce the hepatic and nephritic toxicity caused by cisplatin. Its mechanism may be that specific p166 can increase the ability of cisplatin to penetrate tumor cell lar membrane.


Zhang J.,Renmin University of China | Tan S.-Y.,Renmin University of China | Chen J.-H.,Wuhan KatyGen Pharmaceuticals Inc. | Zhang J.,Wuhan KatyGen Pharmaceuticals Inc. | Chen C.-H.,Wuhan KatyGen Pharmaceuticals Inc.
Chinese Journal of Cancer Biotherapy | Year: 2010

Objective: To study the effect of polypeptide A28, which was designed by computer aided drug designing system, on the cytotoxic effect of cisplatin against colon cancer cells. Methods: Colon cancer cell line HCT-116 and human umbilical vein endothelial cells (HUVEC) were used in the present study. The concentration of polypeptide A28 was 20 μmol/L and those of cisplatin were 10, 30 and 90 μmol/L. The effects of polypeptide A28 combined with cisplatin on the growth of HCT-116 and HUVEC cells were measured by MTT; their effects on the apoptosis of HCT-116 cells were examined by flow cytometry. Results: Cisplatin dose-dependently inhibited proliferation of HCT-116 cells; A28 further enhanced the inhibitory effect of cisplatin on HCT-116 cells and increased apoptosis induction effect of cisplatin on HCT-116 cells, with the growth inhibition rate of the combination group being (43.3 ± 0.03)%, which was significantly higher than that of the cisplatin single group (15.6 ± 0.10)% (P < 0.01). In combination group, when cisplatin concentrations (30, 90 μmol/L) were increased, the inhibitory effects on HCT-116 cells were not increased compared with the 10 μmol/L cisplatin combination group (P > 0.05). A28 combined with cisplatin (1.1, 3.3, 10, 30, or 90 μmol/L) induced apoptosis of more HCT-116 cells than cisplatin single group did (P < 0.01). Csplatin at 10 μmol/L combined with A28 at 20 μmol/L effectively killed HCT-116 cells, whereas with less toxic effect on HUVEC cells. Conclusion: Polypeptide A28 can enhance the cytotoxic effect of cisplatin on colon cancer cell line HCT-116 and decrease its lethal effect on HUVEC.


Li M.,Renmin University of China | Wang J.,Renmin University of China | Tan S.-Y.,Renmin University of China | Chen J.-H.,Wuhan KatyGen Pharmaceuticals Inc. | And 3 more authors.
Molecular Medicine Reports | Year: 2013

The combined use of currently used anticancer genotoxins with other drugs is a therapeutic tool for potentially increasing the efficacy of the genotoxins. In the present study, the effects of a RasGAP-derived peptide, P110 (RasGAP301-316), designed to target Ras-GTPase activating protein SH3 domain-binding proteins (G3BPs), on the chemo-therapeutic agent, cisplatin (DDP), were examined. P110 was demonstrated to enhance the effect of DPP in vitro and in vivo. The results indicate that P110 significantly increased the DDP induced apoptosis in SGC-7901, HCT-116, HeLa and A-549 cells. Furthermore, P110 combined with DDP significantly suppressed the growth of C26 xenograft tumors in a dose-dependent manner. This synergistic effect may be associated with DDP-induced apoptosis, involving the down-regulation of Bcl-2 and the upregulation of Bax, cytochrome c and caspase-3. The results of the present study indicate that P110, in combination with chemotherapeutics, is likely to represent a potential therapeutic strategy for cancer. Copyright © 2013 Spandidos Publications Ltd.


Chen J.,Wuhan University of Science and Technology | Wu Q.-M.,Wuhan University of Science and Technology | Long H.,Wuhan University of Science and Technology | Zhang H.,Wuhan University of Science and Technology | Chen J.-H.,Wuhan KatyGen Pharmaceuticals Inc
World Chinese Journal of Digestology | Year: 2014

Aim: To investigate whether P162 enhances radiosensitivity of esophageal carcinoma cell line Eca109 by inhibiting Hedgehog signaling transcription factor Gli-1. Methods: Eca109 cells (a total dose of 60 Gy) to induce radioresistant esophageal carcinoma cell line Eca109R. The inhibition of cell proliferation was determined by Cell Counting Kit assay. The expression of Gli-1 was detected by immunohistochemistry and immunofluorescence. HE staining was employed to observe the changes in cell morphology. Western blot was employed to determine the nuclear expression of Gli-1 and dynamic changes of Gli-1 in irradiated Eca109 cells. Apoptosis was determined by flow cytometry. The following four groups were included in the experiments: untreated cells, P162-treated cells, irradiated cells, and P162-treated irradiated cells. Eca109 and Eca109R cells were included in each group. Results: Eca109R possessing certain radiation resistance displayed lower ability of growth inhibition than Eca109 cells. Nuclear Gli-1 expression was significantly higher in Eca109R cells than in Eca109 cells (0.45 ± 0.01 vs 0.32 ± 0.01, P < 0.0001). On days 2 and 14 after irradiation, the nuclear expression of Gli-1 in Eca109 cells was higher than that in control cells (0.0882 ± 0.011, 0.3560 ± 0.015 vs 0.2552 ± 0.0103, P < 0.05). In both Eca109R and Eca109 cells, the nuclear expression of Gli-1 was reduced after treatment with 20 μmol/L P162 [0.2553 ± 0.011, 0.2578 ± 0.014 (non-irradiation); 0.1324 ± 0.012, 0.0595 ± 0.011(2 d after irradiation); 0.1741 ± 0.013, 0.2397 ± 0.112 (14 d after irradiation), P < 0.0001]. P162 combined with radiotherapy facilitated cells apoptosis. Conclusion: Nuclear Gli-1 expression is related to radioresistance of esophageal cancer cells. P162 enhances radiosensitivity of Eca109 cell possibly by inhibiting Gli-1 expression and promoting apoptosis. © 2014 Baishideng Publishing Group Co., Limited. Allrights reserved.


Zhang H.,Wuhan University of Science and Technology | Wu Q.-M.,Wuhan University of Science and Technology | Long H.,Wuhan University of Science and Technology | Chen J.,Wuhan University of Science and Technology | Chen J.-H.,Wuhan KatyGen Pharmaceuticals. Inc
World Chinese Journal of Digestology | Year: 2014

Aim: To investigate whether P162 increases the radiosensitivity of esophageal cancer cell line Eca109 by inhibiting the expression of Chk1/2, and to observe its influence on cell cycle progression. Methods: Eca109 cells were exposed to small doses of repeated X-rays to develop a radioresistant cell line Eca109R. Cells were divided into four groups: a group without exposure to either P162 or X-rays, a group exposed only to X-rays, a group exposed only to P162, and a group exposed to both P162 and X-rays. Both Eca109 and Eca109R cell lines were used in each group. The optimal radiation dose was determined by MTT assay. The CCK-8 method was used to determine the optimal drug concentration needed for subsequent experiments. Western blot was used to detect the dynamic changes in Chk1 and Chk2 proteins. The change in cell cycle progression was measured by flow cytometry. Results: The radio-resistant Eca109R cell line was successfully developed. A radiation dose of 6 Gy was used as the optimal radiation dose for subsequent experiments, and 20 mg/L was used as the optimal concentration of P162. Western blot showed that both Eca109 and Eca109R cell lines expressed a small amount of Chk1 and Chk2. After irradiation, Chk1 and Chk2 expression was up-regulated in both cell lines. After treatment with 20 mg/L P162 for 48 h, the expression levels of Chk1 and Chk2 in Eca109 cells were 0.244 ± 0.013 and 0.148 ± 0.011, respectively, and the corresponding values in Eca109R cells were 0.139 ± 0.010 and 0.134 ± 0.008. At 24 h after 6 Gy irradiation, the expression levels of Chk1 and Chk2 in Eca109 cells were 0.154 ± 0.013 and 0.124 ± 0.011, respectively, and the corresponding values in Eca109R cells were 0.083 ± 0.010 and 0.059 ± 0.009. P162 treatment significantly reduced Chk1 and Chk2 expression (P < 0.05 for all). Cell cycle analysis revealed that exposure to P162 alone only slightly reduced the percentage of cells in G2 phase, but exposure to both P162 and X-rays significantly decreased the percentage of cells in G2 phase. Conclusion: Eca109R cells are more radioresistant than Eca109 cells. P162 relieves G2/M phase arrest by inhibiting the expression of Chk1 and Chk2 to increase radiosensitivity of esophageal cancer cell line Eca109. © 2014 Baishideng Publishing Group Co., Limited. All rights reserved.


Patent
Wuhan Katygen Pharmaceuticals Inc. | Date: 2010-09-29

Disclosed herein are polypeptides or their derivatives and their application. The polypeptides and their derivatives can treat or prevent cancer. The polypeptides of the invention have significant lethality to the cancer cells when used alone. When its clinical commonly used chemotherapy drugs such as cisplatin in combination, it can significantly increase the sensitivity of chemotherapeutic agents on cancer cells, to enhance its lethality of cancer cells, to reduce the dosage. The peptides can kill a variety of cancer cells, but without apparent toxicity enhancing effect on normal cells. The prepared peptides of the present invention can be chemically synthesized, high-purity, low molecular weight, specificity, non-immunogenic, safe and reliable.

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