Ma Xiang-yi, Li Shu, Luo Dan-feng, Liu Rong-hua, Lu Yun-ping, Wang Shi-xuan, Ma Ding, Xi Ling
Department of Gynecologic Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
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Zhonghua Zhong Liu Za Zhi. 2013 Oct;35(10):737-41.
Due to their lower risk for induction of resistance, antimicrobial peptides with selective anticancer effect could be developed into a new generation of anticancer drugs. We conjugated an antimicrobial peptide with tumor-targeting peptides (TMTP1) to explore whether it has inhibiting effect on the progression and metastasis of transplanted prostate cancer and gastric cancer in nude mice.
Subcutaneously transplanted human prostate cancer and orthotopically transplanted human gastric cancer in nude mice were prepared. 50 µmol/L PBS (control group), 50 µmol/L TMTP1 (TMTP1 group) or 50 µmol/L TMTP1-GG-D(KLAKLAK)(2) (treatment group) were injected i.p. to the three groups of nude mice, respectively. The binding ability of the novel fusion polypeptide TMTP1-GG-D(KLAKLAK)(2) to the tumors and its antitumor effect were assessed by measurement of tumor volume, histopathological examination of the tumor tissues, testing apoptosis index of tumor cells with TUNEL staining, and survival curve plotting of the mice.
The median survival time of subcutaneous prostate cancer-bearing mice was 50 days in the control group, 55 days in the TMTP1 group, and 70 days in the TMTP1-GG-D(KLAKLAK)(2) group (P < 0.05). The median survival time of the subcutaneous gastric cancer-bearing mice was 25 days in the control group, 30 days in the TMTP1 group, and 45 days in the TMTP1-GG-D(KLAKLAK)(2) group (P < 0.01). The tumor volume in the subcutaneous prostate cancer-bearing mice was (2.5 ± 0.3)cm(3) in the control group, (1.8 ± 0.2) cm(3) in the TMTP1 group, and (0.3 ± 0.1)cm(3) in the TMTP1-GG-D(KLAKLAK)(2) group (P < 0.01). The tumor volume of the subcutaneous gastric cancer-bearing mice was (3.8 ± 0.4) cm(3) in the control group, (3.2 ± 0.2)cm(3) in the TMTP1 group, and (0.4 ± 0.1) cm(3) in the TMTP1-GG-D(KLAKLAK)(2) group (P < 0.01). Large tumors were observed in the stomach of the orthotopic gastric cancer-bearing mice of the control and TMTP1 groups. The tumor volume of the TMTP1-GG-D(KLAKLAK)(2) group was obviously reduced. White metastases in the liver, spleen and abdominal wall were observed in the control and TMTP1 groups (P < 0.01). TUNEL staining revealed that the apoptosis index of the control group was (31.9 ± 1.5)%, TMTP1 group (37.2 ± 2.3)% and TMTP1-GG-D(KLAKLAK)(2) group (69.7 ± 2.1)% (P < 0.01).
The results of our study demonstrate that the novel fusion peptide of antimicriobial peptide conjugated with TMTP1 can effectively inhibit tumor progression and metastasis, therefore, is promising to be a novel effective anticancer drug.
由于具有较低的诱导耐药风险，具有选择性抗癌作用的抗菌肽有望开发成为新一代抗癌药物。我们将一种抗菌肽与肿瘤靶向肽（TMTP1）偶联，以探究其对裸鼠移植性前列腺癌和胃癌的进展及转移是否具有抑制作用。
制备裸鼠皮下移植人前列腺癌和原位移植人胃癌模型。分别对三组裸鼠腹腔注射50 μmol/L PBS（对照组）、50 μmol/L TMTP1（TMTP1组）或50 μmol/L TMTP1-GG-D(KLAKLAK)₂（治疗组）。通过测量肿瘤体积、对肿瘤组织进行组织病理学检查、用TUNEL染色检测肿瘤细胞凋亡指数以及绘制小鼠生存曲线，评估新型融合多肽TMTP1-GG-D(KLAKLAK)₂与肿瘤的结合能力及其抗肿瘤效果。
皮下接种前列腺癌的小鼠，对照组的中位生存时间为50天，TMTP1组为55天，TMTP1-GG-D(KLAKLAK)₂组为70天（P<0.05）。皮下接种胃癌的小鼠，对照组的中位生存时间为25天，TMTP1组为30天，TMTP1-GG-D(KLAKLAK)₂组为45天（P<0.01）。皮下接种前列腺癌的小鼠，对照组肿瘤体积为(2.5±0.3)cm³，TMTP1组为(1.8±0.2) cm³，TMTP1-GG-D(KLAKLAK)₂组为(0.3±0.1)cm³（P<0.01）。皮下接种胃癌的小鼠，对照组肿瘤体积为(3.8±0.4) cm³，TMTP1组为(3.2±0.2)cm³，TMTP1-GG-D(KLAKLAK)₂组为(0.4±0.1) cm³（P<0.01）。对照组和TMTP1组原位接种胃癌的小鼠胃内可见大肿瘤。TMTP1-GG-D(KLAKLAK)₂组肿瘤体积明显减小。对照组和TMTP1组在肝脏、脾脏和腹壁可见白色转移灶（P<0.01）。TUNEL染色显示，对照组凋亡指数为(31.9±1.5)%，TMTP组为(37.2±2.3)%，TMTP1-GG-D(KLAKLAK)₂组为(69.7±2.1)%（P<0.01）。
本研究结果表明，抗菌肽与TMTP1偶联的新型融合肽可有效抑制肿瘤进展和转移，有望成为一种新型有效的抗癌药物。
