生长抑素及其类似物抗肿瘤作用机制研究进展_West China Medical Journal

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高元平 ¹ , 郝卫刚 ¹ , 张海蓉 ²

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Keywords：

生长抑素; 抑制; 肿瘤

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生长抑素（SST）是一种广泛应用于临床的多肽类激素，其对机体几乎所有的生理性内分泌反应均起抑制作用。随着研究的不断深入，其在肿瘤治疗领域的作用越来越受到国内外学者的重视。但SST的抗肿瘤机制尚不清楚，可能通过对肿瘤细胞周期的阻滞，诱导肿瘤细胞凋亡，抑制细胞因子合成与分泌并拮抗其促肿瘤生长作用，抑制肿瘤血管生成，抑制肿瘤细胞黏附及侵袭，提高肿瘤对化学治疗药物的敏感性等途径发挥作用。

Citation： 高元平,郝卫刚,张海蓉. 生长抑素及其类似物抗肿瘤作用机制研究进展. West China Medical Journal, 2012, 27(4): 622-625. doi: Copy

1.	Srikant CB, Shen SH. Octapeptide somatostatin analog SMS 201-995 induces translocation of intracellular PTP1C to membranes in MCF-7 human breast adenocarcinoma cells[J]. Endocrinology, 1996, 137(8): 3461-3468.
2.	Sharma K, Patel YC, Srikant CB. C-terminal region of human somatostatin receptor 5 is required for induction of Rb and G1 cell cycle arrest[J]. Mol Endocrinol, 1999, 13(1): 82-90.
3.	Bousquet C, Puente E, Buscail L, et al. Antiproliferative effect of somatostatin and analogs [J]. Chemotherapy, 2001, 47(1): 30-39.
4.	Theodoropoulou M, Zhang J, Laupheimer S, et al. Octreotide, a somatostatin analogue, mediates its antiproliferative action in pituitary tumor cells by altering phosphatidylinositol 3-kinase signaling and inducing zac1 expression[J]. Cancer Res, 2006, 66(3): 1576-1582.
5.	Pagès P, Benali N, Saint-Laurent N, et al. Sst2 somatostatin receptor mediates cell cycle arrest and induction of p27(Kip1) Evidence for the role of SHP-1[J]. J Biol Chem, 1999, 274(21): 15186-15193.
6.	Held-Feindt J, Forstreuter F, Pufe T, et al. Influence of the somatostatin receptor sst2 on growth factor signal cascades in human glioma cells[J]. Brain Res Mol Brain Res, 2001, 87(1): 12-21.
7.	Dent P, Wang Y, Gu YZ, et al. S49 cells endogenously express subtype 2 somatostatin receptors which couple to increase protein tyrosine phosphatase activity in membranes and down-regulate Raf-1 activity in situ[J]. Cell Signal, 1997, 9(7): 539-549.
8.	Reardon DB, Dent P, Wood SL, et al. Activation in vitro of somatostatin receptor subtypes 2, 3, or 4 stimulates protein tyrosine phosphatase activity in membranes from transfected Ras-tran sformed NIH3T3 cells: coexpression with catalytically inactive SHP-2 blocks responsiveness[J]. Mol Endocrinol, 1997, 11(8): 1062-1069.
9.	Florio T, Yao H, Carey KD, et al. Somatostatin activation of mitogen-activated protein kinase via somatostatin receptor 1 (SSTR1)[J]. Mol Endocrinol, 1999, 13(1): 24-37.
10.	Alderton F, Humphrey PP, Sellers LA, et al. High-intensity p38 kinase activity is critical for p21(cip1) induction and the antiproliferative function of G(i) protein-coupled receptors[J]. Mol Pharmacol, 2001, 59(5): 1119-1128.
11.	Massa A, Barbieri F, Aiello C, et al. The phosphotyrosine phosphatase eta mediates somatostatin inhibition of glioma proliferation via the dephosphorylation of ERK1/2[J]. Ann N Y Acad Sci, 2004, 1030: 264-274.
12.	Kuriyama I, Miyazaki A, Tsuda Y. Inhibitory effect of somatostatin Peptide analogues on DNA polymerase activity and human cancer cell proliferation[J]. Anticancer Res, 2010, 30(12): 4841-4849.
13.	Li M, Wang XC, Li W, et al. Somatostatin receptor-1 induces cell cycle arrest and inhibits tumor growth in pancreatic cancer[J]. Cancer Sci, 2008, 99(11): 2218-2223.
14.	Zhou T, Xiao X, Xu B, et al. Overexpression of SSTR2 inhibited the growth of SSTR2-positive tumors via multiple signaling pathways[J]. 　Acta Oncol, 2009, 48(3): 401-410.
15.	Manoj K, 刘正人, 田锐, 等. 生长抑素受体2基因转染抑制胰腺肿瘤细胞生长机制的探讨[J]. 中华医学杂志, 2004, 84(9): 760-765.
16.	Guillermet GJ, Saint LN, Davenne L, et al. Novel synergistic mechanism for sst2 somatostatin and TNFalpha receptors to induce apoptosis: crosstalk between NF-kappaB and JNK pathways[J]. Cell Death Differ, 2007, 14(2): 197-208.
17.	Georgiadou M, Notas G, Xidakis C, et al. TNF receptors in Kupffer cells[J]. J Recept Signal Transduct Res, 2011, 4(31): 291-298.
18.	Boros LG, Brandes JL, Yusut FI, et al. Inhibition of the oxidtive and nonoxidative pentose pho -sphato pathways by somatostation：apsssible mechanism of antitumor action[J]. Med Hypotheses, 1998, 50(6): 501-506.
19.	Liu ZR, Qin RY, Wu GS. Effect of octreotide on human pancreatic cancer cells after transfected with somatostatin receptor type 2 gene[J]. World J Gastroenterol, 2004, 10(1-5): 2292-2294.
20.	Laklai H, Laval S, Dumartin L, et al. Thrombospondin-1 is a critical effector of oncosuppressive activity of sst2 somatostatin receptor on pancreatic cancer[J]. Proc Natl Acad Sci USA, 2009, 10(42): 17769-17774.
21.	Thangaraju M , Shanua K, Liu D, et al. In terdependent regulation of intracellular acidification and SHP-1 in apoptosis[J]. Cancer Res, 1999, 59(7): 1649-1654.
22.	Arena S, Pattarozzi A, Corsaro A, et al. Somatostatin receptor subtype-dependent regulation of nitric oxide release: involvement of different intracellular pathways[J]. Mol Endocrinol, 2005, 19(1): 255-267.
23.	刘宇斌，邝素娟，黄小穗, 等. 生长抑素类似物奥曲肽抑制肝癌细胞血管内皮生长因子表达的研究[J]. 南方医科大学学报[J]. 2008, 28(9): 1677-1678.
24.	孙培龙，胡静波，林万隆, 等. 术前区域动脉灌注生长抑素和化疗药物对结肠癌细胞增殖、凋亡和血管形成的影响[J]. 现代肿瘤医学, 2007, 15(2): 222-224.
25.	Buscail L, Vernejoul F, Faure P, et al. Regulation of cell proliferation by somatostatin[J]. Ann Endocrinol, 2002, 63(2): 13-18.
26.	Yamaguchi M, Yamada Y, Hosokawa Y, et al. Long-term suppressive effect of octreotide on pro gression of metastatic gastrinoma with multiple endocrine neoplasia type 1: seven-year follow up[J]. Intern Med, 2010, 49(15): 1557-1563.
27.	Ishii A, Imanishi Y, Kobayashi K, et al. The levels of somatostatin receptors in causative tumors of oncogenic osteomalacia are insufficient for their agonist to normalize serum phosphate levels[J]. Calcif Tissue Int, 2010, 86(6): 455-462.
28.	Friedlander TW, Weinberg VK, Small EJ, et al. Effect of the somatostatin analog octreotide acetate on circulating insulin-like　growth factor-1 and related peptides in patients with non-metastatic castration-resistant prostate cancer: Results of a phase II study[J]. Urol Oncol, 2010, 1873-2496.
29.	He Y, Yuan XM, Lei P, et al. The antiproliferative effects of somatostatin receptor subtype 2 in breast cancer cells[J]. Acta Pharmacol Sin, 2009, 30(7): 1053-1059.
30.	Ludvigsen E, Stridsberg M, Taylor JE, et al. Subtype selective interactions of somatostatin and somatostatin analogs with SST1, SST2, and SST5 in BON-1 cells[J]. Med Oncol, 2004, 21(3): 285-295.
31.	Feng Y, Huang T, Gao J, et al. Inhibition of metastatic progression of SSTR2 gene transfection mediated by adenovirus in human pancreatic carcinoma cells[J]. J Huazhong Univ Sci Technolog Med Sci, 2006, 26(1): 68-71.
32.	Kumar M, Liu ZR, Thapa L, et al. Antiangiogenic effect of somatostatin receptor subtype 2 on pancreatic cancer cell line: Inhibition of vascular endothelial growth factor and matrix metallo -proteinase-2 expression in vitro[J]. World J Gastroenterol, 2004, 10(3): 393-399.
33.	Benali N, Cordelier P, Calise D, et al. Inhibition of growth and metastatic progression of pancreatic carcinoma in hamster after somatostatin receptor subtype 2 (sst2) gene expression and administration of cytotoxic somatostatin analog AN-238[J]. Proc Natl Acad Sci USA, 2000, 97(16): 9180-9185.
34.	Tang X, Takekoshi S, Itoh J, et al. Somatostatin analogue inhibits the mobility of prostate carcinoma cells: a new therapeutic method for advanced prostate carcinoma[J]. Int J Oncol, 2010, 37(5): 1077-1083.
35.	Cerovac V, Monteserin-Garcia J, Rubinfeld HT, et al. The somatostatin analogue octreotide confers sensitivity to rapamycin treatment on pituitary tumor cells[J]. Cancer Res, 2010, 70(2): 666-674.
36.	刘延国, 王秀问, 魏军, 等. 奥曲肽对紫杉醇抑制非小细胞肺癌细胞的增效作用[J]. 中国肿瘤生物治疗杂志, 2008, 15(3): 210-216.
37.	秦一雨, 李济宇, 李松岗，等. 生长抑素逆转胆囊癌细胞株耐药性的作用研究 [J]. 中华外科杂志, 2008, 46(5): 381-383.
38.	Songgang L, Jiyu L, Gongwei, et al. Somatostatin enhances the chemosensitivity of GBC-SD cell line to doxorubicin through arresting the cell cycle to Sphase rather than through the P53/Bax-depended apoptosis way in vitro[J]. Hepatogastroenterology, 2009, 56(95): 1253-1260.

1. 　Srikant CB, Shen SH. Octapeptide somatostatin analog SMS 201-995 induces translocation of intracellular PTP1C to membranes in MCF-7 human breast adenocarcinoma cells[J]. Endocrinology, 1996, 137(8): 3461-3468.
2. 　Sharma K, Patel YC, Srikant CB. C-terminal region of human somatostatin receptor 5 is required for induction of Rb and G1 cell cycle arrest[J]. Mol Endocrinol, 1999, 13(1): 82-90.
3. 　Bousquet C, Puente E, Buscail L, et al. Antiproliferative effect of somatostatin and analogs [J]. Chemotherapy, 2001, 47(1): 30-39.
4. 　Theodoropoulou M, Zhang J, Laupheimer S, et al. Octreotide, a somatostatin analogue, mediates its antiproliferative action in pituitary tumor cells by altering phosphatidylinositol 3-kinase signaling and inducing zac1 expression[J]. Cancer Res, 2006, 66(3): 1576-1582.
5. 　Pagès P, Benali N, Saint-Laurent N, et al. Sst2 somatostatin receptor mediates cell cycle arrest and induction of p27(Kip1) Evidence for the role of SHP-1[J]. J Biol Chem, 1999, 274(21): 15186-15193.
6. 　Held-Feindt J, Forstreuter F, Pufe T, et al. Influence of the somatostatin receptor sst2 on growth factor signal cascades in human glioma cells[J]. Brain Res Mol Brain Res, 2001, 87(1): 12-21.
7. 　Dent P, Wang Y, Gu YZ, et al. S49 cells endogenously express subtype 2 somatostatin receptors which couple to increase protein tyrosine phosphatase activity in membranes and down-regulate Raf-1 activity in situ[J]. Cell Signal, 1997, 9(7): 539-549.
8. 　Reardon DB, Dent P, Wood SL, et al. Activation in vitro of somatostatin receptor subtypes 2, 3, or 4 stimulates protein tyrosine phosphatase activity in membranes from transfected Ras-tran sformed NIH3T3 cells: coexpression with catalytically inactive SHP-2 blocks responsiveness[J]. Mol Endocrinol, 1997, 11(8): 1062-1069.
9. 　Florio T, Yao H, Carey KD, et al. Somatostatin activation of mitogen-activated protein kinase via somatostatin receptor 1 (SSTR1)[J]. Mol Endocrinol, 1999, 13(1): 24-37.
10. 　Alderton F, Humphrey PP, Sellers LA, et al. High-intensity p38 kinase activity is critical for p21(cip1) induction and the antiproliferative function of G(i) protein-coupled receptors[J]. Mol Pharmacol, 2001, 59(5): 1119-1128.
11. 　Massa A, Barbieri F, Aiello C, et al. The phosphotyrosine phosphatase eta mediates somatostatin inhibition of glioma proliferation via the dephosphorylation of ERK1/2[J]. Ann N Y Acad Sci, 2004, 1030: 264-274.
12. 　Kuriyama I, Miyazaki A, Tsuda Y. Inhibitory effect of somatostatin Peptide analogues on DNA polymerase activity and human cancer cell proliferation[J]. Anticancer Res, 2010, 30(12): 4841-4849.
13. 　Li M, Wang XC, Li W, et al. Somatostatin receptor-1 induces cell cycle arrest and inhibits tumor growth in pancreatic cancer[J]. Cancer Sci, 2008, 99(11): 2218-2223.
14. 　Zhou T, Xiao X, Xu B, et al. Overexpression of SSTR2 inhibited the growth of SSTR2-positive tumors via multiple signaling pathways[J]. 　Acta Oncol, 2009, 48(3): 401-410.
15. 　Manoj K, 刘正人, 田锐, 等. 生长抑素受体2基因转染抑制胰腺肿瘤细胞生长机制的探讨[J]. 中华医学杂志, 2004, 84(9): 760-765.
16. 　Guillermet GJ, Saint LN, Davenne L, et al. Novel synergistic mechanism for sst2 somatostatin and TNFalpha receptors to induce apoptosis: crosstalk between NF-kappaB and JNK pathways[J]. Cell Death Differ, 2007, 14(2): 197-208.
17. 　Georgiadou M, Notas G, Xidakis C, et al. TNF receptors in Kupffer cells[J]. J Recept Signal Transduct Res, 2011, 4(31): 291-298.
18. 　Boros LG, Brandes JL, Yusut FI, et al. Inhibition of the oxidtive and nonoxidative pentose pho -sphato pathways by somatostation：apsssible mechanism of antitumor action[J]. Med Hypotheses, 1998, 50(6): 501-506.
19. 　Liu ZR, Qin RY, Wu GS. Effect of octreotide on human pancreatic cancer cells after transfected with somatostatin receptor type 2 gene[J]. World J Gastroenterol, 2004, 10(1-5): 2292-2294.
20. 　Laklai H, Laval S, Dumartin L, et al. Thrombospondin-1 is a critical effector of oncosuppressive activity of sst2 somatostatin receptor on pancreatic cancer[J]. Proc Natl Acad Sci USA, 2009, 10(42): 17769-17774.
21. 　Thangaraju M , Shanua K, Liu D, et al. In terdependent regulation of intracellular acidification and SHP-1 in apoptosis[J]. Cancer Res, 1999, 59(7): 1649-1654.
22. 　Arena S, Pattarozzi A, Corsaro A, et al. Somatostatin receptor subtype-dependent regulation of nitric oxide release: involvement of different intracellular pathways[J]. Mol Endocrinol, 2005, 19(1): 255-267.
23. 　刘宇斌，邝素娟，黄小穗, 等. 生长抑素类似物奥曲肽抑制肝癌细胞血管内皮生长因子表达的研究[J]. 南方医科大学学报[J]. 2008, 28(9): 1677-1678.
24. 　孙培龙，胡静波，林万隆, 等. 术前区域动脉灌注生长抑素和化疗药物对结肠癌细胞增殖、凋亡和血管形成的影响[J]. 现代肿瘤医学, 2007, 15(2): 222-224.
25. 　Buscail L, Vernejoul F, Faure P, et al. Regulation of cell proliferation by somatostatin[J]. Ann Endocrinol, 2002, 63(2): 13-18.
26. 　Yamaguchi M, Yamada Y, Hosokawa Y, et al. Long-term suppressive effect of octreotide on pro gression of metastatic gastrinoma with multiple endocrine neoplasia type 1: seven-year follow up[J]. Intern Med, 2010, 49(15): 1557-1563.
27. 　Ishii A, Imanishi Y, Kobayashi K, et al. The levels of somatostatin receptors in causative tumors of oncogenic osteomalacia are insufficient for their agonist to normalize serum phosphate levels[J]. Calcif Tissue Int, 2010, 86(6): 455-462.
28. 　Friedlander TW, Weinberg VK, Small EJ, et al. Effect of the somatostatin analog octreotide acetate on circulating insulin-like　growth factor-1 and related peptides in patients with non-metastatic castration-resistant prostate cancer: Results of a phase II study[J]. Urol Oncol, 2010, 1873-2496.
29. 　He Y, Yuan XM, Lei P, et al. The antiproliferative effects of somatostatin receptor subtype 2 in breast cancer cells[J]. Acta Pharmacol Sin, 2009, 30(7): 1053-1059.
30. 　Ludvigsen E, Stridsberg M, Taylor JE, et al. Subtype selective interactions of somatostatin and somatostatin analogs with SST1, SST2, and SST5 in BON-1 cells[J]. Med Oncol, 2004, 21(3): 285-295.
31. 　Feng Y, Huang T, Gao J, et al. Inhibition of metastatic progression of SSTR2 gene transfection mediated by adenovirus in human pancreatic carcinoma cells[J]. J Huazhong Univ Sci Technolog Med Sci, 2006, 26(1): 68-71.
32. 　Kumar M, Liu ZR, Thapa L, et al. Antiangiogenic effect of somatostatin receptor subtype 2 on pancreatic cancer cell line: Inhibition of vascular endothelial growth factor and matrix metallo -proteinase-2 expression in vitro[J]. World J Gastroenterol, 2004, 10(3): 393-399.
33. 　Benali N, Cordelier P, Calise D, et al. Inhibition of growth and metastatic progression of pancreatic carcinoma in hamster after somatostatin receptor subtype 2 (sst2) gene expression and administration of cytotoxic somatostatin analog AN-238[J]. Proc Natl Acad Sci USA, 2000, 97(16): 9180-9185.
34. 　Tang X, Takekoshi S, Itoh J, et al. Somatostatin analogue inhibits the mobility of prostate carcinoma cells: a new therapeutic method for advanced prostate carcinoma[J]. Int J Oncol, 2010, 37(5): 1077-1083.
35. 　Cerovac V, Monteserin-Garcia J, Rubinfeld HT, et al. The somatostatin analogue octreotide confers sensitivity to rapamycin treatment on pituitary tumor cells[J]. Cancer Res, 2010, 70(2): 666-674.
36. 　刘延国, 王秀问, 魏军, 等. 奥曲肽对紫杉醇抑制非小细胞肺癌细胞的增效作用[J]. 中国肿瘤生物治疗杂志, 2008, 15(3): 210-216.
37. 　秦一雨, 李济宇, 李松岗，等. 生长抑素逆转胆囊癌细胞株耐药性的作用研究 [J]. 中华外科杂志, 2008, 46(5): 381-383.
38. 　Songgang L, Jiyu L, Gongwei, et al. Somatostatin enhances the chemosensitivity of GBC-SD cell line to doxorubicin through arresting the cell cycle to Sphase rather than through the P53/Bax-depended apoptosis way in vitro[J]. Hepatogastroenterology, 2009, 56(95): 1253-1260.

West China Medical Journal

生长抑素及其类似物抗肿瘤作用机制研究进展

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