Recent Advances in Malignant Tumor Therapy by Using of Clostridium Perfringens Enterotoxin_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

 LIANGZheng-Yun , WANGMeng ,  GUANWen-Xian

Department of General Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210093, Jiangsu Province, China;

Corresponding author：

GUANWen-Xian, Email: guan-wx@163.com

Keywords：

Clostridium perfringens enterotoxin; Carboxyl peptide fragment of Clostridium perfringens enterotoxin; Claudin protein; Treatment of tumor

DOI：

10.7507/1007-9424.20150233

Video：

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Objective To study the latest progress of cancer therapy by using clostridium perfringens enterotoxin (CPE). Methods Recent advances in malignant tumor treatment based on the molecular structure and function of CPE and its receptor Claudin-3, -4 was focused. Results CPE is cytotoxic for ovarian, breast, pancreatic, and prostate cancer cells which express its receptor Claudin-3, -4, it is also effective over the xenograft mode of those cancers. But CPE is limitted in clinics because of its side effect. Modifying the molecular structure of CPE had made some progress to reduce its toxicity. Conclusion As the ligand of claudin protein, an important component of tight junction, CPE can attack the tumor cell. It is a potentially a chemotherapeutic drug.

Citation： LIANGZheng-Yun, WANGMeng, GUANWen-Xian. Recent Advances in Malignant Tumor Therapy by Using of Clostridium Perfringens Enterotoxin. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2015, 22(7): 893-987. doi: 10.7507/1007-9424.20150233 Copy

1.	Singh AB, Sharma A, Dhawan P. Claudin family of proteins and cancer: an overview. J Oncol, 2010, 2010: 541957.
2.	Li X, Iida M, Tada M, et al. Development of an anti-claudin-3 and-4 bispecific monoclonal antibody for cancer diagnosis and therapy. J Pharmacol Exp Ther, 2014, 351(1): 206-213.
3.	Gao Z, McClane BA. Use of Clostridium perfringens Enterotoxin and the Enterotoxin Receptor-Binding Domain (C-CPE) for Cancer Treatment: Opportunities and Challenges. J Toxicol, 2012, 2012: 981626.
4.	Nagase S, Doyama R, Yagi K, et al. Recent advances in claudin-targeting technology. Biol Pharm Bull, 2013, 36(5): 708-714.
5.	Bos J, Smithee L, McClane B, et al. Fatal necrotizing colitis following a foodborne outbreak of enterotoxigenic Clostridium perfringens type A infection. Clin Infect Dis, 2005, 40(10): e78-e83.
6.	Kitadokoro K, Nishimura K, Kamitani S, et al. Crystal structure of Clostridium perfringens enterotoxin displays features of beta-pore-forming toxins. J Biol Chem, 2011, 286(22): 19549-19555.
7.	Kojima T, Kyuno D, Sawada N. Targeting claudin-4 in human pancreatic cancer. Expert Opin Ther Targets, 2012, 16(9): 881-887.
8.	Yuan X, Lin X, Manorek G, et al. Recombinant CPE fused to tumor necrosis factor targets human ovarian cancer cells expressing the claudin-3 and claudin-4 receptors. Mol Cancer Ther, 2009, 8(7): 1906-1915.
9.	Saeki R, Kondoh M, Kakutani H, et al. A novel tumor-targeted therapy using a claudin-4-targeting molecule. Mol Pharmacol, 2009, 76(4): 918-926.
10.	Smedley JG, 3rd, Uzal FA, McClane BA. Identification of a prepore large-complex stage in the mechanism of action of Clostridium perfringens enterotoxin. Infect Immun, 2007, 75(5): 2381-2390.
11.	Robertson SL, Smedley JG 3rd, Singh U, et al. Compositional and stoichiometric analysis of Clostridium perfringens enterotoxin complexes in Caco-2 cells and claudin 4 fibroblast transfectants. Cell Microbiol, 2007, 9(11): 2734-2755.
12.	Lin X, Shang X, Manorek G, et al. Regulation of the epithelial-mesenchymal transition by claudin-3 and claudin-4. PLoS One, 2013, 8(6): e67496.
13.	Van Itallie CM, Anderson JM. Architecture of tight junctions and principles of molecular composition. Semin Cell Dev Biol, 2014, 36C: 157-165.
14.	Van Itallie CM, Anderson JM. Claudin interactions in and out of the tight junction. Tissue Barriers, 2013, 1(3): e25247.
15.	Ding L, Lu Z, Lu Q, et al. The claudin family of proteins in human malignancy: a clinical perspective. Cancer Manag Res, 2013, 5: 367-375.
16.	Swisshelm K, Machl A, Planitzer S, et al. SEMP1, a senescence-associated cDNA isolated from human mammary epithelial cells, is a member of an epithelial membrane protein superfamily. Gene, 1999, 226(2): 285-295.
17.	Kominsky SL. Claudins: emerging targets for cancer therapy. Expert Rev Mol Med, 2006, 8(18): 1-11.
18.	Singh AB, Harris RC. Epidermal growth factor receptor activation differentially regulates claudin expression and enhances transepi-thelial resistance in Madin-Darby canine kidney cells. J Biol Chem, 2004, 279(5): 3543-3552.
19.	Kominsky SL, Argani P, Korz D, et al. Loss of the tight junction protein claudin-7 correlates with histological grade in both ductal carcinoma in situ and invasive ductal carcinoma of the breast. Oncogene, 2003, 22(13): 2021-2033.
20.	Michl P, Barth C, Buchholz M, et al. Claudin-4 expression decreases invasiveness and metastatic potential of pancreatic cancer. Cancer Res, 2003, 63(19): 6265-6271.
21.	Tsutsumi K, Sato N, Tanabe R, et al. Claudin-4 expression predicts survival in pancreatic ductal adenocarcinoma. Ann Surg Oncol, 2012, 19 Suppl 3: S491-S499.
22.	Dhawan P, Singh AB, Deane NG, et al. Claudin-1 regulates cellular transformation and metastatic behavior in colon cancer. J Clin Invest, 2005, 115(7): 1765-1776.
23.	Agarwal R, D'Souza T, Morin PJ. Claudin-3 and claudin-4 expression in ovarian epithelial cells enhances invasion and is associated with increased matrix metalloproteinase-2 activity. Cancer Res, 2005, 65 (16): 7378-7385.
24.	Jung H, Jun KH, Jung JH, et al. The expression of claudin-1, claudin-2, claudin-3, and claudin-4 in gastric cancer tissue. J Surg Res, 2011, 167(2): e185-e191.
25.	Zhu JL, Gao P, Wang ZN, et al. Clinicopathological significance of claudin-4 in gastric carcinoma. World J Surg Oncol, 2013, 11: 150.
26.	Mima S, Tsutsumi S, Ushijima H, et al. Induction of claudin-4 by nonsteroidal anti-inflammatory drugs and its contribution to their chemopreventive effect. Cancer Res, 2005, 65(5): 1868-1876.
27.	Katahira J, Inoue N, Horiguchi Y, et al. Molecular cloning and functional characterization of the receptor for Clostridium perfringens enterotoxin. J Cell Biol, 1997, 136(6): 1239-1247.
28.	Fujita K, Katahira J, Horiguchi Y, et al. Clostridium perfringens enterotoxin binds to the second extracellular loop of claudin-3, a tight junction integral membrane protein. FEBS Lett, 2000, 476(3): 258-261.
29.	Robertson SL, Smedley JG 3rd, McClane BA. Identification of a claudin-4 residue important for mediating the host cell binding and action of Clostridium perfringens enterotoxin. Infect Immun, 2010, 78(1): 505-517.
30.	Veshnyakova A, Protze J, Rossa J, et al. On the interaction of Clostridium perfringens enterotoxin with claudins. Toxins (Basel), 2010, 2(6): 1336-1356.
31.	English DP, Santin AD. Claudins overexpression in ovarian oancer: potential targets for clostridium perfringens enterotoxin (CPE) based diagnosis and therapy. Int J Mol Sci, 2013, 14(5): 10412-10437.
32.	Litkouhi B, Kwong J, Lo CM, et al. Claudin-4 overexpression in epithelial ovarian cancer is associated with hypomethylation and is a potential target for modulation of tight junction barrier function using a C-terminal fragment of Clostridium perfringens enterotoxin. Neoplasia, 2007, 9(4): 304-314.
33.	Santin AD, Cane S, Bellone S, et al. Treatment of chemotherapy-resistant human ovarian cancer xenografts in C.B-17/SCID mice by intraperitoneal administration of Clostridium perfringens entero-toxin. Cancer Res, 2005, 65(10): 4334-4342.
34.	Kominsky SL, Tyler B, Sosnowski J, et al. Clostridium perfringens enterotoxin as a novel-targeted therapeutic for brain metastasis. Cancer Res, 2007, 67(17): 7977-7982.
35.	Kominsky SL, Vali M, Korz D, et al. Clostridium perfringens entero-toxin elicits rapid and specific cytolysis of breast carcinoma cells mediated through tight junction proteins claudin 3 and 4. Am J Pathol, 2004, 164(5): 1627-1633.
36.	Santin AD, Bellone S, Marizzoni M, et al. Overexpression of claudin-3 and claudin-4 receptors in uterine serous papillary carcinoma: novel targets for a type-specific therapy using Clostridium perfringens enterotoxin (CPE). Cancer, 2007, 109(7): 1312-1322.
37.	Michl P, Buchholz M, Rolke M, et al. Claudin-4: a new target for pancreatic cancer treatment using Clostridium perfringens entero-toxin. Gastroenterology, 2001, 121(3): 678-684.
38.	Yamaguchi H, Kojima T, Ito T, et al. Effects of Clostridium perfringens enterotoxin via claudin-4 on normal human pancreatic duct epithelial cells and cancer cells. Cell Mol Biol Lett, 2011, 16(3): 385-397.
39.	Long H, Crean CD, Lee WH, et al. Expression of Clostridium perfringens enterotoxin receptors claudin-3 and claudin-4 in prostate cancer epithelium. Cancer Res, 2001, 61(21): 7878-7881.
40.	Maeda T, Murata M, Chiba H, et al. Claudin-4-targeted therapy using Clostridium perfringens enterotoxin for prostate cancer. Prostate, 2012, 72(4): 351-360.
41.	Romanov V, Whyard TC, Waltzer WC, et al. A claudin 3 and claudin 4-targeted Clostridium perfringens protoxin is selectively cytotoxic to PSA-producing prostate cancer cells. Cancer Lett, 2014, 351(2): 260-264.
42.	Suzuki H, Kondoh M, Li X, et al. A toxicological evaluation of a claudin modulator, the C-terminal fragment of Clostridium perfringens enterotoxin, in mice. Pharmazie, 2011, 66(7): 543-546.
43.	Kakutani H, Kondoh M, Saeki R, et al. Claudin-4-targeting of diphtheria toxin fragment A using a C-terminal fragment of Clostridium perfringens enterotoxin. Eur J Pharm Biopharm, 2010, 75(2): 213-217.
44.	Gao Z, Xu X, McClane B, et al. C terminus of Clostridium perfringens enterotoxin downregulates CLDN4 and sensitizes ovarian cancer cells to Taxol and Carboplatin. Clin Cancer Res, 2011, 17(5): 1065-1074.
45.	Li X, Saeki R, Watari A, et al. Tissue distribution and safety evaluation of a claudin-targeting molecule, the C-terminal fragment of Clostridium perfringens enterotoxin. Eur J Pharm Sci, 2014, 52: 132-137.

1. Singh AB, Sharma A, Dhawan P. Claudin family of proteins and cancer: an overview. J Oncol, 2010, 2010: 541957.
2. Li X, Iida M, Tada M, et al. Development of an anti-claudin-3 and-4 bispecific monoclonal antibody for cancer diagnosis and therapy. J Pharmacol Exp Ther, 2014, 351(1): 206-213.
3. Gao Z, McClane BA. Use of Clostridium perfringens Enterotoxin and the Enterotoxin Receptor-Binding Domain (C-CPE) for Cancer Treatment: Opportunities and Challenges. J Toxicol, 2012, 2012: 981626.
4. Nagase S, Doyama R, Yagi K, et al. Recent advances in claudin-targeting technology. Biol Pharm Bull, 2013, 36(5): 708-714.
5. Bos J, Smithee L, McClane B, et al. Fatal necrotizing colitis following a foodborne outbreak of enterotoxigenic Clostridium perfringens type A infection. Clin Infect Dis, 2005, 40(10): e78-e83.
6. Kitadokoro K, Nishimura K, Kamitani S, et al. Crystal structure of Clostridium perfringens enterotoxin displays features of beta-pore-forming toxins. J Biol Chem, 2011, 286(22): 19549-19555.
7. Kojima T, Kyuno D, Sawada N. Targeting claudin-4 in human pancreatic cancer. Expert Opin Ther Targets, 2012, 16(9): 881-887.
8. Yuan X, Lin X, Manorek G, et al. Recombinant CPE fused to tumor necrosis factor targets human ovarian cancer cells expressing the claudin-3 and claudin-4 receptors. Mol Cancer Ther, 2009, 8(7): 1906-1915.
9. Saeki R, Kondoh M, Kakutani H, et al. A novel tumor-targeted therapy using a claudin-4-targeting molecule. Mol Pharmacol, 2009, 76(4): 918-926.
10. Smedley JG, 3rd, Uzal FA, McClane BA. Identification of a prepore large-complex stage in the mechanism of action of Clostridium perfringens enterotoxin. Infect Immun, 2007, 75(5): 2381-2390.
11. Robertson SL, Smedley JG 3rd, Singh U, et al. Compositional and stoichiometric analysis of Clostridium perfringens enterotoxin complexes in Caco-2 cells and claudin 4 fibroblast transfectants. Cell Microbiol, 2007, 9(11): 2734-2755.
12. Lin X, Shang X, Manorek G, et al. Regulation of the epithelial-mesenchymal transition by claudin-3 and claudin-4. PLoS One, 2013, 8(6): e67496.
13. Van Itallie CM, Anderson JM. Architecture of tight junctions and principles of molecular composition. Semin Cell Dev Biol, 2014, 36C: 157-165.
14. Van Itallie CM, Anderson JM. Claudin interactions in and out of the tight junction. Tissue Barriers, 2013, 1(3): e25247.
15. Ding L, Lu Z, Lu Q, et al. The claudin family of proteins in human malignancy: a clinical perspective. Cancer Manag Res, 2013, 5: 367-375.
16. Swisshelm K, Machl A, Planitzer S, et al. SEMP1, a senescence-associated cDNA isolated from human mammary epithelial cells, is a member of an epithelial membrane protein superfamily. Gene, 1999, 226(2): 285-295.
17. Kominsky SL. Claudins: emerging targets for cancer therapy. Expert Rev Mol Med, 2006, 8(18): 1-11.
18. Singh AB, Harris RC. Epidermal growth factor receptor activation differentially regulates claudin expression and enhances transepi-thelial resistance in Madin-Darby canine kidney cells. J Biol Chem, 2004, 279(5): 3543-3552.
19. Kominsky SL, Argani P, Korz D, et al. Loss of the tight junction protein claudin-7 correlates with histological grade in both ductal carcinoma in situ and invasive ductal carcinoma of the breast. Oncogene, 2003, 22(13): 2021-2033.
20. Michl P, Barth C, Buchholz M, et al. Claudin-4 expression decreases invasiveness and metastatic potential of pancreatic cancer. Cancer Res, 2003, 63(19): 6265-6271.
21. Tsutsumi K, Sato N, Tanabe R, et al. Claudin-4 expression predicts survival in pancreatic ductal adenocarcinoma. Ann Surg Oncol, 2012, 19 Suppl 3: S491-S499.
22. Dhawan P, Singh AB, Deane NG, et al. Claudin-1 regulates cellular transformation and metastatic behavior in colon cancer. J Clin Invest, 2005, 115(7): 1765-1776.
23. Agarwal R, D'Souza T, Morin PJ. Claudin-3 and claudin-4 expression in ovarian epithelial cells enhances invasion and is associated with increased matrix metalloproteinase-2 activity. Cancer Res, 2005, 65 (16): 7378-7385.
24. Jung H, Jun KH, Jung JH, et al. The expression of claudin-1, claudin-2, claudin-3, and claudin-4 in gastric cancer tissue. J Surg Res, 2011, 167(2): e185-e191.
25. Zhu JL, Gao P, Wang ZN, et al. Clinicopathological significance of claudin-4 in gastric carcinoma. World J Surg Oncol, 2013, 11: 150.
26. Mima S, Tsutsumi S, Ushijima H, et al. Induction of claudin-4 by nonsteroidal anti-inflammatory drugs and its contribution to their chemopreventive effect. Cancer Res, 2005, 65(5): 1868-1876.
27. Katahira J, Inoue N, Horiguchi Y, et al. Molecular cloning and functional characterization of the receptor for Clostridium perfringens enterotoxin. J Cell Biol, 1997, 136(6): 1239-1247.
28. Fujita K, Katahira J, Horiguchi Y, et al. Clostridium perfringens enterotoxin binds to the second extracellular loop of claudin-3, a tight junction integral membrane protein. FEBS Lett, 2000, 476(3): 258-261.
29. Robertson SL, Smedley JG 3rd, McClane BA. Identification of a claudin-4 residue important for mediating the host cell binding and action of Clostridium perfringens enterotoxin. Infect Immun, 2010, 78(1): 505-517.
30. Veshnyakova A, Protze J, Rossa J, et al. On the interaction of Clostridium perfringens enterotoxin with claudins. Toxins (Basel), 2010, 2(6): 1336-1356.
31. English DP, Santin AD. Claudins overexpression in ovarian oancer: potential targets for clostridium perfringens enterotoxin (CPE) based diagnosis and therapy. Int J Mol Sci, 2013, 14(5): 10412-10437.
32. Litkouhi B, Kwong J, Lo CM, et al. Claudin-4 overexpression in epithelial ovarian cancer is associated with hypomethylation and is a potential target for modulation of tight junction barrier function using a C-terminal fragment of Clostridium perfringens enterotoxin. Neoplasia, 2007, 9(4): 304-314.
33. Santin AD, Cane S, Bellone S, et al. Treatment of chemotherapy-resistant human ovarian cancer xenografts in C.B-17/SCID mice by intraperitoneal administration of Clostridium perfringens entero-toxin. Cancer Res, 2005, 65(10): 4334-4342.
34. Kominsky SL, Tyler B, Sosnowski J, et al. Clostridium perfringens enterotoxin as a novel-targeted therapeutic for brain metastasis. Cancer Res, 2007, 67(17): 7977-7982.
35. Kominsky SL, Vali M, Korz D, et al. Clostridium perfringens entero-toxin elicits rapid and specific cytolysis of breast carcinoma cells mediated through tight junction proteins claudin 3 and 4. Am J Pathol, 2004, 164(5): 1627-1633.
36. Santin AD, Bellone S, Marizzoni M, et al. Overexpression of claudin-3 and claudin-4 receptors in uterine serous papillary carcinoma: novel targets for a type-specific therapy using Clostridium perfringens enterotoxin (CPE). Cancer, 2007, 109(7): 1312-1322.
37. Michl P, Buchholz M, Rolke M, et al. Claudin-4: a new target for pancreatic cancer treatment using Clostridium perfringens entero-toxin. Gastroenterology, 2001, 121(3): 678-684.
38. Yamaguchi H, Kojima T, Ito T, et al. Effects of Clostridium perfringens enterotoxin via claudin-4 on normal human pancreatic duct epithelial cells and cancer cells. Cell Mol Biol Lett, 2011, 16(3): 385-397.
39. Long H, Crean CD, Lee WH, et al. Expression of Clostridium perfringens enterotoxin receptors claudin-3 and claudin-4 in prostate cancer epithelium. Cancer Res, 2001, 61(21): 7878-7881.
40. Maeda T, Murata M, Chiba H, et al. Claudin-4-targeted therapy using Clostridium perfringens enterotoxin for prostate cancer. Prostate, 2012, 72(4): 351-360.
41. Romanov V, Whyard TC, Waltzer WC, et al. A claudin 3 and claudin 4-targeted Clostridium perfringens protoxin is selectively cytotoxic to PSA-producing prostate cancer cells. Cancer Lett, 2014, 351(2): 260-264.
42. Suzuki H, Kondoh M, Li X, et al. A toxicological evaluation of a claudin modulator, the C-terminal fragment of Clostridium perfringens enterotoxin, in mice. Pharmazie, 2011, 66(7): 543-546.
43. Kakutani H, Kondoh M, Saeki R, et al. Claudin-4-targeting of diphtheria toxin fragment A using a C-terminal fragment of Clostridium perfringens enterotoxin. Eur J Pharm Biopharm, 2010, 75(2): 213-217.
44. Gao Z, Xu X, McClane B, et al. C terminus of Clostridium perfringens enterotoxin downregulates CLDN4 and sensitizes ovarian cancer cells to Taxol and Carboplatin. Clin Cancer Res, 2011, 17(5): 1065-1074.
45. Li X, Saeki R, Watari A, et al. Tissue distribution and safety evaluation of a claudin-targeting molecule, the C-terminal fragment of Clostridium perfringens enterotoxin. Eur J Pharm Sci, 2014, 52: 132-137.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Recent Advances in Malignant Tumor Therapy by Using of Clostridium Perfringens Enterotoxin

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