Abstract
Tumor metastasis of epithelium-derived tumors is the major cause of death from malignant tumors. Overexpression of claudin is observed frequently in malignant tumors. However, claudin-targeting antimetastasis therapy has never been investigated. We previously prepared a claudin-4-targeting antitumor molecule that consisted of the C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) fused to protein synthesis inhibitory factor (PSIF) derived from Pseudomonas exotoxin. In the present study, we investigated whether claudin CPE receptors can be a target for tumor metastasis by using the C-CPE-fused PSIF as a claudin-targeting agent. One of the most popular murine metastasis models is the lung metastasis of intravenously injected B16 cells. Therefore, we first investigated the effects of the C-CPE-fused PSIF on lung metastasis of claudin-4-expressing B16 (CL4-B16) cells. Intravenous administration of the C-CPE-fused PSIF suppressed lung metastasis of CL4-B16 cells but not B16 cells. Injection of C-CPE-fused PSIF also inhibited tumor growth and spontaneous lung metastasis of murine breast cancer 4T1 cells inoculated into the subcutis. Treatment with C-CPE-fused PSIF did not show apparent side effects in mice. These findings indicate that claudin targeting may be a novel strategy for inhibiting some tumor metastases.
Footnotes
This work was supported by the Ministry of Education, Culture, Sports, Science, and Technology, Japan [Grant-in-Aid for Scientific Research 21689006], Health and Labor Sciences research grants from the Ministry of Health, Labor, and Welfare of Japan, the Takeda Science Foundation, and a grant from Kansai Biomedical Cluster Project in Saito, which is promoted by the Knowledge Cluster Initiative of the Ministry of Education, Culture, Sports, Science, and Technology of Japan. H.K. and A.T. are supported by research fellowships from the Japan Society for the Promotion of Science for Young Scientists.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.168070.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- CPE
- Clostridium perfringens enterotoxin
- C-CPE
- C-terminal fragment of CPE
- PSIF
- protein synthesis inhibitory factor
- C-CPE-PSIF
- C-CPE-fused PSIF
- CL4-B16
- claudin-4-expressing B16
- TJ
- tight junction
- FBS
- fetal bovine serum
- DMEM
- Dulbecco's modified Eagle's medium
- PBS
- phosphate-buffered saline
- ADR
- adriamycin.
- Received March 10, 2010.
- Accepted May 3, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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