A claudin-targeting molecule as an inhibitor of tumor metastasis.
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.
Saeki
Rie
R
Laboratory of Bio-Functional Molecular Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.
Kondoh
Masuo
M
Kakutani
Hideki
H
Matsuhisa
Koji
K
Takahashi
Azusa
A
Suzuki
Hidehiko
H
Kakamu
Yohei
Y
Watari
Akihiro
A
Yagi
Kiyohito
K
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D062506:Claudin-4; D003016:Clostridium perfringens; D004768:Enterotoxins / Q000235:genetics*; D005098:Exotoxins / Q000235:genetics; D005260:Female; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D011549:Pseudomonas; D011956:Receptors, Cell Surface / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D062506:Claudin-4; C568158:Cldn4 protein, mouse; D004768:Enterotoxins; D005098:Exotoxins; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; C035598:enterotoxin, Clostridium; C105422:Clostridium perfringens enterotoxin receptor