Involvement of aminopeptidase N in enhanced chemosensitivity to paclitaxel in ovarian carcinoma in vitro and in vivo.
Aminopeptidase N (APN/CD13), a 150-kDa metalloproteinase, is a multifunctional cell surface aminopeptidase with ubiquitous expression. Recent studies have suggested that APN/CD13 plays an important role in tumor progression in several human malignancies. In the current study, we investigated the role of APN/CD13 in paclitaxel (PAC)-resistance of ovarian carcinoma (OVCA) cells. We first examined the correlation between APN/CD13 expression and IC50 values of PAC in a variety of OVCA cell lines. Next we investigated whether suppression of APN/CD13 using bestatin, an inhibitor of APN/CD13 activity or the siRNA technique influenced PAC-sensitivity in ES-2 cells, which highly express APN/CD13. Moreover, we investigated the effect of bestatin on peritoneal metastasis using nude mice. We found a negative correlation between APN/CD13 expression and chemosensitivity to PAC in various carcinoma cell lines. Subsequently, we found a significant increase in PAC-sensitivity of APN/CD13 expressing OVCA cells by suppression of this enzyme, using the addition of bestatin or the siRNA technique. Furthermore, in a peritoneal metastasis model using nude mice, combination treatment with PAC and bestatin caused a synergistic increase of survival time compared with PAC alone treatment. (mean survival time: 37.7 +/- 7.0 s and 27.1 +/- 6.6 days, respectively). The present findings showed that APN/CD13 may be involved in decreased sensitivity to PAC in OVCA cells and that the mechanism of this effect involves its enzyme activity at least in part. APN/CD13 may be a therapeutic target for the treatment of OVCA in combination with chemotherapy.
Yamashita
Mamoru
M
Department of Obstetrics and Gynecology, Nagoya Graduate University School of Medicine, Tsurumai-Cho 65, Showa-ku, Nagoya 466-8550, Japan.
Kajiyama
Hiroaki
H
Terauchi
Mikio
M
Shibata
Kiyosumi
K
Ino
Kazuhiko
K
Nawa
Akihiro
A
Mizutani
Shigehiko
S
Kikkawa
Fumitaka
F
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D018826:CD13 Antigens / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D002277:Carcinoma / Q000188:drug therapy / Q000201:enzymology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D017239:Paclitaxel / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D034741:RNA, Small Interfering; D018826:CD13 Antigens; D007930:Leucine; C012211:ubenimex; D017239:Paclitaxel