Oncotarget

Research Papers:

Anti-claudin-4 extracellular domain antibody enhances the antitumoral effects of chemotherapeutic and antibody drugs in colorectal cancer

Rina Fujiwara-Tani _, Takamitsu Sasaki, Yi Luo, Kei Goto, Isao Kawahara, Yukiko Nishiguchi, Shingo Kishi, Shiori Mori, Hitoshi Ohmori, Masuo Kondoh and Hiroki Kuniyasu

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Oncotarget. 2018; 9:37367-37378. https://doi.org/10.18632/oncotarget.26427

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Abstract

Rina Fujiwara-Tani1, Takamitsu Sasaki1, Yi Luo1,2, Kei Goto1, Isao Kawahara1, Yukiko Nishiguchi1, Shingo Kishi1, Shiori Mori1, Hitoshi Ohmori1, Masuo Kondoh3 and Hiroki Kuniyasu1

1Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan

2Jiangsu Province Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China

3Drug Innovation Center, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan

Correspondence to:

Hiroki Kuniyasu, email: cooninh@zb4.so-net.ne.jp

Keywords: claudin; tight junction

Received: August 20, 2018     Accepted: November 26, 2018     Published: December 21, 2018

ABSTRACT

Claudin-4 (CLDN4) is a major epithelial tight junction protein overexpressed in many cancers to maintain the tumor environment. In this report, we aimed to determine the efficacy of targeting CLDN4 in colorectal cancer (CRC) using an anti-CLDN4 extracellular domain antibody, 4D3. CLDN4 was upregulated in CRC metastatic foci. CLDN4 expression in CRC cells was reduced by upregulation of TNFα, which was induced by Clostridium perfringens enterotoxin produced by gut flora. In a nude mouse liver metastasis model, inhibition of metastasis was increased by combination treatment with 5-fluorouracil (FU) and 4D3 compared to that with 5-FU alone. Moreover, combination treatment with 4D3 and anti-epithelial growth factor receptor (EGFR) antibody C225 resulted in more pronounced inhibition of in vitro sphere formation and tumor growth in nude mice compared to that observed with C225 alone. Moreover, the time interval between the administration of 4D3 and that of C225 was important for maximizing the C225-induced inhibition of EGFR phosphorylation. In a nude mouse model, sequential treatment with 4D3 and C225 with a 6-h time interval resulted in more pronounced inhibition of tumor growth than concurrent treatment. These findings suggest that the targeting of CLDN4 enhances the antitumoral effects of chemotherapeutic agents and molecular targeting antibodies when used in combination.


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