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Combined effect of dehydroxymethylepoxyquinomicin and gemcitabine in a mouse model of liver metastasis of pancreatic cancer

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Abstract

Activation of nuclear factor-κB (NF-κB) has been implicated in metastasis of pancreatic cancer. We investigated the effects of the novel NF-κB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) on the inhibition of liver metastasis of pancreatic cancer in a mouse model of clinical liver metastasis. Nude mice were xenografted by intra-portal-vein injection with the human pancreatic adenocarcinomas cell line AsPC-1 via small laparotomy. Mice were treated with DHMEQ and gemcitabine (GEM), alone or in combination. The combination of GEM + DHMEQ showed a stronger antitumor effect than either monotherapy. Apoptosis induction in the metastatic foci was greatest in the DHMEQ + GEM group. Significant reductions in the numbers of neovessels were also seen in the DHMEQ and/or GEM groups. Cell growth inhibition assays revealed no synergistic effect of combination therapy, although each monotherapy had an individual cytotoxic effect. Combination therapy produced the greatest inhibition of tumor cell invasiveness in chemoinvasion assay. In addition, combination therapy significantly down-regulated the expression level of matrix metalloproteinase (MMP)-9 mRNA in AsPC-1 cells. DHMEQ also markedly down-regulated interleukin-8 and MMP-9, while GEM caused moderate down-regulation of vascular endothelial growth factor in metastatic foci, demonstrated by quantitative reverse transcription-polymerase chain reaction. These results demonstrate that DHMEQ can exert anti-tumor effects by inhibiting angiogenesis and tumor cell invasion, and by inducing apoptosis. Combination therapy with DHMEQ and GEM also showed potential efficacy. DHMEQ is a promising drug for the treatment of advanced pancreatic cancer.

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Abbreviations

NF-κB:

Nuclear factor-κB

DHMEQ:

Dehydroxymethylepoxyquinomicin

CMC:

Chrolomethylcellulose

FBS:

Fetal bovine serum

PBS:

Phosphate-buffered saline

MVD:

Microvessel density

VEGF:

Vascular endothelial growth factor

MMP:

Matrix metalloproteinase

IL-8:

Interleukin-8

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Authors and Affiliations

  1. Department of Surgery, Kitasato Institute Hospital, 5-9-1 Shirogane, Minato-ku, Tokyo, 108-8642, Japan

    Keiichi Suzuki

  2. Department of Surgery, Kawasaki City Hospital, 12-1 Shinkawadori, Kawasaki, Kanagawa, 210-0013, Japan

    Koichi Aiura

  3. Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan

    Sachiko Matsuda, Osamu Itano & Yuko Kitagawa

  4. Biomedical Laboratory, Kitasato Institute Hospital, 5-9-1 Shirogane, Minato-ku, Tokyo, 108-8642, Japan

    Osamu Takeuchi

  5. Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Kanagawa, 3-14-1 Hiyoshi, Kouhoku-ku, Yokohama, 223-0061, Japan

    Kazuo Umezawa

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  1. Keiichi Suzuki
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  2. Koichi Aiura
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  3. Sachiko Matsuda
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Correspondence to Keiichi Suzuki.

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Suzuki, K., Aiura, K., Matsuda, S. et al. Combined effect of dehydroxymethylepoxyquinomicin and gemcitabine in a mouse model of liver metastasis of pancreatic cancer. Clin Exp Metastasis 30, 381–392 (2013). https://doi.org/10.1007/s10585-012-9544-7

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  • DOI: https://doi.org/10.1007/s10585-012-9544-7

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