High antitumor activity of pladienolide B and its derivative in gastric cancer

Authors

  • Momoko Sato,

    1. Department of Gastroenterology and Oncology, Institutes of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
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  • Naoki Muguruma,

    1. Department of Gastroenterology and Oncology, Institutes of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
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  • Tadahiko Nakagawa,

    1. Department of Gastroenterology and Oncology, Institutes of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
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  • Koichi Okamoto,

    1. Department of Gastroenterology and Oncology, Institutes of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
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  • Tetsuo Kimura,

    1. Department of Gastroenterology and Oncology, Institutes of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
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  • Shinji Kitamura,

    1. Department of Gastroenterology and Oncology, Institutes of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
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  • Hiromi Yano,

    1. Department of Gastroenterology and Oncology, Institutes of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
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  • Katsutaka Sannomiya,

    1. Department of Gastroenterology and Oncology, Institutes of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
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  • Takahiro Goji,

    1. Department of Gastroenterology and Oncology, Institutes of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
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  • Hiroshi Miyamoto,

    1. Department of Gastroenterology and Oncology, Institutes of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
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  • Toshiya Okahisa,

    1. Department of Gastroenterology and Oncology, Institutes of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
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  • Hiroaki Mikasa,

    1. Medical Education Sapport Center, Faculty of Medicine, Tokushima University, Tokushima, Japan
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  • Satoshi Wada,

    1. Department of Gastroenterology, Oe Kyodo Hospital, Yoshinogawa, Japan
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  • Masao Iwata,

    1. Tsukuba Research Laboratories, Eisai Co., Ltd, Tsukuba, Japan
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  • Tetsuji Takayama

    Corresponding author
    1. Department of Gastroenterology and Oncology, Institutes of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
    • Tetsuji Takayama, Department of Gastroenterology and Oncology, Institutes of Health Biosciences, University of Tokushima Graduate School, 3-18-15, Kuramoto-cho, Tokushima 770-8503, Japan.

      Tel: +81-88-633-7124; Fax: +81-88-633-9235;

      E-mail: takayama@md.pikara.ne.jp

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  • Funding information

    None declared.

Abstract

The antitumor activity of pladienolide B, a novel splicing inhibitor, against gastric cancer is totally unknown and no predictive biomarker of pladienolide B efficacy has been reported. We investigated the antitumor activity of pladienolide B and its derivative on gastric cancer cell lines and primary cultured cancer cells from carcinomatous ascites of gastric cancer patients. The effect of pladienolide B and its derivative on six gastric cancer cell lines was investigated using a MTT assay and the mean IC50 values determined to be 1.6 ± 1.2 (range, 0.6–4.0) and 1.2 ± 1.1 (range, 0.4–3.4) nM, respectively, suggesting strong antitumor activity against gastric cancer. The mean IC50 value of pladienolide B derivative against primary cultured cells from 12 gastric cancer patients was 4.9 ± 4.7 nM, indicative of high antitumor activity. When 18 SCID mice xenografted with primary cultured cells from three patients were administered the pladienolide B derivative intraperitoneally, all tumors completely disappeared within 2 weeks after treatment. Histological examination revealed a pathological complete response for all tumors. In the xenograft tumors after treatment with pladienolide B derivative, immature mRNA were detected and apoptotic cells were observed. When the expressions of cell-cycle proteins p16 and cyclin E in biopsied gastric cancer specimens were examined using immunohisctochemistry, positivities for p16 and cyclin E were significantly and marginally higher, respectively, in the low-IC50 group compared with the high-IC50 group, suggesting the possibility that they might be useful as predictive biomarkers for pladienolide B. In conclusion, pladienolide B was very active against gastric cancer via a mechanism involving splicing impairment and apoptosis induction.

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