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Inostamycin prevents malignant phenotype of cancer: inhibition of phosphatidylinositol synthesis provides a therapeutic advantage for head and neck squamous cell carcinoma

Authors

  • Yuh Baba,

    Corresponding author
    1. Department of Otolaryngology, Tochigi National Hospital, Tochigi 320-8580, Japan
    2. Department of Otolaryngology, Head and Neck Surgery, Keio University, Tokyo 160-0082, Japan
    3. Department of Biochemistry and Molecular Biology, Kanagawa Dental College, Yokosuka 238-8580, Japan
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  • Yasumasa Kato,

    Corresponding author
    1. Department of Biochemistry and Molecular Biology, Kanagawa Dental College, Yokosuka 238-8580, Japan
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  • Kaoru Ogawa

    1. Department of Otolaryngology, Head and Neck Surgery, Keio University, Tokyo 160-0082, Japan
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yuh_baba@hotmail.com or yasumasa_kato@live.jp

Abstract

Head and neck squamous cell carcinoma is the sixth most common type of neoplasm worldwide, but its prognosis has not improved significantly in recent years. Therefore, efforts need to be intensified to gain a better understanding of this disease and develop novel treatment strategies. Inhibition of cytidine 5′-diphosphate 1,2-diacyl-sn-glycerol: inositol transferase by inostamycin, an antibiotic isolated from Streptomyces sp. MH816-AF15, induces G1 cell cycle arrest accompanied by a decrease in cyclin D1 and phosphorylated RB protein levels, along with suppression of in vitro invasive ability through reduced production of matrix metalloproteinases (MMP-2 and MMP-9) and cell motility in head and neck cancer cell lines. Furthermore, inostamycin abrogated the stimulatory effect of VEGF (vascular endothelial growth factor) on growth and migration activities of endothelial cells by targeting extracellular signal-regulated kinase-cyclin D1 and p38 pathways, respectively. Because inostamycin has both antiproliferative and anti-invasive abilities, inhibition of phosphatidylinositol synthesis could be a potent therapeutic strategy for head and neck cancer as the ‘cancer dormant therapy’, i.e. a therapeutic concept to prolong ‘time to treatment failure’ or ‘time to progression’.

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