Inhibition of inducing multidrug resistance in human osteosarcoma cells by histone deacetylase inhibitor and DNA methylation inhibitor

• Project/Area Number: 24592247
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Hyogo Medical University
• Principal Investigator: TERADA NOBUYUKI 兵庫医科大学, 医学部, 名誉教授 (50150339)
• Co-Investigator(Kenkyū-buntansha): NAKASHO Keiji 兵庫医科大学, 医学部, 教授 (00217712) ; YAMANEGI Koji 兵庫医科大学, 医学部, 講師 (00434944) ; YAMADA Naoko 兵庫医科大学, 医学部, 講師 (10319858) ; HATA Masaki 兵庫医科大学, 医学部, 研究生(研究員) (10446057) ; OHYAMA Hideki 兵庫医科大学, 医学部, 非常勤講師 (90280685)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 骨肉腫 / 薬剤耐性 / 非ステロイド系抗炎症剤

Outline of Final Research Achievements

We investigated that the combination of histone deacetylase (HDAC) inhibitor, hydralazine (DNA methylation inhibitor) and celecoxib (nonsteroidal anti-inflammatory drugs, cyclooxygenase-2 inhibitor) inhibit inducing the expression of multidrug resistance (MDR) protein (MDR-1, MRP-1) in osteosarcoma cells without inhibiting cytotoxic sensitivity. The combination of HDAC inhibitor and celecoxib significantly inhibits cell-proliferation. This combination showed different reactions depending on the type of cells but generally inhibited. HDAC inhibitor alone increased MDR activity, however, combined with celecoxib reduced the activity depended on MDR-1 and MRP-1. These results suggest that combined treatment of HDAC inhibitor, hydralazine and celecoxib may be a useful for enhancing the effect of chemotherapy for osteosarcoma.

Research Products

• [Journal Article] Sodium valproate, a histone deacetylase inhibitor, modulates the vascular endothelial growth inhibitor-mediated cell death in human osteosarcoma and vascular endothelial cells. (2015)
  • Author(s): Yamanegi K, Kawabe M, Futani H, Nishiura H, Yamada N, Kato-Kogoe N, Kishimoto H, Yoshiya S, Nakasho K.
  • Journal Title: Int J Oncol Volume: 46 Issue: 5 Pages: 1994-2002
  • DOI: 10.3892/ijo.2015.2924
  • Peer Reviewed
• [Journal Article] Expression of interleukin-34 and colony stimulating factor-1 in the stimulated periodontal ligament cells with tumor necrosis factor-α. (2015)
  • Author(s): Kawabe M, Ohyama H, Kato-Kogoe N, Yamada N, Yamanegi K, Nishiura H, Hirano H, Kishimoto H, Nakasho K.
  • Journal Title: Med Mol Morphol. Volume: -
  • Peer Reviewed
• [Journal Article] Estrogen decreases the expression of claudin-5 in vascular endothelial cells in the murine uterus. (2014)
  • Author(s): Hata M, Yamanegi K, Yamada N, Ohyama H, Yukitatsu Y, Nakasho K, Okamura H, Terada N.
  • Journal Title: Endocr J Volume: -
  • NAID: 130004443978
  • Peer Reviewed
• [Journal Article] Decreased expression of VE-cadherin and claudin-5 and increased phosphorylation of VE-cadherin in vascular endothelium in nasal polyps. (2013)
  • Author(s): Yukitatsu Y, Hata M, Yamanegi K, Yamada N, Ohyama H, Nakasho K, Kojima Y, Oka H, Tsuzuki K, Sakagami M, Terada N.
  • Journal Title: Cell Tissue Res Volume: 352 Issue: 3 Pages: 647-657
  • DOI: 10.1007/s00441-013-1583-0
  • Peer Reviewed
• [Journal Article] Hypoxia downregulates the expression of cell surface MICA without increasing soluble MICA in osteosarcoma cells in a HIF-1α-dependent manner. (2012)
  • Author(s): Yamada N, Yamanegi K, Ohyama H, Hata M, Nakasho K, Futani H, Okamura H, Terada N.
  • Journal Title: Int J Oncol. Volume: 41(6) Issue: 6 Pages: 2005-2012
  • DOI: 10.3892/ijo.2012.1630
  • Peer Reviewed
• [Journal Article] Downregulation of matrix metalloproteinase-9 mRNA by valproic acid plays a role in inhibiting the shedding of MHC class I-related molecules A and B on the surface of human osteosarcoma cells. (2012)
  • Author(s): Yamanegi K, Yamane J, Kobayashi K, Ohyama H, Nakasho K, Yamada N, Hata M, Fukunaga S, Futani H, Okamura H, Terada N.
  • Journal Title: Oncol Rep. Volume: 28(5) Issue: 5 Pages: 1585-1590
  • DOI: 10.3892/or.2012.1981
  • Peer Reviewed
• [Journal Article] Valproic acid cooperates with hydralazine to augment the susceptibility of human osteosarcoma (2012)
  • Author(s): Yamanegi K, Yamane J, Kobayashi K, Kato-Kogoe N, Ohyama H, Nakasho K, YamadaN, Hata M, Fukunaga S, Futani H, Okamura H, Terada N.
  • Journal Title: cells to Fas- and NK cell-mediated cell death.Int J Oncol. Volume: 41(1) Pages: 83-91
  • DOI: 10.3892/ijo.2012.1438
  • Peer Reviewed
• [Presentation] 骨肉腫細胞における低酸素誘導性の細胞表面MICAの発現低下 (2012)
  • Author(s): 山田 直子、山根木 康嗣、大山 秀樹、中正 恵二、秦 正樹、寺田 信行
  • Organizer: 日本分子生物学会
  • Place of Presentation: 福岡
• [Presentation] ヒストン脱アセチル化阻害剤を用いた腫瘍血管新生抑制 (2012)
  • Author(s): 山根木康嗣、小林健太、中正恵二、大山秀樹、山田直子、秦正樹、寺田信行
  • Organizer: 日本病理学会総会
  • Place of Presentation: 東京
• [Presentation] 低酸素による細胞表面MICAの糖鎖修飾の低下
  • Author(s): 山田直子, 山根木康嗣, 大山秀樹, 寺田信行, 中正恵二
  • Organizer: 第36回日本分子生物学会
  • Place of Presentation: 神戸