HDAC inhibition against pancreatic cancer

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K09399
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Sapporo Medical University
• Principal Investigator: Michihiro Ono 札幌医科大学, 医学部, 助教 (80634675)
• Co-Investigator(Kenkyū-buntansha): 宮西 浩嗣 札幌医科大学, 医学部, 准教授 (60372819) ; 菊地 尚平 札幌医科大学, 医学部, 助教 (80515792) ; 加藤 淳二 札幌医科大学, 医学部, 教授 (20244345)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: HDAC阻害剤 / 膵癌 / 細胞周期停止

Outline of Final Research Achievements

Pancreatic cancer is highly chemo-resistant associated with oncogenic mutations such as KRAS and/or p53. Selective class IIa HDAC inhibitor TMP269 treatment showed increased FoxO3a expression in a dose dependent manner with immunoblotting and modest cell growth inhibition effect at 57.5 μM of IC50 dose for 48-hour treatment against AsPC-1 in MTT. G1/S arrest was observed with cell cycle assay. Upregulated p21Waf1/Cip1 and downregulated CDK2 and 4/6 and cyclin D1 and D2 expressions were further observed, consistent with inducing G1/S arrest and transcriptionally activated FoxO3a. Importantly, upregulated p21Waf1/Cip1 was observed in AsPC-1 p53 null cell line, suggesting independent with p53 pathway. These findings suggest upregulated FoxO3a induced by HDAC class IIa inhibition activated its transcription and resulted in cell growth inhibition.

Free Research Field

胆道・膵臓系腫瘍

Academic Significance and Societal Importance of the Research Achievements

通常の化学療法剤では極めて難治性の膵癌診療において、選択的HDAC class IIa 阻害剤が細胞増殖抑制効果を示し、新規治療戦略の可能性を示した。特にp53やRASなど、遺伝子異常が通常の化学療法剤の治療抵抗性に関与しているが、TMP269がp53欠損株においても、p53非依存性にp21の発現増強を介して、細胞増殖抑制効果を示しており、治療抵抗性の克服に対しても、可能性を示した。