Strategy for prevention of acquired resistance and overcoming of natural resistance to decitabine in colorectal cancer cells

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K15531
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Medical pharmacy
• Research Institution: Kobe Pharmaceutical University
• Principal Investigator: Mika Hosokawa 神戸薬科大学, 薬学部, 助教 (70548271)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: デシタビン / 獲得耐性 / 自然耐性 / エピジェネティック / 大腸がん

Outline of Final Research Achievements

Colorectal cancer cells acquired resistance by the long-term exposure with a DNA methyltransferase (DNMT) inhibitor, decitabine (DAC). In acquired resistant cells to DAC, the expression of dCK (active enzyme of DAC) decreased. Acquired resistance to DAC was partly improved by another DNMT inhibitor, azacytidine, which is metabolized into active form by different enzyme from dCK. On the other hand, the mechanism of natural resistance to DAC in colorectal cancer cells, which originally showed resistance to DAC, was different from that of acquired resistance to DAC. In natural resistant cells to DAC, synergistic cytotoxic effects were observed when DAC was treated with WNT signal pathway inhibitor or anti-cancer drug, oxaliplatin.

Free Research Field

生物薬剤学

Academic Significance and Societal Importance of the Research Achievements

DNAメチル基転移酵素(DNMT)阻害薬デシタビン(DAC)を用いてがん治療を行っている際に、DACの長期投与により効果が低下する耐性が認められた場合の対策法に関する知見が得られた。治療前からDACに対して耐性を示す場合においても、DACと併用することで効果を高める可能性のある物質が見出された。
本研究で得られた成果は、エピジェネティック機構を標的とする新規抗がん剤であるデシタビンを有効活用するための有益な情報になると考えられる。