ヒト由来培養がん細胞を用いた薬物代謝酵素シトクロムP-450分子種等の変動要因に関する研究～エピジェネティクス関連事象や細胞の三次元的培養環境を中心に～

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タイトル別名
  • Modulation of Expression of Drug Metabolizing Enzymes and Augmentation of Anti-cancer Drug Effects: Through Epigenetics and Three-dimensional Cancer Cell Culture Systems
  • ヒト ユライ バイヨウ ガン サイボウ オ モチイタ ヤクブツ タイシャ コウソ シトクロム P-450プン コダネ トウ ノ ヘンドウ ヨウイン ニ カンスル ケンキュウ : エピジェネティクス カンレン ジショウ ヤ サイボウ ノ サンジゲンテキ バイヨウ カンキョウ オ チュウシン ニ

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<p>Since commencing my role as a professor in a newly established Department of Pharmacodynamics and Molecular Genetics at the School of Pharmacy, Iwate Medical University, on April 1, 2007, my research has focused on modifying gene expression of cytochrome P-450 (CYP) in established human colon cancer cells. Additionally, I have been investigating methods to enhance the anti-tumor effects of irinotecan (CPT-11) and 5-fluorouracil (5-FU) using epigenetic modifying inhibitors of DNA methyltransferase and histone deacetylase. Treating colon cancer cells with a DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine (DAC), led to elevated expression levels of CYP1B1 and CYP3A4 through demethylation of the promoter regions of related genes. Furthermore, the administration of DAC and the histone deacetylase inhibitor depsipeptide [(DEP), an anti-cancer drug romidepsin] significantly increased the cellular sensitivities of human colon cancer cells to CPT-11 and 5-FU, respectively. Remarkably, DAC treatment also increased colon cancer cell sensitivity to SN-38, an active metabolite of CPT-11, through the suppression of the anti-apoptotic protein Bcl-2. DEP increased colon cancer cell sensitivity to 5-FU in association with increased expressions of tumor-suppressor p21 and major histocompatibility complex class II genes. Another facet of my research is centered around understanding the gene regulatory mechanisms of the CYP1 family through aryl hydrocarbon receptors (AhR)s under glucose-deprivation stress and in three-dimensional (3D) culture systems of human solid tumor cells. In the 3D culture of human liver cancer cells, I found Pregnane X Receptor being implicated in the regulation of CYP1A2, which aligns with the in vivo mode of CYP1A2 expression.</p>

収録刊行物

  • 薬学雑誌

    薬学雑誌 143 (12), 1013-1025, 2023-12-01

    公益社団法人 日本薬学会

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