高橋 典子

所属：衛生化学・病態機能制御学研究室
職位：教授
学位：薬学博士
最終学歴：京都大学大学院薬学研究科博士課程

（教育活動：担当授業科目）
衛生学II (3年生)、研究の現場 (2年生)、研究特論I (3年生)、研究特論II (4年生)、基礎演習Ⅳ (4年生)、衛生学特論 (5年生)、食生活と保健衛生 (5年生)、総合薬学演習II (6年生)、環境保健学特論I (大学院)
基礎実習I (1年生)、薬学科物理系実習II (2年生)、卒論準備実習 (3年生)、卒論 (3~6年生)

（研究活動）
指針：流行の研究はなるべく避け、オリジナリティーのある研究を行う。
概要：生体維持に必須であるビタミンA酸 (レチノイン酸, RA) の新しいメカニズムを解明することによって、新しいターゲットを見出し、そこから病態に対する新しい治療薬を創製する。特に、社会的に大きな問題であり関心の高い癌、老化、生活習慣病に焦点をあてて研究を行ない、これら疾病に対する治療薬と予防薬の開発を最終目標とする。
内容：ビタミンAは視覚の正常化、成長促進作用、感染予防、上皮組織 (皮膚) の機能維持に不可欠な栄養素である。これらに加え多岐の薬理作用 (抗癌、皮膚病予防、神経保護、抗酸化、免疫賦活作用) を有する。特に、ビタミンAの生理活性化体であるRAは急性前骨髄球性白血病患者の治療に使われている。RAの新しい作用メカニズムを解明し、癌を始め皮膚病、神経疾患、生活習慣病に対する新規の医薬品・予防剤の開発のための基盤構築を行う。
1. 癌の治療・予防に関する研究
1) 抗癌作用メカニズムの解明と抗癌剤のターゲット探索： 多岐にわたり劇的な作用を現すRAが特異的受容体 (RAR) を介して抗癌作用を示すと説明されているが、実際には矛盾点も多い。ビタミンAの抗癌作用メカニズムを翻訳後タンパク質修飾 (レチノイレーション、レチノイル化) の観点から明らかにし、抗癌作用の新規ターゲットを見出す。
2) 創薬： RAの研究から新たに得られた知見を応用し、抗癌剤開発を目指した研究を行う。また、有効な抗癌剤であるレチノイドの癌治療における薬剤耐性および副作用の原因を究明し、未だ有効な治療薬のない膵臓あるいは胆道癌 (薬剤抵抗性癌) に対する抗癌剤を創製する
2. 皮膚・神経に関する研究：細胞増殖・分化・細胞死
器官の形成には、細胞増殖・分化・細胞死が時間的・空間的に規則正しくプログラムされている。皮膚・神経細胞に着目し、これらの細胞の機能とRAによる分化、細胞周期、アポトーシスメカニズムの制御との関連を明らかにする。
3. 生活習慣病 (糖尿病・高脂血症等) に関する研究：ダイエットターゲット探索
糖尿病と肥満との相関性はよく知られている。また、RAは脂肪細胞の脂肪蓄積を抑制する。そこで生活習慣病の予防剤・治療薬の開発を目指し、RAによる脂肪蓄積制御のメカニズムを解明して、ダイエットターゲットを見出す。

（所属学会）
日本レチノイド研究会、日本生化学会、日本分子生物学会、日本薬学会、日本薬学会構造活性相関部会、日本油化学会、日本薬学会環境・衛生部会、日本薬学会生物系薬学部会、米国癌学会 (AACR)、米国生化学分子生物学会 (ASBMB)、米国細胞生物学会 (ASCB)

（学内活動：役職・委員等）
評議委員会委員、環境保全センター長、廃棄物対策委員会委員長、廃棄物自主監査委員会委員長、医薬品化学研究所運営会議副委員長、共同機器研究施設・機器管理委員会委員、出版・刊行物委員会アドバイザー、卒業試験問題検討委員会委員、卒業試験評価委員会委員、国家試験問題検討委員会委員

（学外活動：委員会委員等）
私立大学環境保全協議会理事、日本生化学会評議員、日本レチノイド研究会幹事、日本薬学会構造活性相関部会幹事、薬剤師国家試験委員会委員、日本生化学会「生化学」企画委員 (2001-07)、日本学術振興会専門委員 (2003-05)

（受賞歴）
日本薬学会学術貢献賞を受賞 (2022)、日本薬学会学術振興賞を受賞(2002)、財団法人持田記念医学薬学振興財団第14回研究助成金を受賞(1996)、財団法人内藤記念科学振興財団第28回内藤記念科学奨励金を受賞(1996)、公益信託林女性自然科学者研究助成基金を受賞(1997)、星薬科大学大谷記念研究奨励金を受賞(1998)、財団法人三共生命科学研究振興財団研究助成を受賞(1999)、星薬科大学表彰を受賞(2002)、財団法人三共生命科学研究振興財団研究助成を受賞(2007)

（主な著書・論文）

TAKAHASHI, N., SAITO, T., GODA, Y., AND TOMITA, K.: Participation of Microsomal Aldehyde Reductase in Long-Chain Fatty Alcohol Synthesis in the Rat Brain, Biochim. Biophys. Acta, 963, 243-247 (1988).

TAKAHASHI, N., BREITMAN, T. R., SAITO, T. AND ICHIKAWA, A.: The Monocytic Differentiation of HL60 Induced by Rat Kidney NADPH-Linked High-Km Aldehyde Reductase Protein, J. Biol. Chem., 264, 15624-15627 (1989).

TAKAHASHI, N. AND BREITMAN, T. R.: Retinoic Acid Acylation (Retinoylation) of a Nuclear Protein in the Human Acute Myeloid Leukemia Cell Line HL60, J. Biol. Chem., 264, 5159-5163 (1989).

TAKAHASHI, N. AND BREITMAN, T. R.: Retinoylation of HL-60 Proteins: Comparison to Labeling by Palmitic and Myristic Acids, J. Biol. Chem., 265, 19158-19162 (1990).

TAKAHASHI, N., BREITMAN, T. R.: Retinoic Acid Acylation (Retinoylation), Methods Enzymol., 189, 233-238 (1990)

TAKAHASHI, N., LIAPI, C., ANDERSON, W. B. AND BREITMAN, T. R.: Retinoyaltion of the cAMP-Binding Regulatory Subunits of Type I and Type II cAMP-Dependent Protein Kinases in HL60 cells, Arch. Biochem. Biophys., 290, 293-302 (1991).

TAKAHASHI, N. AND BREITMAN, T. R.: Covalent Binding to Proteins of Ligands for Steroid Hormone Receptors in HL60 Cells, Proc. Natl. Acad. Sci. USA, 89, 10807-10811 (1992).

TAKAHASHI, N. AND BREITMAN, T. R.: Retinoylation of Vimentin in the Human Myeloid Leukemia Cell Line HL60, J. Biol. Chem., 269, 5913-5917 (1994).

TAKAHASHI, N. AND BREITMAN, T. R.: Retinoylation of Proteins, In: Blomhoff R, ed., Vitamin A in Health and Disease, New York: Marcel Dekker Inc., 257-273 (1994).

TAKAHASHI, N., SAUSVILLE, E. A. AND BREITMAN, T. R.: N-(4-Hydroxyphenyl) retinamide (Fenretinide) Enhances Retinoic Acid-Induced Differentiation and Retinoylation of Proteins, Clinical Cancer Research, 1, 637-642 (1995).

TAKATSUKA, J., TAKAHASHI, N. AND DELUCA, L. M.: Retinoic Acid Metabolism and Inhibition of Cell Proliferation: an Unexpected Liaison, Cancer Research, 56, 675-678 (1996).

TAKAHASHI, N., DELUCA, L. M. AND BREITMAN, T. R.: Decreased Retinoylation in NIH 3T3 Cells Transformed with Activated Ha-ras, Biochem. Biophys. Res. Commun., 239, 80-84 (1997).

TAKAHASHI, N., FUKUI, T., IWAHORI, A., KUBO, Y., HOSOE, T. AND KAWAI, K.: Induction of Differentiation and Apoptosis in Human Promyelocytic Leukemia HL60 Cell Line by a New Type of Steroids, Exp. Cell Res., 245, 313-320 (1998).

TAIMI, M., BREITMAN, T. R., AND TAKAHASHI, N.: Isoforms of cyclic AMP-dependent protein kinase in human myeloid leukemia (HL60) and breast tumor (MCF-7) cells, Arch. Biochem. Biophys., 392: 137-144 (2001)

WADA, M., FUKUI, T., KUBO, Y. AND TAKAHASHI, N.: Characterization of Retinoyl-CoA Synthetase in Rat Tissues, J. Biochemistry, 130(3), 457-463 (2001).

TAMAGAWA, K., EBINE, T., SHIMIZU, K., MAITANI, Y., FUKUI, T., KAWAI, K. AND TAKAHASHI, N.: Antitumor Efficacy In Vitro and In Vivo of Falconensones, a New Type of Polyene, Clinical Cancer Research, 7, 3551-3558 (2001).

TAKAHASHI, N., TAMAGAWA, K., KUBO, Y., FUKUI, T., WAKABAYASHI, H. and HONDA, T.: Enhancement of antioxidant activity of p-alkylaminophenols by alkyl chain elongation, Bioorganic Medicinal Chemistry, 1 (15), 3255-3260 (2003).

KUBO, Y., WADA, M., OHBA, T. AND TAKAHASHI, N.: Formation of retinoylated protein from retinoyl-CoA in rat tissue, J. Biochem., 138, 493-500 (2005).

TAKAHASHI, N., HONDA, T. AND OHBA, T.: Anticancer and superoxide scavenging activities of p-alkylaminophenols having various length alkyl chains, Bioorg. Med. Chem., 14, 409-417 (2006).

OHBA, T., YAMAUCHI, T., HIGASHIYAMA, K. AND TAKAHASHI, N.: Potent anticancer activities of novel aminophenol analogues against various cancer cell lines, Bioorg Med Chem. 15, 847-53 (2007).

KUBO, Y., OHBA, T. AND TAKAHASHI, N.: Proteins in human myeloid leukemia cell line HL60 reacting with retinoic acid monoclonal antibodies, J. Biochem., 144, 349-355 (2008).

TAKAHASHI, N., WATANABE, Y., MAITANI, Y., YAMAUCHI, T., HIGASHIYAMA, K. AND OHBA T.: p-Dodecylaminophenol derived from the synthetic retinoid, fenretinide: Antitumor efficacy in vitro and in vivo against human prostate cancer and mechanism of action, Int. J. Cancer, 122, 689-698 (2008).

TAKAHASHI, N., AND FUJIU, Y.: Cytokeratins 16 and 10 bind to retinoic acid covalently in skin tissues of mice, Br. J. Dermatol., 162, 974-979 (2010).

TAKAHASHI, N. AND FUJIU, Y.: Effects of the aminophenol analogue, p-dodecylaminophenol in mouse skin, J. Invest. Dermatol., 130, 1258-1267 (2010).

TAKAHASHI, N., EGAWA, R., IMAI, M., TAKAHASHI, K., OHBA, T., AND IMAIZUMI, M.: The anti-tumor agent, p-DDAP potently suppresses proliferation through apoptosis in human neuroblastoma NB-39-nu cells, Cancer Lett.,297, 252-258 (2010).

TAKAHASHI, N. AND TAKASU, S.: A close relationship between type 1 diabetes and vitamin A-deficiency and MMP and HAase activities in skin tissues, Exp. Dermatol., 20, 899-904 (2011).

KATO, E., SASAKI, Y., and TAKAHASHI, N.: Sodium dl-α-tocopheryl-6-O-phosphate inhibits PGE2 production in keratinocytes induced by UVB, IL-1β and peroxidants. Bioorg. Med. Chem., 19 (21), 6348-6355 (2011).

IMAI, M. and TAKAHASHI, N.: Growth inhibition and mechanism of action of p-dodecylaminophenol against refractory human pancreatic cancer and cholangiocarcinoma, Bioorg. Med. Chem., 20(8), 2520-2526 (2012).

KATO, E. and TAKAHASHI, N.: Improvement by sodium dl-a-tocopheryl-6-O-phosphate treatment of moisture-retaining ability in stratum corneum through increased ceramide levels, Bioorg. Med. Chem., 20(12), 3837-3842 (2012).

SAGARA, C., TAKAHASHI, K., KAGECHIKA, H., and TAKAHASHI, N.: Molecular mechanism of 9-cis-retinoic acid inhibition of adipogenesis in 3T3-L1 cells, Biochem. Biophys. Res. Commun., 427(2), 398-403 (2013).

TAKAHASHI, N., TAKEDA, K., and IMAI, M.: Inhibitory effects of p-dodecylaminophenol on the invasiveness of human fibrosarcoma cell line HT1080, Bioorg. Med. Chem., 21, 6015–6021 (2013).

KOMORI, Y., IMAI, M., YAMAUCHI, T., HIGASHIYAMA, K., and TAKAHASHI, N.: Effect of p-aminophenols on tyrosinase activity. Bioorg. Med. Chem., 22 (15), 3994-4000 (2014).

TAKAHASHI, N., IMAI, M., and KOMORI, Y.: Inhibitory effects of p-alkylaminophenol on melanogenesis. Bioorg. Med. Chem., 22 (17), 4677-4683 (2014).

TAKAHASHI, K., UCHIDA, N., KITANAKA, C., SAGARA, C., IMAI, M., and TAKAHASHI, N.: Inhibition of ASCT2 is essential in all-trans retinoic acid-induced reduction of adipogenesis in 3T3-L1 cells. FEBS Open Bio, 5, 571-578 (2015).

IMAI, M., KUMAOKA, T., HOSAKA, M., SATO, Y., LI, C., SUDOH, M., TAMADA, Y., YOKOE, H., SAITO, S., TSUBUKI, M., and TAKAHASHI, N.: Inhibitory effects of hydroxylated cinnamoyl esters on lipid absorption and accumulation. Bioorg. Med. Chem., 23 (13), 3788-3795 (2015).

TAKAHASHI, N., OHBA, T., IMAI, M., HASEGAWA, S., TAKAHASHI, K., YAMASAKI, M., and KAMEOKA, Y.: Retinoylation (covalent modification by retinoic acid) of Rho-GDIβ in the human myeloid leukemia cell line HL60 and its functional significance. Biochim. Biophys. Acta., 1861 (12 Pt A), 2011-2019 (2016).

HASEGAWA S., INOUE D., YAMASAKI M., LI C., IMAI M., TAKAHASHI N., and FUKUI T.: Site-specific cleavage of acetoacetyl-CoA synthetase by legumain. FEBS Lett., 590 (11), 1592-1601 (2016).

YAMASAKI, M., HASEGAWA, S., IMAI, M., TAKAHASHI, N., and FUKUI, T.: High-fat diet-induced obesity stimulates ketone body utilization in osteoclasts of the mouse bone. Biochem. Biophys. Res. Commun., 473 (2), 654-661 (2016).

LI, C., IMAI, M., MATSUURA, T., HASEGAWA, S., YAMASAKI, M., and TAKAHASHI, N.: Inhibitory effects of retinol are greater than retinoic acid on the growth and adhesion of human refractory cancer cells. Biol. Pharm. Bull., 39 (4), 636-640 (2016).

TAKAHASHI, N., KOYAMA, S., HASEGAWA, S., YAMASAKI, M., and IMAI, M.: Anticancer efficacy of p-dodecylaminophenol against high-risk and refractory neuroblastoma cells in vitro and in vivo. Bioorg Med Chem Lett., 27 (20), 4664-4672 (2017).

LI, C., IMAI, M., HASEGAWA, S., YAMASAKI, M., and TAKAHASHI, N.: Growth inhibition of refractory human gallbladder cancer cells by retinol, and its mechanism of action. Biol. Pharm. Bull., 40 (4), 495-503 (2017).

LI, C., IMAI, M., YAMASAKI, M., HASEGAWA, S., and TAKAHASHI, N.: Effects of pre- and post-administration of vitamin A on the growth of refractory cancers in xenograft mice. Biol. Pharm. Bull., 40 (4), 486-494 (2017).

SAKAI, A., IMAI, M., TAKAHASHI, K., HASEGAWA, S., YAMASAKI, M., OHBA, T., and TAKAHASHI, N.: Protein kinase A activation by retinoic acid in the nuclei of HL60 cells. Biochim. Biophys. Acta., 1861 (2), 276-285 (2017).

TAKAHASHI, N., KOYAMA, S., HASEGAWA, S., YAMASAKI, M., and IMAI, M.: Anticancer efficacy of p-dodecylaminophenol against high-risk and refractory neuroblastoma cells in vitro and in vivo. Bioorg. Med. Chem. Lett., 27, 4664-4672 (2017).

HASEGAWA, S., IMAI, M., YAMASAKI, M., TAKAHASHI, N., and FUKUI, T.: Transcriptional regulation of acetoacetyl-CoA synthetase by Sp1 in neuroblastoma cells. Biochem. Biophys. Res. Commun., 495, 652-658 (2018).

HIDAKA, M., KOSAKA, K., TSUSHIMA, S., UCHIDA, C., TAKAHASHI, K., TAKAHASHI, N., TSUBUKI, M., HARA, Y., and UCHIDA, T.: Food polyphenols targeting peptidyl prolyl cis/trans isomerase Pin1, Biochem. Biophys. Res. Commun., 499, 681-687 (2018).

TAKAHASHI, N., KAKE, T., HASEGAWA, S., and IMAI, M.: Effects of Post-administration of β-Carotene on Diet-induced Atopic Dermatitis in Hairless Mice. J. Oleo Sci., 68, 793-802 (2019).

IMAI, M., YOKOE, H., TSUBUKI, M., and TAKAHASHI, N.: Growth inhibition of human breast and prostate cancer cells by cinnamic acid derivatives and their mechanism of action. Biol. Pharm. Bull., 42, 1134-1139 (2019).

IZUMISAWA, T., KANEKO, T., SOMA, M., IMAI, M., WAKUI, N., HASEGAWA, H., HORINO, T., and TAKAHASHI, N.: Augmented renal clearance of vancomycin in hematologic malignancy patients. Biol. Pharm. Bull., 42, 2089-2094 (2019).

KAKE, T., IMAI, M., and TAKAHASHI, N.: Effects of β-carotene on oxazolone-induced atopic dermatitis in hairless mice. Exp. Dermatol., 28, 1044-1050 (2019).

IZUMISAWA, T., WAKUI, N., KANEKO, T., SOMA, M., IMAI, M., SAITO D., HASEGAWA, H., HORINO, T., TAKAHASHI, N.: Increased Vancomycin Clearance in Patients with Solid Malignancies. Biol. Pharm. Bull., 43, 1081-1087 (2020).

HASEGAWA, S., IMAI, M., YAMASAKI,　M., TAKAHASHI, N.: Isolation and characterization of human acetoacetyl-CoA synthetase splice variants. Gene Reports, 19, 100665 (2020).

SAITO, D., IMAI, M., YAMADA, C., and TAKAHASHI. N.: Changes in the levels of α-actinin-4 in differentiating human myeloid leukemia cells induced by retinoic acid. Biochim. Biophys. Acta Mol. Cell Res. 2021 Jan 14:118968 (2021). doi: 10.1016/j.bbamcr.2021.118968.

YAMASAKI, M., HASEGAWA, S., IMAI, M., FUKUI, T., and TAKAHASHI, N.: Browning Effect of Brominated Flame Retardant, TBBP-A, on Undifferentiated Adipocytes. BPB Reports, 4 (1) 41-46 (2021).

SAITO, D., IMAI, M., HASEGAWA, S., YAMASAKI, M., and TAKAHASHI. N.: A splicing factor phosphorylated by protein kinase A is increased in HL60 cells treated with retinoic acid. Biochim Biophys Acta Mol Cell Res, 1869, 119142 (2022).

TAKAHASHI, N.: Inhibitory effects of vitamin A and its derivatives on cancer cell growth not mediated by retinoic acid receptors. Biol Pharm Bull, 45, 1213–1224 (2022).

TAKAHASHI, N., SAITO, D., HASEGAWA, S., YAMASAKI, M., and IMAI, M.: Vitamin A in health care: Suppression of growth and induction of differentiation in cancer cells by vitamin A and its derivatives and their mechanisms of action. Pharmacol. Ther. 230, 107942 (2022).