Improvement of drug resistance with epigenetic drugs

• Project/Area Number: 24790529
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Applied pharmacology
• Research Institution: Chiba University
• Principal Investigator: SATO Hiromi 千葉大学, 薬学研究科(研究院), 助教 (30506887)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 薬物耐性 / sunitinib / 腎細胞癌 / 悪性中皮腫 / connexin / P-gp / がん薬物療法 / 併用効果 / エピジェネティック治療薬 / TKI / 薬剤耐性 / ABCG2

Research Abstract

We aimed to search an appropriate drug which sensitize sunitinib efficacy in renal cell carcinoma (RCC). Finally epigenetic drugs (sodium butyrate, TSA) came out as good combination partners via blockage of RTK signaling which is sunitinib targeted pathway, upregulation of anti-tumor factor of RCC, connexin, or cell cycle regulation. Another candidate was multi drug resistance improving drug (elacridar) via inhibition of drug efflux pump, p-glycoprotein. Furthermore, it has been shown that connexin could also improve sunitinib resistance in malignant mesothelioma cells.

Research Products

• [Journal Article] Identification of a Predictive Biomarker for the Beneficial Effect of Keishibukuryogan, a Kampo (Japanese Traditional) Medicine, on Patients with Climacteric Syndrome. (2014)
  • Author(s): Takao Namiki, Hiromi Sato, Yukari Matsumoto, Haruka Kakikura, Koichi Ueno, Atsushi Chino, Hideki Okamoto, Akito Hisanaga, Akiyo Kaneko, Toshiaki Kita, Maki Kihara, Makio Shozu, Katsutoshi Terasawa.
  • Journal Title: Evidence-Based Complementary and Alternative Medicine Volume: Article ID: 962109 Issue: 1 Pages: 1-8
  • DOI: 10.1155/2014/962109
  • Peer Reviewed
• [Journal Article] Synergistic effect of combined treatment with gamma-tocotrienol and statin on human malignant mesothelioma cells. (2013)
  • Author(s): Guligena Tuerd, Saki Ichinomiya, Hiromi Sato, Sana Siddig, Eriko Suwa, Hiroki Iwata,Tomohiro Yano, Koichi Ueno
  • Journal Title: Cancer Letters Volume: 33 Issue: 1 Pages: 116-127
  • DOI: 10.1016/j.canlet.2013.07.015
  • Peer Reviewed
• [Journal Article] A dual inhibitor of MDR-1 and ABCG2, elacridar, enhances cytotoxic effects of sunitinib on RCC cell lines (2013)
  • Author(s): Sato H, Siddig S, Suzuki R, Uzu M, Suzuki S, Nomura Y, Uehara T, Sekine Y, Arano Y, Ueno K
  • Journal Title: Proc Am Assoc Canc Res Volume: Vol.54 Pages: 983-983
  • Peer Reviewed
• [Journal Article] Connexin might be involved in anti - cancer combination effect of sunitinib and sodium butyrate (2013)
  • Author(s): Uzu M, Sato H, Suzuki R, Okuzawa H, Siddig S, Tuerdi G, Suzuki S, Nomura Y, Sekine Y, Yano T, Ueno K
  • Journal Title: Proc Am Assoc Canc Res Volume: Vol.54 Pages: 1043-1043
  • Peer Reviewed
• [Journal Article] Bee venom phospholipase A2-induced phasic contractions in mouse rectum: Independent roles of eicosanoid and gap junction proteins and their loss in experimental colitis (2013)
  • Author(s): Nomura R, Yanagihara M, Sato H, Matsumoto K, Tashima K, Horie S, Chen S, Fujino H, Ueno K, Murayama T
  • Journal Title: Eur J Pharmacol Volume: 718 Issue: 1-3 Pages: 314-322
  • DOI: 10.1016/j.ejphar.2013.08.015
  • Peer Reviewed
• [Journal Article] Cyclolepis genistoides D. Don (palo azul) promotes differentiation of adipocytes and regulates adipokine expression. (2013)
  • Author(s): Hiromi Sato, Momoko Ishikawa, Asami Funaki, Yuki Kimura, Hiroya Yoshida,Hideki Fukata, Hideo Hasegawa, Koichi Ueno.
  • Journal Title: Nutrition Research Volume: 33 Issue: 11 Pages: 922-931
  • DOI: 10.1016/j.nutres.2013.07.012
  • Peer Reviewed
• [Journal Article] A dual inhibitor of MDR-1 and ABCG2,elacridar, enhances cytotoxic effects of sunitinib on RCC cell lines. (2013)
  • Author(s): Sato H, Siddig S, Suzuki R, Uzu M, Suzuki S, Nomura Y, Uehara T, Sekine Y, Arano Y, Ueno K.
  • Journal Title: Proc Am Assoc Canc Res Volume: 54 Pages: 983-983
  • Peer Reviewed
• [Journal Article] Connexin might be involved in anti-cancer combination effect of sunitinib and sodium butyrate. (2013)
  • Author(s): Uzu M, Sato H, Suzuki R, Okuzawa H, Siddig S, Tuerdi G, Suzuki S, Nomura Y, Sekine Y, Yano T, Ueno K.
  • Journal Title: Proc Am Assoc Canc Res Volume: 54 Pages: 1043-1043
  • Peer Reviewed
• [Journal Article] The Effect of Sex Hormones on Peroxisome Proliferator-Activated Receptor Gamma Expression and Activity in Mature Adipocytes (2013)
  • Author(s): Sato H, Sugai H, Kurosaki H, Ishikawa M, Funaki A, Kimura Y, Ueno K.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 36 Issue: 4 Pages: 564-573
  • DOI: 10.1248/bpb.b12-00868
  • NAID: 130003361388
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed
• [Journal Article] New 2-Aryl-1,4-naphthoquinone-1-oxime Methyl Ether Compound Induces Microtubule Depolymerization and Subsequent Apoptosis (2012)
  • Author(s): H. Sato, R. Yamada, M. Yanagihara, H. Okuzawa, H. Iwata, A. Kurosawa, S. Ichinomiya, R. Suzuki, H. Okabe, T. Yano, T. Kumamoto, N. Suzuki, T. Ishikawa, K. Ueno.
  • Journal Title: Journal of Pharmacological Sciences Volume: 118 Issue: 4 Pages: 467-478
  • DOI: 10.1254/jphs.11229FP
  • NAID: 10030572009
  • ISSN: 1347-8613, 1347-8648
  • Peer Reviewed
• [Presentation] 腎がん細胞におけるHDAC阻害薬trichostatin Aとsunitinibの併用効果 (2014)
  • Author(s): 加柴達朗,宇津美秋,佐藤洋美,鈴木梨菜,上野光一
  • Organizer: 第134回日本薬学会年会
  • Place of Presentation: 熊本
  • Year and Date: 2014-03-29
• [Presentation] 腎細胞癌におけるP-glycoproteinおよびABCG2阻害がスニチニブ感受性に与える影響 (2014)
  • Author(s): 佐藤洋美, Sana Siddig,宇津美秋,加柴達朗,グシ宮城圭佑,関根祐子,上野光一
  • Organizer: 第87回日本薬理学会年会
  • Place of Presentation: 仙台
  • Year and Date: 2014-03-19
• [Presentation] 腎がん細胞におけるHDAC阻害薬trichostatin Aとsunitinibの併用効果. (2014)
  • Author(s): 加柴 達朗, 宇津 美秋, 佐藤 洋美, 鈴木 梨菜, 上野 光一.
  • Organizer: 第134回日本薬学会年会
  • Place of Presentation: 熊本
• [Presentation] 腎細胞癌におけるP-glycoproteinおよびABCG2阻害がスニチニブ感受性に与える影響. (2014)
  • Author(s): 佐藤 洋美, Sana Siddig, 宇津 美秋, 加柴 達朗, グシ宮城 圭佑, 関根 祐子, 上野 光一.
  • Organizer: 第87回日本薬理学会年会
  • Place of Presentation: 仙台
• [Presentation] Cytotoxic effects of sunitinib was enhanced by a dual inhibitor of P-gp/ABCG2, elacridar in RCC cell lines (2013)
  • Author(s): 佐藤洋美,宇津美秋,矢野友啓,上野光一
  • Organizer: 第72回日本癌学会学術総会
  • Year and Date: 2013-10-05
• [Presentation] Sunitinib及びsodium butyrateの併用効果に対するconnexin32の関与 (2013)
  • Author(s): 宇津美秋,佐藤洋美,矢野友啓,上野光一
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-10-04
• [Presentation] Connexin might be involved in anti - cancer combination effect of sunitinib and sodium butyrate (2013)
  • Author(s): Miaki Uzu, Hiromi Sato, Rina Suzuki, Hiroko Okuzawa, Sana Siddig, Guligena Tuerdi, Sayumi Suzuki, Yuki Nomura, Yuko Sekine, Tomohiro Yano, Koichi Ueno
  • Organizer: 104th AACR
  • Place of Presentation: Washington, DC (USA)
  • Year and Date: 2013-04-07
• [Presentation] A dual inhibitor of MDR-1 and ABCG2,elacridar, enhances cytotoxic effects of sunitinib on RCC cell lines (2013)
  • Author(s): Hiromi Sato, Sana Siddig, Rina Suzuki, Miaki Uzu, Sayumi Suzuki, Yuki Nomura, Tomoya Uehara, Yuko Sekine, Yasushi Arano, and Koichi Ueno
  • Organizer: 104th AACR
  • Place of Presentation: Washington, DC (USA)
  • Year and Date: 2013-04-07
• [Presentation] Sunitinib及びsodium butyrateの併用効果に対するconnexinの関与 (2013)
  • Author(s): 宇津美秋,佐藤洋美,鈴木梨菜,奥澤紘子,岩田紘樹, Siddig SANA, Tuerdi GULIGNA、上野光一
  • Organizer: 第133回薬学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2013-03-28
• [Presentation] MDR-1 and ABCG2 inhibitor, elacridar, enhances cytotoxic effects of sunitinib on RCC cell lines (2013)
  • Author(s): Sana Siddig, Hiromi Sato, Rina Suzuki, Miaki Uzu, Sayumi Suzuki, Yuki Nomura and Koichi Ueno
  • Organizer: 第86回日本薬理学会年会
  • Place of Presentation: 福岡
  • Year and Date: 2013-03-21
• [Presentation] Sunitinib及びsodium butyrateの併用効果に対するconnexin32の関与. (2013)
  • Author(s): 宇津 美秋, 佐藤 洋美, 矢野 友啓, 上野 光一.
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Cytotoxic effects of sunitinib was enhanced by a dual inhibitor of P-gp/ABCG2, elacridar in RCC cell lines. (2013)
  • Author(s): 佐藤 洋美, 宇津 美秋, 矢野 友啓, 上野 光一.
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] 悪性中皮種におけるsunitinibの抗がん作用に対するconnexin43の関与. (2013)
  • Author(s): 宇津 美秋、佐藤 洋美, 加柴 達朗、グシ宮城 圭佑、鈴木 さゆみ、Guligena Tuerdi、山田 遼太、上野 光一.
  • Organizer: 次世代を担う医療薬理シンポジウム
  • Place of Presentation: 熊本
• [Presentation] Connexin might be involved in anti-cancer combination effect of sunitinib and sodium butyrate. (2013)
  • Author(s): Miaki Uzu, Hiromi Sato, Rina Suzuki, Hiroko Okuzawa, Sana Siddig, Guligena Tuerdi, Sayumi Suzuki, Yuki Nomura, Yuko Sekine, Tomohiro Yano, Koichi Ueno.
  • Organizer: 104th AACR Annual Meeting 2013
  • Place of Presentation: Washington DC, USA
• [Presentation] A dual inhibitor of MDR-1 and ABCG2,elacridar, enhances cytotoxic effects of sunitinib on RCC cell lines. (2013)
  • Author(s): Hiromi Sato, Sana Siddig, Rina Suzuki, Miaki Uzu, Sayumi Suzuki, Yuki Nomura, Tomoya Uehara, Yuko Sekine, Yasushi Arano, and Koichi Ueno.
  • Organizer: 104th AACR Annual Meeting 2013
  • Place of Presentation: Washington DC, USA
• [Presentation] マカルピンの前駆体として合成された p-キノンモノオキシムは分裂期停止を介した細胞死を誘導する (2013)
  • Author(s): 佐藤洋美、鈴木さゆみ、柳原碧、山田遼太、黒澤絢子、鈴木紀行、石川勉、上野光一．
  • Organizer: 第86回日本薬理学会年会
  • Place of Presentation: 福岡国際会議場
• [Presentation] MDR-1 and ABCG2 inhibitor, elacridar, enhances cytotoxic effects of sunitinib on RCC cell lines (2013)
  • Author(s): Sana Siddig, Hiromi Sato, Rina Suzuki, Miaki Uzu, Sayumi Suzuki, Yuki Nomura and Koichi Ueno.
  • Organizer: 第86回日本薬理学会年会
  • Place of Presentation: 福岡国際会議場
• [Presentation] sunitinib及びsodium butyrateの併用効果に対するconnexinの関与 (2013)
  • Author(s): 宇津美秋、佐藤洋美、鈴木梨菜、奥澤紘子、岩田紘樹、Siddig SANA、Tuerdi GULIGNA、上野光一．
  • Organizer: 第133回薬学会年会
  • Place of Presentation: パシフィコ横浜
• [Presentation] γ-トコトリエノールとスタチンの併用が小胞体ストレスに及ぼす影響 (2013)
  • Author(s): Tuerdi GULIGNA、一之宮紗紀、佐藤洋美、野村由貴、siddig SANA、矢野友啓、関根祐子、上野光一．
  • Organizer: 第133回薬学会年会
  • Place of Presentation: パシフィコ横浜
• [Presentation] マカルピンの前駆体として合成された新規p-キノンモノオキシムの抗腫瘍活性 (2013)
  • Author(s): 鈴木さゆみ、佐藤洋美、柳原碧、山田遼太、黒澤絢子、鈴木梨菜、宇津美秋、Sana SIDDIG、野村由貴、Guligena TUERDI、鈴木紀行、関根祐子、石川勉、上野光一．
  • Organizer: 第133回薬学会年会
  • Place of Presentation: パシフィコ横浜
• [Presentation] ヒトがん細胞株におけるヒスタミンH4受容体の発現と機能 (2013)
  • Author(s): 野村由貴、佐藤洋美、鈴木さゆみ、佐藤友美、Guligena TUERDI、土居亮介、諏訪映里子、山浦克典、関根祐子、上野光一．
  • Organizer: 第133回薬学会年会
  • Place of Presentation: パシフィコ横浜
• [Presentation] 性ホルモンがPPARγアゴニストの薬理作用に及ぼす影響 (2013)
  • Author(s): 木村友紀、佐藤洋美、船木麻美、佐藤友美、石川桃子、Guligena TUERDI、菅井波名、上野光一．
  • Organizer: 第133回薬学会年会
  • Place of Presentation: パシフィコ横浜
• [Presentation] Combination effect of HDAC inhibitor and Sunitinib in renal cancer cells (2012)
  • Author(s): Rina Suzuki, Hiromi Sato, Miaki Uzu, Sana Siddig, Guligena Tuerdi, Koici Ueno
  • Organizer: 第6回次世代を担う若手医療薬科学シンポジウム
  • Place of Presentation: 京都
  • Year and Date: 2012-11-24
• [Presentation] Combination effect of gamma-tocotrienol and statins against growth of malignant mesothelioma. (2012)
  • Author(s): 佐藤洋美、矢野友啓、上野光一．
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ホテルロイトン札幌
• [Presentation] Combination effect of gamma-tocotrienol and statins against growth of malignant mesothelioma (2012)
  • Author(s): Hiromi Sato, Guligena Tuerdi, Saki Ichinomiya, Sana Siddig, Rina Suzuki, Miaki Uzu, Sayumi Suzuki, Yuki Nomura, and Koichi Ueno.
  • Organizer: 第6回次世代を担う若手医療薬科学シンポジウム
  • Place of Presentation: 京都大学
• [Presentation] Combination effect of HDAC inhibitor and Sunitinib in renal cancer cells (2012)
  • Author(s): Rina Suzuki, Hiromi Sato, Miaki Uzu, Sana Siddig, Guligena Tuerdi, Koici Ueno.
  • Organizer: 第6回次世代を担う若手医療薬科学シンポジウム
  • Place of Presentation: 京都大学
• [Presentation] Possibility of connexin involvement in anti-cancer effect of sunitinib and sodium butyrate combination (2012)
  • Author(s): Miaki Uzu, Hiromi Sato, Rina Suzuki, Sana Siddig, Guligena Tuerdi, Koici Ueno.
  • Organizer: 第6回次世代を担う若手医療薬科学シンポジウム
  • Place of Presentation: 京都大学
• [Book] Mesotheliomas - Synonyms and Definition, Epidemiology, Etiology, Pathogenesis, Cyto-Histopathological Features, Clinic, Diagnosis, Treatment, Prognosis.(Chapter 10) (2013)
  • Author(s): Sato H, Ueno K
  • Total Pages: 244
  • Publisher: Intech
• [Book] Chapter 10 : Connexin 43 Enhances the Cisplatin-Induced Cytotoxicity in Mesothelioma Cells, Mesotheliomas - Synonyms and Definition, Epidemiology, Etiology, Pathogenesis, Cyto - Histopathological Features, Clinic, Diagnosis, Treatment, Prognosis.(Alexander Zubritsky (Ed.)) (2012)
  • Author(s): Sato H, Ueno K
  • Publisher: InTech(ISBN : 978-953-307-845-8)
• [Remarks] 高齢者薬剤学研究室
  • URL: http://www.p.chiba-u.ac.jp/lab/koreisha/index.html