Improvement of drug resistance with epigenetic drugs

2013 Fiscal Year Final Research Report

• 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
• Keywords: 薬物耐性 / sunitinib / 腎細胞癌 / 悪性中皮腫 / connexin / P-gp

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] Synergistic effect of combined treatment with gamma - tocotrienol and statin on human malignant mesothelioma cells (2013)
  • Author(s): Tuerdi G, Ichinomiya S, Sato H, Siddig S, Suwa E, Iwata H, Yano T, Ueno K
  • Journal Title: Cancer Letters Volume: Vol. 33 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
  • 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
  • Peer Reviewed
• [Journal Article] A new 2-aryl-1,4-naphthoquinone-1-oxime methyl ether compound induces microtubule depolymerization and subsequent apoptosis (2012)
  • Author(s): Sato H, Yamada R, Yanagihara M, Okuzawa H, Iwata H, Kurosawa A, Ichinomiya S, Suzuki R, Okabe H, Yano T, Kumamoto T, Suzuki N, Ishikawa T, Ueno K
  • Journal Title: Journal of Pharmacological Sciences Volume: Vol. 118 Pages: 467-478
  • DOI: 10.1254/jphs.11229FP
  • 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] 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] 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
• [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
  • Total Pages: 153-168
  • Publisher: InTech(ISBN : 978-953-307-845-8)