Exploration of mechanism of drug resisitance in cancer acidic condition and development of novel therapeutic drug

• Project/Area Number: 26830108
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor therapeutics
• Research Institution: The University of Tokushima
• Principal Investigator: NAKAMURA Shingen 徳島大学, 大学病院, 助教 (10511321)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: がん酸性環境 / pim2 / 酸性環境 / 多発性骨髄腫 / cucurbitacin

Outline of Final Research Achievements

Tumor acidity has been known to confer drug resistance in cancers, however, therapeutic drug targetting tumor acidic microenvironment have not been developed. Pim2 was highly upregulated in myeloma cells, and SIRT1, BCRP, monocarbonic transporter were upregulated in acidic condition. Pim inhibitor improved all of these change. We explored compound library in faculty of pharmaceutical sciences,and found cucurbitacinB was one of a candidates of therapeutic drugs for targeting tumor acidic condition.

Research Products

• [Journal Article] Susceptibility to bendamustine considerably varies among myeloma cells, but is enhanced in acidic conditions (2016)
  • Author(s): Shingen NAKAMURA , Hirokazu MIKI , Asuka ODA , Ryota AMACHI , Jumpei TERAMACHI , Kimiko SOGABE , Hikaru FUJINO , Tomoko MARUHASHI , Shiro FUJII , Kumiko KAGAWA and Masahiro ABE
  • Journal Title: International Journal of Myeloma Volume: 6 Pages: 7-11
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 多発性骨髄腫 (2016)
  • Author(s): 安倍正博、三木浩和、中村信元
  • Journal Title: 臨床血液 Volume: 57 Pages: 260-269
  • NAID: 130005145479
• [Journal Article] Effective impairment of myeloma cells and their progenitors by blockade of monocarboxylate transportation. (2015)
  • Author(s): Hanson DJ, Nakamura S, Amachi R, Hiasa M, Oda A1, Tsuji D, Itoh K, Harada T, Horikawa K, Teramachi J, Miki H, Matsumoto T, Abe M.
  • Journal Title: oncotarget Volume: 6 Pages: 33568-33586
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Human immunodeficiency virus-positive secondary syphilis mimicking cutaneous T-cell lymphoma (2015)
  • Author(s): Yamashita M, Fujii Y, Ozaki K, Urano Y, Iwasa M, Nakamura S, Fujii S, Abe M, Sato Y, Yoshino T
  • Journal Title: Diagn Pathol. Volume: 10 Pages: 8-8
  • Peer Reviewed / Open Access
• [Journal Article] Lipopolysaccharide-Induced CXCL10 mRNA Level and Six Stimulant-mRNA Combinations in Whole Blood: Novel Biomarkers for Bortezomib Responses Obtained from a Prospective Multicenter Trial for Patients with Multiple Myeloma. (2015)
  • Author(s): Watanabe T, Mitsuhashi M, Sagawa M, Ri M, Suzuki K, Abe M, Ohmachi K, Nakagawa Y, Nakamura S, Chosa M, Iida S, Kizaki M.
  • Journal Title: PLoS One Volume: 10
  • NAID: 120006871197
  • Peer Reviewed / Open Access
• [Journal Article] Pim-2 kinase is an important target of treatment for tumor progression and bone loss in myeloma. (2015)
  • Author(s): Hiasa M, Teramachi J, Oda A, Amachi R, Harada T, Nakamura S, Miki H, Fujii S, Kagawa K, Watanabe K, Endo I, Kuroda Y, Yoneda T, Tsuji D, Nakao M, Tanaka E, Hamada K, Sano S, Itoh K, Matsumoto T, Abe M
  • Journal Title: Leukemia Volume: 29 Pages: 207-217
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Induction of endoplasmic reticulum stress by bortezomib sensitizes myeloma cells to DR5-mediated cell death (2015)
  • Author(s): Miki H, Nakamura S, Oda A, Amachi R, Watanabe K, Hanson D, Teramachi J, Hiasa M, Yagi H, Sogabe K, Takahashi M, Maruhashi T, Udaka K, Harada T, Fujii S, Nakano A, Kagawa K, Ri M, Iida S, Ozaki S, Matsumoto T, Abe M.
  • Journal Title: International Journal of Myeloma Volume: 5 Pages: 1-7
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Cytotoxic efficacy of Pim inhibitors and anti-myeloma agents in combination (2015)
  • Author(s): Shingen Nakamura, Hirokazu Miki, Hirofumi Tenshin, Ryota Amachi, Derek Hanson, Keiichiro Watanabe, Jumpei Teramachi, Asuka Oda, Kimiko Sogabe, Hikaru Fujino, Tomoko Maruhashi, Shiro Fujii ,Kumiko Kagawa, Masahiro Abe
  • Organizer: 日本血液学会
  • Place of Presentation: 石川県立音楽堂、ANAクラウンプラザホテル金沢、 ホテル日航金沢、ホテル金沢、ほか （石川県金沢市）
  • Year and Date: 2015-10-16
• [Presentation] Alteration of Pim-2 expression by clinically available anti-myeloma agents: combinatory anti-myeloma effects with Pim inhibition (2015)
  • Author(s): Shingen Nakamura, Hirokazu Miki, Hirofumi Tenshin, Ryota Amachi, Derek Hanson, Keiichiro Watanabe, Jumpei Teramachi Asuka Oda, Kimiko Sogabe, Hikaru Fujino, Tomoko Maruhashi, Shiro Fujii ,Kumiko Kagawa, Masahiro Abe
  • Organizer: international myeloma workshop
  • Place of Presentation: Rome（Italy）
  • Year and Date: 2015-09-23
  • Int'l Joint Research
• [Presentation] Combinatory effects of Pim inhibitor with clinically available anti-myeloma agents (2015)
  • Author(s): Shingen Nakamura, Hirokazu Miki, Hirofumi Tenshin, Ryota Amachi, Derek Hanson, Keiichiro Watanabe, Jumpei Teramachi, Asuka Oda, Kimiko Sogabe, Hikaru Fujino, Tomoko Maruhashi, Shiro Fujii ,Kumiko Kagawa, Masahiro Abe
  • Organizer: 日本骨髄腫学会
  • Place of Presentation: くまもと森都心プラザ （熊本県熊本市）
  • Year and Date: 2015-05-17
• [Presentation] Cytotoxic efficacy of Pim inhibitors and anti-myeloma agents in combination (2015)
  • Author(s): Shingen Nakamura, Hirokazu Miki, Hirofumi Tenshin, Ryota Amachi, Derek Hanson, Keiichiro Watanabe, Jumpei Teramachi, Asuka Oda, Kimiko Sogabe, Hikaru Fujino, Tomoko Maruhashi, Shiro Fujii ,Kumiko Kagawa, Masahiro Abe
  • Organizer: 日本骨髄腫学会
  • Place of Presentation: くまもと森都心プラザ（熊本県熊本市）
  • Year and Date: 2015-05-17
• [Presentation] 酸が惹起する骨髄腫細胞の酸感受と生存シグナルの悪循環 (2014)
  • Author(s): 天知良太 日浅雅博、寺町順平、Hanson Derek、小田明日香、渡邉佳一郎、 遠藤逸朗、田中栄二、松本俊夫、安倍正博
  • Organizer: 癌と骨病変研究会
  • Place of Presentation: 千代田放送会館（東京都千代田区）
  • Year and Date: 2014-11-16
• [Presentation] Progressive vicious cycle between acid sensing and survival signaling in myeloma cells (2014)
  • Author(s): 天知良太 日浅雅博、寺町順平、Hanson Derek、小田明日香、渡邉佳一郎、 遠藤逸朗、田中栄二、松本俊夫、安倍正博
  • Organizer: 日本血液学会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] Progressive vicious cycle between acid sensing and survival signaling in myeloma cells. American Society for Bone and Mineral Research (2014)
  • Author(s): Ryota Amachi,Masahiro Hiasa, Jumpei Teramachi, Asuka Oda, Derek Hanson, Keiichiro Watanabe, Itsuro Endo, Eiji Tanaka, Toshio Matsumoto, Masahiro Abe
  • Organizer: American Society for Bone and Mineral Research
  • Place of Presentation: アメリカ（ヒューストン）
  • Year and Date: 2014-09-12 – 2014-09-15
• [Presentation] Progressive vicious cycle between acid sensing and survival signaling in myeloma cells (2014)
  • Author(s): Ryota Amachi ,Masahiro Hiasa, Jumpei Teramachi, Asuka Oda, Derek Hanson, Keiichiro Watanabe, Itsuro Endo, Eiji Tanaka, Toshio Matsumoto, Masahiro Abe
  • Organizer: Australian and New Zealand Bone and Mineral Society
  • Place of Presentation: ニュージーランド（クイーンズタウン）
  • Year and Date: 2014-09-07 – 2014-09-10
• [Presentation] 酸が惹起する骨髄腫細胞の酸感受と生存シグナルの悪循環 (2014)
  • Author(s): 天知良太 日浅雅博、寺町順平、小田明日香、渡邉佳一郎、遠藤逸朗、田中栄二、 松本俊夫、安倍正博
  • Organizer: 第32回日本骨代謝学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2014-07-24 – 2014-07-26