Unique anti-myeloma activity by thiazolidine-2,4-dione compounds with Pim inhibiting activity

• Material Type: 博士論文
• Title: Unique anti-myeloma activity by thiazolidine-2,4-dione compounds with Pim inhibiting activity
• Author/Editor: Fujii, Shiro; Nakamura, Shingen; Oda, Asuka; Miki, Hirokazu; Tenshin, Hirofumi; Teramachi, Jumpei; Hiasa, Masahiro; Bat-Erdene, Ariunzaya; Maeda, Yusaku; Oura, Masahiro; Takahashi, Mamiko; Iwasa, Masami; Endo, Itsuro; Yoshida, Sumiko; Aihara, Ken-ichi; Kurahashi, Kiyoe; Harada, Takeshi; Kagawa, Kumiko; Nakao, Michiyasu; Sano, Shigeki; Abe, Masahiro
• Author Heading: Fujii, Shiro; Nakamura, Shingen; Oda, Asuka; Miki, Hirokazu; Tenshin, Hirofumi; Teramachi, Jumpei; Hiasa, Masahiro; Bat-Erdene, Ariunzaya; Maeda, Yusaku; Oura, Masahiro; Takahashi, Mamiko; Iwasa, Masami; Endo, Itsuro; Yoshida, Sumiko; Aihara, Ken-ichi; Kurahashi, Kiyoe; Harada, Takeshi; Kagawa, Kumiko; Nakao, Michiyasu; Sano, Shigeki; Abe, Masahiro
• Publication, Distribution, etc.: Wiley
• Publication Date: 2018-01-12
• Publication Date (W3CDTF): 2018-01-12
• Alternative Title: Pim阻害活性を有するチアゾリジン-2,4-ジオン誘導体のユニークな抗骨髄腫活性; Anti-myeloma Activity by Thiazolidine-2,4-dione compounds
• Periodical title: British Journal of Haematology
• No. or year of volume/issue: 180 2
• Volume: 180
• Issue: 2
• Pages: 246-258
• ISSN (Periodical Title): ISSN : 0007-1048; ISSN : 1365-2141
• Degree grantor/type: 徳島大学
• Date Granted: 2018-09-13
• Dissertation Number: 甲第3206号
• Degree Type: 博士（医学）
• Text Language Code: eng
• Subject Heading: multiple myeloma; PIM2; thiazolidine‐2; 4-dione compounds; breast cancer resistance protein; proteasome inhibitor; BCRP
• Target Audience: 一般
• Note (General): Proviral Integrations of Moloney virus 2 (PIM2) kinase is overexpressed in multiple myeloma (MM) cells, and regarded as an important therapeutic target. Here, we aimed to validate the therapeutic efficacy of different types of PIM inhibitors against MM cells for their possible clinical application. Intriguingly, the thiazolidine 2,4 dione family compounds SMI 16a and SMI 4a reduced PIM2 protein levels and impaired MM cell survival preferentially in acidic conditions, in contrast to other types of PIM inhibitors, including AZD1208, CX 6258 and PIM447. SMI 16a also suppressed the drug efflux function of breast cancer resistance protein, minimized the sizes of side populations, and reduced in vitro colony forming capacity and in vivo tumorigenic activity in MM cells, suggesting impairment of their clonogenic capacity. PIM2 is known to be subject to ubiquitination-independent proteasomal degradation. Consistently, the proteasome inhibitors bortezomib and carfilzomib increased PIM2 protein levels in MM cells without affecting its mRNA levels. However, SMI 16a mitigated the PIM2 protein increase and cooperatively enhanced anti MM effects in combination with carfilzomib. Collectively, the thiazolidine 2,4 dione family compounds SMI 16a and SMI 4a uniquely reduce PIM2 protein in MM cells, which may contribute to their profound efficacy in addition to their immediate kinase inhibition. Their combination with proteasome inhibitors is envisioned.
• Format (IMT): application/pdf
• Access Restrictions: インターネット公開
• Related Material (DOI): 10.1111/bjh.15033
• Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）; https://irdb.nii.ac.jp
• Original Data Provider (Database): 徳島大学 : 徳島大学機関リポジトリ

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