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ID 112752
タイトル別表記
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
著者
藤井, 志朗 徳島大学大学院医科学教育部(プロテオミクス医科学専攻) 徳島大学 教育研究者総覧 KAKEN研究者をさがす
Oda, Asuka Tokushima University
Bat-Erdene, Ariunzaya Tokushima University
Maeda, Yusaku Tokushima University
大浦, 雅博 Tokushima University
Takahashi, Mamiko Tokushima University
Iwasa, Masami Tokushima University
キーワード
multiple myeloma
PIM2
thiazolidine‐2
4-dione compounds
breast cancer resistance protein
proteasome inhibitor
BCRP
資料タイプ
学位論文
抄録
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.
掲載誌名
British Journal of Haematology
ISSN
00071048
13652141
cat書誌ID
AA00574570
AA11618011
出版者
Wiley
180
2
開始ページ
246
終了ページ
258
発行日
2018-01-12
備考
内容要旨・審査要旨・論文本文の公開
本論文は, 著者Shiro Fujiiの学位論文として提出され, 学位審査・授与の対象となっている。
This is the peer reviewed version of the following article: Fujii, S. , Nakamura, S. , Oda, A. , Miki, H. , Tenshin, H. , Teramachi, J. , Hiasa, M. , Bat‐Erdene, A. , Maeda, Y. , Oura, M. , Takahashi, M. , Iwasa, M. , Endo, I. , Yoshida, S. , Aihara, K. , Kurahashi, K. , Harada, T. , Kagawa, K. , Nakao, M. , Sano, S. and Abe, M. (2018), Unique anti‐myeloma activity by thiazolidine‐2,4‐dione compounds with Pim inhibiting activity. Br J Haematol, 180: 246-258, which has been published in final form at https://doi.org/10.1111/bjh.15033. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
EDB ID
出版社版DOI
出版社版URL
フルテキストファイル
言語
eng
著者版フラグ
博士論文全文を含む
文科省報告番号
甲第3206号
学位記番号
甲医第1380号
学位授与年月日
2018-09-13
学位名
博士(医学)
学位授与機関
徳島大学
部局
病院
医学系
歯学系
薬学系