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ID 112752
Title Alternative
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
Author
Oda, Asuka Tokushima University
Bat-Erdene, Ariunzaya Tokushima University
Maeda, Yusaku Tokushima University
Oura, Masahiro Tokushima University
Takahashi, Mamiko Tokushima University
Iwasa, Masami Tokushima University
Keywords
multiple myeloma
PIM2
thiazolidine‐2
4-dione compounds
breast cancer resistance protein
proteasome inhibitor
BCRP
Content Type
Thesis or Dissertation
Description
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.
Journal Title
British Journal of Haematology
ISSN
00071048
13652141
NCID
AA00574570
AA11618011
Publisher
Wiley
Volume
180
Issue
2
Start Page
246
End Page
258
Published Date
2018-01-12
Remark
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
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第3206号
Diploma Number
甲医第1380号
Granted Date
2018-09-13
Degree Name
Doctor of Medical Science
Grantor
Tokushima University
departments
University Hospital
Medical Sciences
Oral Sciences
Pharmaceutical Sciences