Anti-myeloma Activity by Thiazolidine-2,4-dione compounds
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
breast cancer resistance protein
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.
British Journal of Haematology
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.
k3206_abstract_review.pdf 346 KB
k3206_fulltext.pdf 1.83 MB