Anti-myeloma Activity by Thiazolidine-2,4-dione compounds
Oda, Asuka Tokushima University
Bat‐Erdene, Ariunzaya Tokushima University
Maeda, Yusaku Tokushima University
Takahashi, Mamiko Tokushima University
Iwasa, Masami Tokushima University
breast cancer resistance protein
Pim-2 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 Pim-2 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. Pim-2 is known to be subject to ubiquitination-independent proteasomal degradation. Consistently, the proteasome inhibitors bortezomib and carfilzomib increased Pim-2 protein levels in MM cells without affecting its mRNA levels. However, SMI-16a mitigated the Pim-2 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 Pim-2 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
John Wiley & Sons Ltd
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.
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