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

Abstract

Proviral Integrations of Moloney virus 2 (PIM2) 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 tumourigenic activity in MM cells, suggesting impairment of their clonogenic capacity. PIM2 is known to be subject to ubiquitination-independent proteasomal degradation. Consistent with this, 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.

Protein kinase PIM2: A simple PIM family kinase with complex functions in cancer metabolism and therapeutics

“…Multiple myeloma (MM), characterized by an abnormal increase in monoclonal paraprotein and the accumulation of cancerous plasma cells, is a progressive and debilitating malignancy 39 . Research has shown that PIM2 kinase is overexpressed in MM cells, and that the kinase inhibitors SMI-16a and SMI-4a can both reduce its kinase activity in MM cells 40 . PIM2 expression has also been shown to be up-regulated in bone marrow stromal cells, acting as a negative regulator for osteoblastogenesis, and PIM2 inhibition suppressed MM tumor progression and prevented bone destruction in vivo 41 .…”

“…SMI-16a has been shown to destroy clone formation in MM cells, and their tumorigenic ability in vivo under acidic conditions, which restores the anti-MM effects of Dox. The accumulation of PIM2 in MM cells can be reduced using proteasome inhibitors, and SMI-16a has been shown to enhance the cytotoxic effects of carfilzomib by inhibiting the accumulation of PIM2 by proteasome inhibitors 40 . PIM2 has also been shown to act as a negative regulator for osteoblastogenesis.…”

“…Treatment with AZD1208 has been shown to suppress the Ser-112 phosphorylation of proapoptotic BAD. Suppresses the drug-efflux function of breast cancer resistance protein 40. Reduces the capacities for both colony formation and tumorigenic activity in MM cells.…”

PIM Kinases in Multiple Myeloma

“…Similar to SMI-4a, SMI-16a reduces the capacities of colony formation of MM cells and their tumorigenic activity in vivo under acidic conditions, and restores the anti-MM effects of Doxorubicin [ 74 ]. Additionally, SMI-16a was also shown to increase the cytotoxic effects of carfilzomib by inhibiting the PIM2 accumulation [ 84 ].…”

The diversity of the plasmablast signature across species and experimental conditions: A meta‐analysis

“…Although its role in the B‐cell differentiation process is not well understood, FKBP11 was not only found as a putative target of IRF4 initiating the pre‐PB stage [44] but also increased in lupus B cells inducing B‐cell tolerance breakdown [45]. Additionally, we underlined proteins involving in cell survival that may be valuable targets for controlling lymphoid neoplastic disorders such as PIM2 , TRIB1 , SEL1L and ELL2 [46,47]. On the other hand, the human PB signature encompassed 283 genes mostly involved in cell activation (Figure C,D).…”