In vitro assessment of the efficiency of the PIM‑1 kinase pharmacological inhibitor as a potential treatment for Burkitt's lymphoma

Abstract

Burkitt's lymphoma is an aggressive form of lymphoma affecting B lymphocytes. It occurs endemically in Africa and sporadically in the rest of the world. Due to the high proliferation rate of this tumor, intensive multi-drug treatment is required; however, the risk of tumor syndrome lysis is high. Overexpression of the proto-oncogene proviral integration of the Moloney murine leukemia virus (PIM-1) kinase is associated with the development of hematological abnormalities, including Burkitt's lymphoma (BL). PIM-1 primarily exerts anti-apoptotic activities through BAD phosphorylation. The aim of the present study was to investigate the in vitro efficiency of a PIM-1 kinase pharmacological inhibitor (PIM1-1) in BL. The impact of PIM1-1 was evaluated in terms of the viability and apoptosis status of the BL B cell lines, Raji and Daudi, compared with K562 leukemia cells, which highly express PIM-1. Cell viability and apoptotic status were assessed with western blotting, and PIM-1 gene expression was assessed with reverse transcription-quantitative PCR. After 48 h of treatment, PIM1-1 inhibited the Daudi, Raji and K562 cell viability with a half-maximal inhibitory concentration corresponding to 10, 20 and 30 µM PIM1-1, respectively. A significant decrease of ERK phosphorylation was detected in PIM1-1-treated Daudi cells, confirming the antiproliferative effect. The addition of 10 µM PIM1-1 significantly decreased the PIM-1 protein and gene expression in Daudi cells. An inhibition of the pro-apoptotic BAD phosphorylation was observed in the Daudi cells treated with 0.1-1 µM PIM1-1 and 10 µM PIM1-1 decreased BAD phosphorylation in the Raji cells. The apoptotic status of both PIM1-1-treated cells lines were confirmed with the detection of cleaved capase-3. However, no change in cell viability and PIM-1 protein expression was observed in the 10 µM PIM1-1-treated K562 cells. In conclusion, the findings indicated that the PIM1-1 pharmacological inhibitor may have therapeutic potential in BL, but with lower efficiency in leukemia.

Anti-Leukaemic Activity of Rilpivirine Is Mediated by Aurora A Kinase Inhibition

“…This is based on the observation that the expression of PIM1 kinase could not be detected in three AML cell lines examined (HL-60, NB4, and U937) (Supplementary Figure S7), consistent with previous reports [35,36]. Notably, one chronic myeloid leukaemia cell line, K-562, was included in some preliminary experiments of this study, considering its higher expression of PIM1 [37]. Consistently, the K-562 cell line showed overexpression of PIM1 (Supplementary Figure S7), but surprisingly it was not sensitive to the selective and potent PIM1 kinase inhibitor, AZD1208 (K i against PIM1 < 1 nM), and displayed comparatively high GI 50 value (~38 µM) (Supplementary Figure S8A).…”

Role and mechanism of PIM family in the immune microenvironment of diffuse large B cell lymphoma

“…PIM1 can enhance the activity of Bcl-2 by phosphorylating B cell lymphoma-2 protein (Bcl-2), thus promoting the proliferation of tumor cells and further promoting the invasion and migration of tumors [ 7 ]. It was also found that PIM1 can also phosphorylate the pro-apoptotic protein Bad, inactivating it, preventing the apoptosis of tumor cells, and promoting the survival of the cells [ 8 ]. PIM2 is highly expressed in malignancies, such as lymphoma and multiple myeloma [ 9 ].…”