Differential Effects of AZD-1208 and SMI-4a, Two Pim-1 Kinase Inhibitors on Primary HAM/TSP and ATL Cells
Résumé
Adult T-cell Leukemia-lymphoma (ATL), an aggressive neoplasm etiologically associated with HTLV-1, is a chemoresistant malignancy. Proviral integration site for Moloney murine leukemia virus-1 (Pim-1) is a critical enzyme that is involved in cell growth, differentiation, survival, apoptosis, senescence and drug resistance. Interaction of Pim-1 with different proteins and association with various signaling pathways make it one of the important antitumor targets. Aberrant elevation of Pim-1 kinase is associated with numerous types of cancer. In this study, we showed that Pim-1 kinase is highly expressed in ATL, as well as in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Numerous Pim-1 inhibitors are under preclinical studies or clinical trials, such as AZD1208. An increasing number of new Pim-1 inhibitors are still developing and undergoing preclinical investigations. Next, we compared the effect of two PIM-1 inhibitors, AZD-1208 and SMI-4a on HTLV-1-derived cells lines and ex vivo cultured primary HAM/TSP and ATL leukemic cells. Our results show a differential effects between AZD on survival and proliferation of vs. HTLV-1 derived cells lines. Our results underscore the strong therapeutic potential of Pim kinase inhibition for the treatment of HTLV related pathogenesis such as HAM/TSP and ATL 3
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