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- W67883132 abstract "Small molecules that can disrupt cell signaling by inhibiting protein-protein interactions hold promise for the development of therapeutics against leukemia. This study tested the effect of two compounds, XX-650-23 and tubacin, on cell survival and proliferation of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cells, respectively. The cAMP response element-binding protein (CREB) is a nuclear transcription factor involved in cell proliferation, differentiation, and survival. Phosphorylated CREB recruits histone acetyltransferase, CREB-binding protein (CBP), and subsequent target gene expression occurs. The small molecule XX-650-23, identified through in silico screening methods, disrupts the CREB:CBP complex. We tested its effects on various AML cell lines using MTT and trypan blue exclusion assays. XX-650-23 preferentially targets AML cells, yielding 50 percent inhibitory concentrations (IC50s) ranging from 910 nM to 2.3 µM; we found that it synergizes with cytarabine. XX-650-23 delays the cell cycle in the G1/S phase and downregulates CREB target genes, such as cyclins A and D. Our results suggest that XX-650-23 delays the cell cycle, which stresses the cell, activating caspases involved in apoptosis, as indicated by PARP cleavage of HL60 cells.Histone deacetylase 6 (HDAC6), which deacetylates a-tubulin, has become a target for developing drugs to treat cancer. Previous studies demonstrated that inhibition of HDAC6 in multiple myeloma (MM) cells results in apoptosis. The small molecule tubacin (a tubulin acetylation inducer) inhibits HDAC6. We observed a higher antiproliferative effect of tubacin in ALL cells than in normal hematopoietic cells. Treatment with tubacin suppresses proliferation in ALL cells, with IC50s ranging from 1.2 µM to 2 µM. We found that it increased acetylation of a-tubulin within 30 minutes of treatment. Our study revealed that tubacin alone inhibits the aggresome pathway, resulting in an accumulation of polyubiquitinated proteins and apoptosis. Furthermore, unlike in MMs, it activated signaling pathways that do not involve JNK/SAP. We demonstrated that it indirectly inhibits the Na + /K + -ATPase pump, yielding lower K + and higher Ca + concentrations in the cytosol. Our results suggest that targeting CREB or HDAC6 alone or in combination with chemotherapy could provide a novel approach to treat AML and ALL, respectively." @default.
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- W67883132 date "2013-01-01" @default.
- W67883132 modified "2023-09-27" @default.
- W67883132 title "Targeted Therapies for Acute Leukemia" @default.
- W67883132 hasPublicationYear "2013" @default.
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