BCL2 inhibitor ABT-199 and JNK inhibitor SP600125 exhibit synergistic cytotoxicity against imatinib-resistant Ph+ ALL cells

Abstract

Imatinib (IMT), a specific tyrosine kinase inhibitor (TKI), has drastically changed the treatment strategy for Ph+ ALL (Philadelphia chromosome-positive acute lymphoblastic leukemia). However, TKI resistance remains a serious problem for patient prognosis. Here, a Ph+ ALL cell line NphA2 and the IMT-resistant subline NphA2/STIR were analyzed to identify a potential novel treatment strategy. We also examined other Ph+ ALL cells, MR87 and its IMT-resistant subline, MR87/STIR. IMT induced apoptosis of NphA2 and MR87 but had no effect on resistant sublines. Increased phosphorylated ERK and BCL2, but not BCL-XL, were observed in NphA2/STIR compared with NphA2. NphA2/STIR but not NphA2 was moderately sensitive to U0126, an ERK inhibitor. Interestingly, SP600125, a JNK inhibitor, was potent in cell growth inhibition and apoptosis induction of both parental and IMT-resistant NphA2 and MR87 cells. Moreover, NphA2 and MR87 and their IMT-resistant sublines were sensitive to ABT-199, a specific BCL2 inhibitor. The combination of SP600125 and ABT-199 synergistically suppressed both parental and IMT-resistant cells, including one with T315I mutation, suggesting that Ph+ ALL exhibits high sensitivity to ABT-199 and SP600125 regardless of TKI resistance. This combination might be a possible therapeutic strategy for Ph+ ALL in the future.

Guanine and nucleotide binding protein 3 promotes odonto/osteogenic differentiation of apical papilla stem cells via JNK and ERK signaling pathways

“…SCAPs at passage 2-5 were used in the subsequent experiments. To address the potential roles of JNK and ERK signaling pathways, specific JNK inhibitor (20 µ M; SP600125), specific ERK inhibitor (20 µ M; U0126; both from Beyotime Institute of Biotechnology) and dimethyl sulfoxide (20 µ M; Sigma-Aldrich; Merck KGaA, Darmstadt, Germany) as a control were respectively added to the SCAPs, and the cells were incubated at 37°C for 5 min ( 29 , 30 ). As for the characterization of cultured SCAPs, the cells were digested with trypsin (Roche Applied Science), collected and incubated with fluorochrome-conjugated rabbit anti-human antibodies: Cluster of differentiation (CD)90-fluorescein isothiocyanate (FITC; 561969), CD44-phycoerythrin (PE; 561858), CD45-allophycocyanin (560973) and CD14-PE-cyanine 7 (560919; all at 0.5 mg/ml; BD Biosciences, San Jose, CA, USA) for 1 h at 4°C in the dark to detect the SCAPs phenotype ( 31 , 32 ).…”

Molecular Approaches to Treating Pediatric Leukemias

“…Moreover, the combination of dasatinib and venetoclax resulted in superior antileukemic efficacy compared to either agent alone in Ph+ ALL xenografts (84). Another report showed that the combination of venetoclax and the JNK inhibitor SP600125 exhibited synergistic cytotoxicity against imatinib-resistant Ph+ ALL cells (85).…”

A Highly Selective In Vitro JNK3 Inhibitor, FMU200, Restores Mitochondrial Membrane Potential and Reduces Oxidative Stress and Apoptosis in SH-SY5Y Cells

“…In this case, we included an p38 inhibitor (SB203580) [ 27 ] and a JNK inhibitor, SP600125 [ 28 ] in our analysis. According to previous studies, SP600125 (10 µM) was considered cytotoxic in different cell lines such as four different leukemia cell lines (U937, K562, HL60, and THP-1) [ 29 ], NphA2 cells [ 30 ], while SB203580 and SP600125 at 20 µM did not alter cell viability neither in MCF7 cells [ 31 ] nor in JEG-3 cells [ 32 ]. However, it is known that distinct cell lines respond differently to cytotoxic compounds.…”