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Abstract – In acute promyelocytic leukemia patients, Arsenic trioxide induces complete remission. However, certain forms of myeloid leukemia patients are less responsive to As2O3 therapy. APL t NB4 cells are more sensitive to As2O3 apoptosis induction than other types of myeloid leukemia cells, such as HL-60 and K562 cells. Lower GSTu03c0 levels in NB4 cells are lower than those of other forms of myeloid leukemia cells. Therefore, As2O3-induction of apoptosis in other forms of myeloid leukemia cells by inhibition of GSTu03c0. We investigated the combination of As2O3's ethynic acid and a more potent non-diuretic EA analogue ethacrynic acid-butyl ester, a known GSTu03c0 inhibitor, to cause apoptosis in HL-60 and K562 cells. At physiologically safe dosages, As2O3 in HL-60 cells and K562 cells did not cause apoptosis in HL-60 cells nor in K562 cells. As2O3 plus EA at 60 bcM is synergistic to cause apoptosis in both HL-60 and K562 cells as determined by Annexin V staining, PARP cleavage, and caspase activation. According to CompuSyn software, the combined index of As2O3 with EABE would cause apoptosis in K562 cells calculated by CompuSyn software was less than 1. 0, which indicated synergism. The combination of As2O3 and EABE treatment, as well as the upregulation of the Bcl-2 homology 3 -only pro-apoptotic protein NOXA, led to the induction of Apoptosis by the combination of As2O3 and EABE. Induction of As2O3 plus EABE by siRNA, the apoptosis was prevented from being introduced, while Mcl-1's knock-down raised the apoptosis induction of As2O3 plus EABE. NoXA bind to Mcl-1 was discovered in the K562 cells treated with As2O3 plus EABE, according to Immunoprecipiation with Mcl-1 antibody.
Source link: https://doi.org/10.1158/1538-7445.am10-1030
Abstract Previously, we found that four human pancreatic cancer cell lines underwent robust cell death, assassination of ATP decline and ROS accumulation when treated with clinically acceptable concentrations of arsenic trioxide, ascorbic acid, and disulfiram. P16 deficiency and Kras mutations account for more than 85% of human PCs. Little or no toxicity of the mice to the AAA treatment was reported. The Frank PC was zero in AAA-treated mice and 31% in controls. In AAA-treated mice, the mean number of PanIN-3 lesions/mouse decreased from 14. 1 in controls to 1. 58 in AAA-treated mice. In AAA treated mice, the mean number of PanIN-2 lesions decreased from 5. 18 in controls to 1. 67 in AAA treated mice. The mean number of PanIN-1 lesions in control mice was 14. 2 and in AAA-treated mice was 16. 0, p=0. 81, showing no difference in PanIN-1 prevalence. PanIN-1 lesions were low, with preliminary results from immunohistochemical staining of the PanIN lesions for VDAC showing that PanIN-1 lesions were low, and PanIN-2 and 3 lesions have high, VDAC expression. VDAC expression is vital to AAA sensitiveity, according to this study, and suggests a similar mechanism of action in vivo as in vitro. Although data collection is ongoing, this is the first treatment that has been shown to block PanIN and tumor formation in any genetically engineered mouse model for PC. AAA either arrests or destroys pre-cancerous lesions after the Panin-1 stage, or PanIN-2 and PanIN-3 lesions are destroyed by AAA in a VDAC-dependent manner, according to the reports.
Source link: https://doi.org/10.1158/1538-7445.am2011-lb-229
Patients with acute promyelocytic leukemia patients have complete remission, with both trans retinoic acid and arsenic trioxide. ATRA promoted differentiation by using the PML-RARu03b1 fusion protein from APL's APL-derived NB4 cell line, but ATO mainly induced apoptosis, according to ATRA's report. ATRA and ATO's investigation of Mcl-1 and p-ERK was conducted in NB4 and its subclone R4 cells, HL-60, and its subcloned HL-60/Res cells. Both NB4 and R4 cells contain PML-RARu03b1, while HL-60 and Res cells contain RARu03b1. Both NB4 and HL-60 cells were stimulated by ATRA, but not in R4 cells or Res cells. ATO treatment reduced Mcl-1 in both NB4 and R4 cells but not in HL-60 or in Res cells, which were consistent with apoptosis induction and down-regulation of p-ERK. Both NB4 and R4 cells contain PML-RARu03b1, which is degraded by ATO, implying that PML-RARu03b1 plays a role in ATO-mediated down-regulation of Mcl-1. After ATO treatment, U937/PR9 cells with the inducible expression of PML-RARu03b1 were used to analyze the effects of PML-RARu03b1 on the regulation of Mcl-1. These results reveal that ATRA raises the level of Mcl-1 by overcoming transcriptional compression and activating RAR/u03b1; u03b1, while ATR decreases the number of Mcl-1 by inactivating ERK as a result of PML-RAR degradation, leading to the deposition of PML-RAR u03b1. After ATO-treatment sensitizes apoptosis induction, the increased amount of Mcl-1 following ATRA therapy helps protect cell death and promotes differentiation, but the reduced amount of Mcl-1 following ATR treatment sensitizes apoptosis induction.
Source link: https://doi.org/10.1158/1538-7445.am2011-5479
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