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Background/aim: Deregulated activation of signaling through the RAS/RAF/mitogen-activated protein kinase/extracellular signal-regulated kinase (RAS/RAF/MEK/ERK) and signal transducer and activator of transcription (STAT) pathways is involved in numerous hematological malignancies, making it an attractive therapeutic target. This study aimed to assess the effect of the combination of ERK2 inhibitor VX-11e and STAT3 inhibitor STA-21 on acute lymphoblastic leukemia cell lines REH and MOLT-4., Materials and Methods: REH and MOLT-4 cell lines were cultured with each drug alone and in combination. Cell viability, ERK activity, cell cycle distribution, apoptosis and oxidative stress induction were assessed by flow cytometry. Protein levels of STAT3, phospho-STAT3, protein tyrosine phosphatase 4A3 (PTP4A3), survivin, p53 and p21 were determined by western blotting., Results: VX-11e in combination with STA-21 significantly inhibited cell viability, induced G 0 /G 1 cell-cycle arrest, enhanced production of reactive oxygen species, and induced apoptosis. These effects were associated with an increased level of p21 protein in REH cells and with reduced levels of phopho-STAT3, survivin and PTP4A3 proteins in MOLT-4 cells., Conclusion: Our findings provide a rationale for combined inhibition of RAS/RAF/MEK/ERK and STAT3 pathways in order to enhance anticancer effects against acute lymphoblastic leukemia cells., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: In various cancer cells, the level of sulfane sulfur-containing compounds is decreased compared to normal cells. In the present study the effect of N-acetyl-L-cysteine (NAC), which acts as a precursor of H 2 S synthesis, on the human neuroblastoma SH-SY5Y cell proliferation, the activity of 3-mercaptopyruvate sulfurtransferase (MPST), and the level of sulfane sulfur were investigated., Materials and Methods: SH-SY5Y cells were treated with NAC, while untreated cells were used as the control. The toxicity of NAC on the cells was studied by the LDH cytotoxicity assay; cell proliferation was examined by the MTT method. MPST activity and sulfane sulfur level were also analyzed in the NAC-treated cells., Results: The addition of NAC to the medium, in non-cytotoxic concentrations, resulted in inhibition of the SH-SY5Y cell proliferation after 48 h of culture. The MPST activity and the level of sulfane sulfur-containing compounds were also elevated under the same culture conditions., Conclusion: The antiproliferative activity of NAC in the SH-SY5Y cells was associated with an increase in the MPST activity and consequently with an increase in the intracellular level of sulfane sulfur in these cells., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: In certain cancers, accumulation of cystathionine has been observed. The present study investigated the effect of cystathionine on astrocytoma (U373) cell proliferation, the activity of γ-cystathionase (CTH) and changes in thiols levels., Materials and Methods: The methods used in the study included cytotoxicity assay, crystal violet staining method, CTH activity assay and reverse phase-high performance liquid chromatography (RP-HPLC)., Results: The addition of cystathionine to the culture medium resulted in an increase of cystathionine level in U373 cells after 24 h of culture. Reduction of intracellular cystathionine level after 48 and 72 h of culture was associated with increased L-cysteine and L-cystine levels and stimulation of cell proliferation. Interestingly, a decrease in intracellular L-cysteine and L-cystine levels during the first hours of culture was observed., Conclusion: Elevated levels of cystathionine resulted in increased U373 cell proliferation by increasing the L-cysteine levels and GSH/GSSG ratio (especially after 72 h of the culture), but not with a simultaneous increase in the levels of total glutathione., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Histone deacetylase inhibitors (HDACi) have been extensively studied as potential candidates for treatment of various malignancies, including leukemia, since they not only induce growth inhibition, cell cycle arrest and apoptosis of cancer cells, but can also increase the sensitivity of cancer cells to chemotherapeutic drugs. The aim of this study was to investigate the effect of two HDACi, trichostatin A (TSA) and valproic acid (VPA), on etoposide-induced apoptosis in human leukemia cell lines., Materials and Methods: Viability, apoptosis rate, caspase activity, mitochondrial membrane potential and expression of BCL2 mRNA were assessed in HL60 and U937 cell lines treated with 250 nM TSA or 1.25 mM VPA alone or followed by 5 μM etoposide., Results: Preincubation of HL60 cells with TSA or VPA significantly potentiated etoposide-induced cytotoxicity and apoptosis, which was associated with activation of caspases and loss of mitochondrial membrane potential. Similar effects were not observed in U937 cells. Expression of BCL2 mRNA was strongly down-regulated after treatment of cells with HDACi alone but did not show additive effect with etoposide., Conclusion: Combination of HDACi with etoposide can have a synergistic effect on increased apoptosis in leukemia cells but this effect depends on the cancer cell type and other factors such as the concentration of drugs and the administration schedule.