Saeid Taghiloo; Abolghasem Ajami; Reza Alizadeh-Navaei; Ehsan Zaboli; Hossein Asgarian-Omran
Abstract
Background: Several PI3K/Akt/mTOR pathway inhibitors and TLR agonists induce tumor cell death. However, the mechanisms of these therapeutic approaches in acute myeloid leukemia (AML) cells are still unknown. Objectives: To investigate the effects of BEZ235, as a dual inhibitor of PI3K and mTOR pathways, ...
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Background: Several PI3K/Akt/mTOR pathway inhibitors and TLR agonists induce tumor cell death. However, the mechanisms of these therapeutic approaches in acute myeloid leukemia (AML) cells are still unknown. Objectives: To investigate the effects of BEZ235, as a dual inhibitor of PI3K and mTOR pathways, and TLR7/8 agonist R848 on the expression and regulation of the immune inhibitory molecules in myeloid leukemia cells. Methods: WEHI-3 leukemia cells were incubated with dual PI3K and mTOR inhibitor BEZ235 and TLR7/8 agonist R848 for 48 hrs. Firstly, cell viability was assessed by MTT method. The semi-quantitative relative mRNA expression of Galectin-9 (Gal-9), PD-L1, PVR, and STAT3 was assessed according to HPRT as a housekeeping gene. Finally, the protein expression of phosphorylated STAT3 was evaluated by western blotting analysis. Results: WEHI-3 cells showed growth inhibition following treatment with BEZ235 and R848 whose combination exerted more proliferation arrest. The mRNA expression of Gal-9, PD-L1 and PVR immune checkpoint molecules significantly reduced in treated cells with BEZ235 and R848. Combined treatment indicated more reduction compared with the single treatment. Finally, the expression and phosphorylation of STAT3 were down-regulated after a single or dual treatment with BEZ235 and R848. Conclusion: Our results conclude that treatment with the combination of BEZ235 and R848 interferes with immune evasion mechanisms through STAT3-signaling pathway in WEHI-3 leukemia cells.
Mohammad Hasan Sheikhha; Mehdi Kalantar; Khalid Tobai; John A. Liu Yin
Volume 2, Issue 3 , September 2005, , Pages 141-151
Abstract
Background: The glutathione S-transferase (GST) family of metabolising enzymes plays an important role in the detoxification of mutagens and carcinogens. The expression of many of these cancer susceptibility enzymes is genetically polymorphic. An increased frequency of GST-null genotypes has been associated ...
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Background: The glutathione S-transferase (GST) family of metabolising enzymes plays an important role in the detoxification of mutagens and carcinogens. The expression of many of these cancer susceptibility enzymes is genetically polymorphic. An increased frequency of GST-null genotypes has been associated with several malignancies. Objective: To investigate the rate of GSTT1 and GSTM1 null genotypes in AML patients and to determine its importance in prognosis of the disease. Methods: DNA was extracted by phenol/chloroform method from peripheral blood or bone marrow of 180 white Caucasian patients. A multiplex PCR method was used simultaneously to amplify regions of GSTM1, GSTT1, and b-globin genes in genomic DNA. The survival curves were analyzed by the Kaplan-Meier method and compared by the log-rank test (Mantel-Cox) using the SPSS software program. Results: Of the total of 180 patients, 23 cases (12.8%) showed null genotypes in both genes, while in 52 patients (28.9%) both genes were wild-types. GSTM1 null-GSTT1 wild-type was detected in 91 patients (50.6%) and GSTM1 wild-type-GSTT1 null genotype was detected in 14 patients (7.8%). These rates are within the upper limit of the rates detected in the normal European population. There was no significant difference in the overall survival and in disease free survival between different groups. Conclusion: These observations suggest that the inherited absence of the GSTT1 and GSTM1 carcinogen detoxification pathway may be related to carcinogenesis but it is not an important determinant of prognosis in AML.