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Salidroside overcomes dexamethasone resistance in T-acute lymphoblastic leukemia cells.

ABSTRACT: The aim of the present study was to analyze whether the use of salidroside (SAL) could overcome dexamethasone (DEX) resistance in T-acute lymphocytic leukemia cells. The human T-ALL DEX-resistant cell line, CEM-C1 and the DEX-sensitive cell line, CEM-C7 were used in the current study. The proliferation inhibition rates in these cells, treated with SAL and DEX alone, and in combination were detected using a Cell Counting Kit-8 assay, while the morphological changes of the cells were observed using an inverted microscope. Reverse transcription-quantitative PCR was used to detect the mRNA expression levels of the c-Myc and LC3 genes, while flow cytometry was used to detect the cell cycle distribution and the rate of apoptosis. In addition, western blot analysis was used to detect the protein expression levels of c-Myc, BCL-2, Bax, cleaved PARP and LC3. and acridine orange staining was used to detect the changes in acidic autophagy vesicles. It was found that SAL could effectively inhibit cell proliferation and induce apoptosis in the CEM-C1 and CEM-C7 cells. In addition, SAL promoted the induction of autophagy. The protein expression levels of c-Myc in the CEM-C1 cells were significantly higher compared with that in the CEM-C7 cells. SAL downregulated the mRNA expression levels of the c-Myc gene and protein in a dose-dependent manner. This suggested that SAL could inhibit the proliferation of the CEM-C1 and CEM-C7 cells, induce apoptosis and autophagy and overcome DEX resistance in the CEM-C1 cells. The mechanism may be associated with the downregulation of c-Myc.

SUBMITTER: Niu YN

PROVIDER: S-EPMC8097222 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Response to dexamethasone (DEXA), as a hallmark drug in the treatment of childhood acute lymphoblastic leukemia (ALL), is one of the pivotal prognostic factors in the prediction of outcome in ALL. Identification of predictive markers of chemoresistance is beneficial to selecting of the best therapeutic protocol with the lowest effect adverse. Hence, we aimed to find drug targets using the 2DE/MS proteomics study of a DEXA-resistant cell line (REH) as a model for poor DEXA responding patients before and after drug treatment. Using the proteomic methods, three differentially expressed proteins were detected, including voltage dependent anion channel 1 (VDAC1), sorting Nexin 3 (SNX3), and prefoldin subunit 6 (PFDN6). We observed low expression of three proteins after DEXA treatment in REH cells. We subsequently verified low expression of resulted proteins at the mRNA level using the quantitative PCR method. These proteins are promising proteins because of their important roles in drug resistance and regulation of apoptosis (VDAC1), protein trafficking (SNX3), and protein folding (PFDN6). Additionally, mRNA expression level of these proteins was assessed in 17 bone marrow samples from children with newly diagnosed ALL and 7 non-cancerous samples as controls. The results indicated that independent of the molecular subtypes of leukemia, mRNA expression of VDAC1, SNX3, and PFDN6 decreased in ALL samples compared with non-cancerous samples particularly in VDAC1 (p < 0.001). Additionally, mRNA expression of three proteins was also declined in high-risk samples compared with standard risk cases. These results demonstrated diagnostic and prognostic value of these proteins in childhood ALL. Furthermore, investigation of protein-protein interaction using STRING database indicated that these proteins involved in the signaling pathway of NR3C1 as dexamethasone target. In conclusion, our proteomic study in DEXA resistant leukemic cells revealed VDAC1, SNX3, and PFDN6 are promising proteins that might serve as potential biomarkers of prognosis and chemotherapy in childhood ALL.

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Salidroside overcomes dexamethasone resistance in T-acute lymphoblastic leukemia cells.

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