ABSTRACT
OBJECTIVE@#To explore whether bortezomib and a Bcl-2 inhibitor exhibit synergistic anti-tumor effect in human acute T lymphoblastic leukemia cells.@*METHODS@#MTT assay was used to determine the cytotoxicity of bortezomib in the absence or presence of Bcl-2 inhibitors (obatoclax, AT-101 and ABT-199) in Jurkat cells. The effects of drug treatment on the expression of Bcl-2 family proteins, LC3B, p62, ubiquitin, BiP/Grp78, p-JNK, p-p38 and CHOP proteins were examined by Western blotting. Flow cytometry was used to determine the effects of bortezomib and Bcl-2 inhibitors (obatoclax, AT-101 and ABT-199) on cell apoptosis. Quantitative real-time PCR was used to measure the mRNA expression levels of the key regulatory factors of unfolded protein reaction (UPR). A zebrafish xenograft model was used to study the anti-tumor effect of bortezomib, obatoclax and their combination in vivo.@*RESULTS@#Bortezomib or Bcl-2 inhibitors alone inhibited the cell viability of Jurkat cells, but only obatoclax and bortezomib showed synergistic cytotoxicity and pro-apoptotic effect. Obatoclax, rather than AT-101 and ABT- 199, blocked autophagic flux in the cells evidenced by concomitant accumulation of LC3B-Ⅱ and p62. Both bortezomib and obatoclax alone caused accumulation of polyubiquinated proteins, and their combination showed a synergistic effect, which was consistent with their synergistic cytotoxicity. The dual blockade of proteasome and autophagy by the combination of bortezomib and obatoclax triggered unfolded protein response followed by cell apoptosis. Preventing UPS dysfunction by tauroursodeoxycholic acid (TUDCA) significantly attenuated the cytotoxicity and pro-apoptotic effect of bortezomib in combination with obatoclax. In zebrafish xenograft models, bortezomib combined with obatoclax significantly decreased tumor foci formation.@*CONCLUSIONS@#Bortezomib and obatoclax for dual blockade of protein degradation pathways show synergistic anti-tumor effect in human acute T lymphoblastic leukemia cells.
Subject(s)
Humans , Antineoplastic Agents , Apoptosis , Bortezomib , Cell Line, Tumor , Drug Synergism , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Proteolysis , Proto-Oncogene Proteins c-bcl-2 , PyrrolesABSTRACT
Objective To analyze the prognostic value of vascular endothelial growth factor in acute leukemia .Methods 73 pa-tients with acute leukemia as the leukemia group and 80 patients as the control group were selected .The serum and bone marrow tissue taken by puncture biopsy of posterior superior iliac spine of the leukemia group were collected The serum of the control group was collected and compared .The expression of vascular endothelial growth factor was detected by immunohistochemistry .Results The acute leukemia patients with positive and negative serum VEGF or with positive and negative bone marrow VEGF were fol-lowed .The positive expression of serum VEGF was found in 19 recurrent cases of acute myeloid leukemia (57 .58% ) and the nega-tive expression of serum VEGF was found in 1 recurrent cases (20 .00% ) .The recurrence rate in patients with positive serum VEGF was higher than that in patients with negative serum VEGF ,and the difference was statistically significant (P<0 .05);the positive expression of serum VEGF was found in 16 recurrent cases of acute lymphoblastic leukemia (51 .62% );the positive expres-sion of bone marrow VEGF was found in 17 recurrent cases of acute myeloid leukemia and 17 recurrent cases of acute lymphoblastic leukemia respectively (48 .57% ) .The serum VEGF level and the bone marrow VEGF were measured on follow-up one year after treatment ,which showed the levels of recurrent cases of acute myeloid leukemia and acute lymphoblastic leukemia were all higher than those of Remission patients ,and the difference was statistically significant (P< 0 .01) .Conclusion The levels of VEGF in blood and bone marrow cells can be highly expressed in the initial treatment and recurrence of acute leukemia ,especially in the re-lapsed condition ,the expression level is higher ,but the expression level is significantly decreased in the remission state .Increased expression of VEGF in blood and bone marrow cells may help to predict an increased risk of recurrence .
ABSTRACT
Objective:To observe the clinical efficacy of calcium dobesilate combined with valsartan in the treatment of IgA ne-phropathy. Methods:Totally 58 cases of IgA nephropathy were randomly divided into the treatment group and the control group. The control group enrolled 29 cases given valsartan 160 mg · d-1 . The treatment group included 29 cases treated with calcium dobesilate 500 mg·time-1 ,tid,and valsartan 160 mg·d-1 . After 6 months, the following indicators were observed, such as blood pressure,fi-brinogen,urea nitrogen,serum creatinine,blood uric acid,and 24-hour urinary ( Upro) . Results: After 6 months, UA and Upro of the two groups were significantly declined than those before the treatment(the control group P<0. 05,the treatment group P<0. 01). Upro of the treatment group was declined from (1. 48 ± 0. 84) g/24h to (0. 41 ± 0. 22) g/24h,and there was statistical significance com-pared with the control group (P<0.05). BUN, Scr and FIB were decreased significantly(P <0.05),while no significant change showed in those in the control group after the treatment. Conclusion:Calcium dobesilate combined valsartan can effectively reduce Up-ro and improve renal function in IgA nephropathy.