The Effect of Ruxolitinib on the Expression of VEGF and HIF-1α in Leukemia HEL Cells
Abstract
To investigate the effect of Ruxolitinib on the expression of vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 alpha (HIF-1α) in HEL cells. Methods The HEL cells were treated with Ruxolitinib in different concentrations (1 nmol/L, 5 nmol/L, 10 nmol/L, 50 nmol/L, 100 nmol/L, 500 nmol/L). The growth inhibition of Ruxolitinib on HEL cells was detected by CCK-8 assay; the mRNA expression level ofJAK2 were measured by RT-PCR and the protein level of p-JAK2, VEGF, HIF-1α were observed by Western blot after treated with Ruxolitinib for 24, 48, 72 h. Chick chorioallantoic membrane (CAM) test was used to testify the effect of Ruxolitinib on angiogenesis. Results Ruxolitinib with different concentrations could inhibit HEL cells proliferation. RT-PCR showed that the mRNA level ofJAK2 decreased in a concentration-dependent manner and Western blot demonstrated that the expression levels of p-JAK2, VEGF and HIF-1α were lower in Ruxolitinib treatment groups than those in control group (P <0.05) after HEL cells were treated with different concentrations of Ruxolitinib for 24, 48, 72 h. Ruxolitinib significantly suppressed blood vessels’ formation in CAM. Conclusion Ruxolitinib can inhibit VEGF, HIF-1α expression and angiogenesis of HEL leukemia cells by inhibiting JAK2 pathway.
Keywords: Myeloproliferative neoplasms, Ruxolitinib, Angiogenesis, VEGF HIF-1α
Full Text:
PDFReferences
CONSTANTINESCU SN, GIRARDOT M, PECQUET C. Mining for JAK-STAT mutations in cancer. Trends Biochem Sci,2008,33(3); 122-131.
CHASE А, BRYANT C, SCORE J, et at. Ruxolitinib as potential targeted therapy for patients with JAK2 rearrangementsr. Haematologica,2013,98(3):404-408.
OKUS, TAKENAKA К. KURIYAMA T. JAK2 V617F uses distinct signalling pathways to induce cell proliferation and neutrophil activation. Br J Haematol, 2010, 150(3): 334- 344.
RUBERT J.QIAN Z, ANDRAOS R, et al. Bim and Mcl-1 exert key roles in regulating JAK2V617F cell survival. BMC Cancer,2011 (11): 24. doi: 10. 1186/1471-2407-11-24.
SHI JG.CHEN X,MCGEE RF, elal. The pharmacokinetics, pharmacodynamics, and safety of orally dosed INCB018424 phosphate in healthy volunteers..! Clin Pharmacol. 2011, 51 (12):1644- 1654.
VANNUCCH1 AM.KILADJIAN JJ,GRIESSHAMMER M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med,2015,372(5) :426-435.
ORITANIK, OKAMOTO S, TAUCHI T. et al. A multinational, open-label, phase 2 study ruxolitinib in Asian patients with myelofibrosis: Japanese subset analysis. Int J Hematol ,2015,101(3) :295-304.
HARRISON C,KILADJIAN JJ, AL-ALI HK, et al. JAK inhibition with ruxolitinib versus best assailable therapy for myelofibrosis. N Engl J Med,2012,366(9) ;787-798.
] QUINTAS-CARDAMA A, VADD1 K, LIU P, et al. Preclinical characterization of the selective JAK1/2 inhibit or INCB018424; therapeutic implications for the treatment of myeloproliferative neoplasms. Blood. 2010, 115 ( 15 ); 3109- 3117.
SONG G, LI Y, JIANG G. Role of VEGF/VEGFR in the pathogenesis of leukemias and as treatment targets. Oncol Rep,2012,28(6): 1935-1944.
NEGAARD HF.IVERSEN N, BOWITZ-LOTHE IM,et al. Increased bone marrow microvascular density in haematological malignanciesis associated with differential regulation of angiogenic factors. Leukemia,2009,23( 1): 162- 169.
PANTELIK, ZAGORIANAKOU N, BA I M, et al. Angiogenesis in chronic myeloproliferative diseases detected by CD34 expression. P'ur J Haematol.2004 ,72(6): 410-415.
BOVERI E,PASSAMONTI F.RUMI E,et al. Bone marrow microvessel density in chronic myeloproliferative disorders: a study of 115 patients with clinicopathological and molecular correlations. Br J Haematol,2009,140(2): 162-168.
MEDINGER M, SKODA R. GRATWOL A, et al. Angiogenesis and vascular endothelial growth factor/receptor expression in myeloproliferative neoplasms; correlation with clinical parameters and JAK2-V617F mutational status. Br J Haematol,2009,146(2): 150-157.
Refbacks
- There are currently no refbacks.
