MODULATION OF LEUKOTRIENE SIGNALING INHIBITING CELL GROWTH IN CHRONIC MYELOID LEUKEMIA
(Abstract release date: 05/19/16)
EHA Library. Yektaei-Karin E. 06/09/16; 134707; PB1807
Elham Yektaei-Karin
Contributions
Contributions
Abstract
Abstract: PB1807
Type: Publication Only
Background
The introduction of tyrosine kinase inhibitors (TKI) has dramatically improved the outcome in chronic myeloid leukemia (CML). However, for most patients cure remains unlikely due to residual, detectable leukemic stem cells. This may be due to aberrant regulation of BCR-ABL-independent signaling pathways. One such suggested pathway leads to the formation of leukotrienes (LT), inflammatory mediators indicated to play a role also in the tumorigenicity of several malignancies (e.g. in the colon, prostate, breast, lung). We have previously shown that CML patient-derived myeloid cells have an elevated capacity to synthesize LT, paired by an increased expression of the enzyme LTC4 synthase (LTC4S). Recently an up-regulation of the arachidonate 5-lipoxygenase (5-LO) gene was observed in BCR-ABL-positive CML mice, together with an improved animal survival when this enzyme was pharmacologically inhibited.
Aims
To examine the effect of leukotriene-signaling-modulating compounds on the growth of human CML cells.
Methods
Human CML cells were grown in 3-day in vitro cultures (MTT), with and without addition of different specific blockers of LT-signaling and tyrosine kinase inhibitors (TKI). Protein expression was determined by Western blot.
Results
The cysteinyl-LT1-receptor (CysLT1rec) antagonist montelukast significantly reduced the growth of K562, KCL22 and KU812 CML cells in culture in a dose-dependent manner (IC50 1.1-1.7 μM, i.e. clinically achievable concentrations). Montelukast also inhibited the growth of the CysLT1rec-expressing colon cancer cell line HCT116, but not of normal fibroblasts. As expected, several TKIs, including imatinib, also clearly suppressed the growth of the CML cells. When combining montelukast with imatinib an additive inhibition occurred. Similarly, inhibition of CML cell growth was also evident after addition of the 5-LO-inhibitor BWA4C, the 5-LO-activating protein (FLAP) inhibitor licofelone and the LTB4(BLT)1-receptor antagonist LY293111. All three CML cell lines where shown to express 5-lipoxygenase, LTA4hydrolase and LTC4S, key enzymes in the formation of bioactive leukotrienes.
Conclusion
Our data indicate that blocking of LT-signaling selectively suppresses expansion of human CML cells and may thus provide an additional therapeutic possibility targeting residual disease in this leukemia. Some of the tested pharmaceuticals are already in clinical practice for non-hematological disorders, facilitating the initiation of prospective CML intervention trials.
Session topic: E-poster
Type: Publication Only
Background
The introduction of tyrosine kinase inhibitors (TKI) has dramatically improved the outcome in chronic myeloid leukemia (CML). However, for most patients cure remains unlikely due to residual, detectable leukemic stem cells. This may be due to aberrant regulation of BCR-ABL-independent signaling pathways. One such suggested pathway leads to the formation of leukotrienes (LT), inflammatory mediators indicated to play a role also in the tumorigenicity of several malignancies (e.g. in the colon, prostate, breast, lung). We have previously shown that CML patient-derived myeloid cells have an elevated capacity to synthesize LT, paired by an increased expression of the enzyme LTC4 synthase (LTC4S). Recently an up-regulation of the arachidonate 5-lipoxygenase (5-LO) gene was observed in BCR-ABL-positive CML mice, together with an improved animal survival when this enzyme was pharmacologically inhibited.
Aims
To examine the effect of leukotriene-signaling-modulating compounds on the growth of human CML cells.
Methods
Human CML cells were grown in 3-day in vitro cultures (MTT), with and without addition of different specific blockers of LT-signaling and tyrosine kinase inhibitors (TKI). Protein expression was determined by Western blot.
Results
The cysteinyl-LT1-receptor (CysLT1rec) antagonist montelukast significantly reduced the growth of K562, KCL22 and KU812 CML cells in culture in a dose-dependent manner (IC50 1.1-1.7 μM, i.e. clinically achievable concentrations). Montelukast also inhibited the growth of the CysLT1rec-expressing colon cancer cell line HCT116, but not of normal fibroblasts. As expected, several TKIs, including imatinib, also clearly suppressed the growth of the CML cells. When combining montelukast with imatinib an additive inhibition occurred. Similarly, inhibition of CML cell growth was also evident after addition of the 5-LO-inhibitor BWA4C, the 5-LO-activating protein (FLAP) inhibitor licofelone and the LTB4(BLT)1-receptor antagonist LY293111. All three CML cell lines where shown to express 5-lipoxygenase, LTA4hydrolase and LTC4S, key enzymes in the formation of bioactive leukotrienes.
Conclusion
Our data indicate that blocking of LT-signaling selectively suppresses expansion of human CML cells and may thus provide an additional therapeutic possibility targeting residual disease in this leukemia. Some of the tested pharmaceuticals are already in clinical practice for non-hematological disorders, facilitating the initiation of prospective CML intervention trials.
Session topic: E-poster
Abstract: PB1807
Type: Publication Only
Background
The introduction of tyrosine kinase inhibitors (TKI) has dramatically improved the outcome in chronic myeloid leukemia (CML). However, for most patients cure remains unlikely due to residual, detectable leukemic stem cells. This may be due to aberrant regulation of BCR-ABL-independent signaling pathways. One such suggested pathway leads to the formation of leukotrienes (LT), inflammatory mediators indicated to play a role also in the tumorigenicity of several malignancies (e.g. in the colon, prostate, breast, lung). We have previously shown that CML patient-derived myeloid cells have an elevated capacity to synthesize LT, paired by an increased expression of the enzyme LTC4 synthase (LTC4S). Recently an up-regulation of the arachidonate 5-lipoxygenase (5-LO) gene was observed in BCR-ABL-positive CML mice, together with an improved animal survival when this enzyme was pharmacologically inhibited.
Aims
To examine the effect of leukotriene-signaling-modulating compounds on the growth of human CML cells.
Methods
Human CML cells were grown in 3-day in vitro cultures (MTT), with and without addition of different specific blockers of LT-signaling and tyrosine kinase inhibitors (TKI). Protein expression was determined by Western blot.
Results
The cysteinyl-LT1-receptor (CysLT1rec) antagonist montelukast significantly reduced the growth of K562, KCL22 and KU812 CML cells in culture in a dose-dependent manner (IC50 1.1-1.7 μM, i.e. clinically achievable concentrations). Montelukast also inhibited the growth of the CysLT1rec-expressing colon cancer cell line HCT116, but not of normal fibroblasts. As expected, several TKIs, including imatinib, also clearly suppressed the growth of the CML cells. When combining montelukast with imatinib an additive inhibition occurred. Similarly, inhibition of CML cell growth was also evident after addition of the 5-LO-inhibitor BWA4C, the 5-LO-activating protein (FLAP) inhibitor licofelone and the LTB4(BLT)1-receptor antagonist LY293111. All three CML cell lines where shown to express 5-lipoxygenase, LTA4hydrolase and LTC4S, key enzymes in the formation of bioactive leukotrienes.
Conclusion
Our data indicate that blocking of LT-signaling selectively suppresses expansion of human CML cells and may thus provide an additional therapeutic possibility targeting residual disease in this leukemia. Some of the tested pharmaceuticals are already in clinical practice for non-hematological disorders, facilitating the initiation of prospective CML intervention trials.
Session topic: E-poster
Type: Publication Only
Background
The introduction of tyrosine kinase inhibitors (TKI) has dramatically improved the outcome in chronic myeloid leukemia (CML). However, for most patients cure remains unlikely due to residual, detectable leukemic stem cells. This may be due to aberrant regulation of BCR-ABL-independent signaling pathways. One such suggested pathway leads to the formation of leukotrienes (LT), inflammatory mediators indicated to play a role also in the tumorigenicity of several malignancies (e.g. in the colon, prostate, breast, lung). We have previously shown that CML patient-derived myeloid cells have an elevated capacity to synthesize LT, paired by an increased expression of the enzyme LTC4 synthase (LTC4S). Recently an up-regulation of the arachidonate 5-lipoxygenase (5-LO) gene was observed in BCR-ABL-positive CML mice, together with an improved animal survival when this enzyme was pharmacologically inhibited.
Aims
To examine the effect of leukotriene-signaling-modulating compounds on the growth of human CML cells.
Methods
Human CML cells were grown in 3-day in vitro cultures (MTT), with and without addition of different specific blockers of LT-signaling and tyrosine kinase inhibitors (TKI). Protein expression was determined by Western blot.
Results
The cysteinyl-LT1-receptor (CysLT1rec) antagonist montelukast significantly reduced the growth of K562, KCL22 and KU812 CML cells in culture in a dose-dependent manner (IC50 1.1-1.7 μM, i.e. clinically achievable concentrations). Montelukast also inhibited the growth of the CysLT1rec-expressing colon cancer cell line HCT116, but not of normal fibroblasts. As expected, several TKIs, including imatinib, also clearly suppressed the growth of the CML cells. When combining montelukast with imatinib an additive inhibition occurred. Similarly, inhibition of CML cell growth was also evident after addition of the 5-LO-inhibitor BWA4C, the 5-LO-activating protein (FLAP) inhibitor licofelone and the LTB4(BLT)1-receptor antagonist LY293111. All three CML cell lines where shown to express 5-lipoxygenase, LTA4hydrolase and LTC4S, key enzymes in the formation of bioactive leukotrienes.
Conclusion
Our data indicate that blocking of LT-signaling selectively suppresses expansion of human CML cells and may thus provide an additional therapeutic possibility targeting residual disease in this leukemia. Some of the tested pharmaceuticals are already in clinical practice for non-hematological disorders, facilitating the initiation of prospective CML intervention trials.
Session topic: E-poster
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