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Increased Levels of NF-kB-Dependent Markers in Cancer-Associated Deep Venous Thrombosis.

Malaponte G, Signorelli SS, Bevelacqua V, Polesel J, Taborelli M, Guarneri C, Fenga C, Umezawa K, Libra M - PLoS ONE (2015)

Bottom Line: However, their combined role in cancer-associated deep vein thrombosis (DVT) and the molecular mechanisms, involved in its pathophysiology, needs further investigations.Accordingly, significantly higher NF-kB activity was observed in cancer patients DVT+ than DVT-.NF-kB inhibition was associated with decreased levels of all molecules in both cancer DVT+ and DVT-.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical and Biotechnological Sciences, Section of General & Clinical Pathology and Oncology, University of Catania, Catania, Italy.

ABSTRACT
Several studies highlight the role of inflammatory markers in thrombosis as well as in cancer. However, their combined role in cancer-associated deep vein thrombosis (DVT) and the molecular mechanisms, involved in its pathophysiology, needs further investigations. In the present study, C-reactive protein, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1β), matrix metalloproteases-9 (MMP-9), vascular endothelial growth factor (VEGF), tissue factor (TF), fibrinogen and soluble P-selectin, were analyzed in plasma and in monocyte samples from 385 cancer patients, of whom 64 were concomitantly affected by DVT (+). All these markers were higher in cancer patients DVT+ than in those DVT-. Accordingly, significantly higher NF-kB activity was observed in cancer patients DVT+ than DVT-. Significant correlation between data obtained in plasma and monocyte samples was observed. NF-kB inhibition was associated with decreased levels of all molecules in both cancer DVT+ and DVT-. To further demonstrate the involvement of NF-kB activation by the above mentioned molecules, we treated monocyte derived from healthy donors with a pool of sera from cancer patients with and without DVT. These set of experiments further suggest the significant role played by some molecules, regulated by NF-kB, and detected in cancer patients with DVT. Our data support the notion that NF-kB may be considered as a therapeutic target for cancer patients, especially those complicated by DVT. Treatment with NF-kB inhibitors may represent a possible strategy to prevent or reduce the risk of DVT in cancer patients.

No MeSH data available.


Related in: MedlinePlus

Nuclear factor (NF)–kB p65 subunit activity in monocytes from cancer patients with and without DVT and effect of DHMEQ.The activated NF-kB p65 subunit was significantly higher in cancer patients DVT+ and DVT- than in healthy controls (P< 0.0001). (ANOVA test). NF-kB p65 subunit was significantly higher in cancer patients DVT+ than in those DVT- (P< 0.001) (t-test). To examine the effects of DHMEQ, monocytes were treated with 10 μg/mL DHMEQ. As control experiments, DMSO was used instead of DHMEQ. Monocytes from cancer patients DVT+ were more responsive to DHMEQ than those from DVT-. Intriguingly, no effect of DHMEQ there was in healthy monocytes. The results are shown as the means ± SD. OD, optical density; DVT, Deep Vein thrombosis; DMSO, dimethyl sulfoxide; DHEMQ, dehydroxymethylepoxyquinomicin.
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pone.0132496.g002: Nuclear factor (NF)–kB p65 subunit activity in monocytes from cancer patients with and without DVT and effect of DHMEQ.The activated NF-kB p65 subunit was significantly higher in cancer patients DVT+ and DVT- than in healthy controls (P< 0.0001). (ANOVA test). NF-kB p65 subunit was significantly higher in cancer patients DVT+ than in those DVT- (P< 0.001) (t-test). To examine the effects of DHMEQ, monocytes were treated with 10 μg/mL DHMEQ. As control experiments, DMSO was used instead of DHMEQ. Monocytes from cancer patients DVT+ were more responsive to DHMEQ than those from DVT-. Intriguingly, no effect of DHMEQ there was in healthy monocytes. The results are shown as the means ± SD. OD, optical density; DVT, Deep Vein thrombosis; DMSO, dimethyl sulfoxide; DHEMQ, dehydroxymethylepoxyquinomicin.

Mentions: Activation of NF-kB p65 subunit in unstimulated monocytes, from cancer patients DVT+ and DVT- and from healthy control, was analyzed by a sensitive ELISA assay. This assay has the advantage of being 10-fold more sensitive than electrophoresis mobility shift assay (EMSA) and allows greater flexibility in the experimental step. As shown in Fig 2, NF-kB p65 subunit activity in monocytes varied in all examined groups. Higher NF-kB p65 subunit activity was observed in cancer patients DVT+ and DVT- than in healthy controls (p< 0.0001). Significant differences of NF-kB p65 activity were also detected between cancer patients DVT+ and DVT- (p< 0.0001). It was already shown that NF-kB regulates several molecules including those analyzed in the present study [41,42]. Accordingly, all these markers positively correlated with NF-kB activity (Table 4). The identification of these markers may recognize NF-kB as an attractive target for therapeutic intervention. Therefore, we thought to inhibit NF-kB by DHMEQ, a known NF-kB inhibitor [46,47]. The effect of DHMEQ, at the dose of 10 μg/ml, on NF-kB p65 subunit activity inhibition in monocytes from the two groups of cancer patients, was explored (Fig 2). Control experiments with DMSO have been included (Fig 2). Notably, DHMEQ was not effective in monocytes from healthy controls at different dose and time (S1 Fig). Although, DHMQ caused the reduction of cell viability of monocytes derived from cancer patients DVT+ and DVT-, this effect was not observed in monocytes from healthy controls (S2 Fig).


Increased Levels of NF-kB-Dependent Markers in Cancer-Associated Deep Venous Thrombosis.

Malaponte G, Signorelli SS, Bevelacqua V, Polesel J, Taborelli M, Guarneri C, Fenga C, Umezawa K, Libra M - PLoS ONE (2015)

Nuclear factor (NF)–kB p65 subunit activity in monocytes from cancer patients with and without DVT and effect of DHMEQ.The activated NF-kB p65 subunit was significantly higher in cancer patients DVT+ and DVT- than in healthy controls (P< 0.0001). (ANOVA test). NF-kB p65 subunit was significantly higher in cancer patients DVT+ than in those DVT- (P< 0.001) (t-test). To examine the effects of DHMEQ, monocytes were treated with 10 μg/mL DHMEQ. As control experiments, DMSO was used instead of DHMEQ. Monocytes from cancer patients DVT+ were more responsive to DHMEQ than those from DVT-. Intriguingly, no effect of DHMEQ there was in healthy monocytes. The results are shown as the means ± SD. OD, optical density; DVT, Deep Vein thrombosis; DMSO, dimethyl sulfoxide; DHEMQ, dehydroxymethylepoxyquinomicin.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4507873&req=5

pone.0132496.g002: Nuclear factor (NF)–kB p65 subunit activity in monocytes from cancer patients with and without DVT and effect of DHMEQ.The activated NF-kB p65 subunit was significantly higher in cancer patients DVT+ and DVT- than in healthy controls (P< 0.0001). (ANOVA test). NF-kB p65 subunit was significantly higher in cancer patients DVT+ than in those DVT- (P< 0.001) (t-test). To examine the effects of DHMEQ, monocytes were treated with 10 μg/mL DHMEQ. As control experiments, DMSO was used instead of DHMEQ. Monocytes from cancer patients DVT+ were more responsive to DHMEQ than those from DVT-. Intriguingly, no effect of DHMEQ there was in healthy monocytes. The results are shown as the means ± SD. OD, optical density; DVT, Deep Vein thrombosis; DMSO, dimethyl sulfoxide; DHEMQ, dehydroxymethylepoxyquinomicin.
Mentions: Activation of NF-kB p65 subunit in unstimulated monocytes, from cancer patients DVT+ and DVT- and from healthy control, was analyzed by a sensitive ELISA assay. This assay has the advantage of being 10-fold more sensitive than electrophoresis mobility shift assay (EMSA) and allows greater flexibility in the experimental step. As shown in Fig 2, NF-kB p65 subunit activity in monocytes varied in all examined groups. Higher NF-kB p65 subunit activity was observed in cancer patients DVT+ and DVT- than in healthy controls (p< 0.0001). Significant differences of NF-kB p65 activity were also detected between cancer patients DVT+ and DVT- (p< 0.0001). It was already shown that NF-kB regulates several molecules including those analyzed in the present study [41,42]. Accordingly, all these markers positively correlated with NF-kB activity (Table 4). The identification of these markers may recognize NF-kB as an attractive target for therapeutic intervention. Therefore, we thought to inhibit NF-kB by DHMEQ, a known NF-kB inhibitor [46,47]. The effect of DHMEQ, at the dose of 10 μg/ml, on NF-kB p65 subunit activity inhibition in monocytes from the two groups of cancer patients, was explored (Fig 2). Control experiments with DMSO have been included (Fig 2). Notably, DHMEQ was not effective in monocytes from healthy controls at different dose and time (S1 Fig). Although, DHMQ caused the reduction of cell viability of monocytes derived from cancer patients DVT+ and DVT-, this effect was not observed in monocytes from healthy controls (S2 Fig).

Bottom Line: However, their combined role in cancer-associated deep vein thrombosis (DVT) and the molecular mechanisms, involved in its pathophysiology, needs further investigations.Accordingly, significantly higher NF-kB activity was observed in cancer patients DVT+ than DVT-.NF-kB inhibition was associated with decreased levels of all molecules in both cancer DVT+ and DVT-.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical and Biotechnological Sciences, Section of General & Clinical Pathology and Oncology, University of Catania, Catania, Italy.

ABSTRACT
Several studies highlight the role of inflammatory markers in thrombosis as well as in cancer. However, their combined role in cancer-associated deep vein thrombosis (DVT) and the molecular mechanisms, involved in its pathophysiology, needs further investigations. In the present study, C-reactive protein, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1β), matrix metalloproteases-9 (MMP-9), vascular endothelial growth factor (VEGF), tissue factor (TF), fibrinogen and soluble P-selectin, were analyzed in plasma and in monocyte samples from 385 cancer patients, of whom 64 were concomitantly affected by DVT (+). All these markers were higher in cancer patients DVT+ than in those DVT-. Accordingly, significantly higher NF-kB activity was observed in cancer patients DVT+ than DVT-. Significant correlation between data obtained in plasma and monocyte samples was observed. NF-kB inhibition was associated with decreased levels of all molecules in both cancer DVT+ and DVT-. To further demonstrate the involvement of NF-kB activation by the above mentioned molecules, we treated monocyte derived from healthy donors with a pool of sera from cancer patients with and without DVT. These set of experiments further suggest the significant role played by some molecules, regulated by NF-kB, and detected in cancer patients with DVT. Our data support the notion that NF-kB may be considered as a therapeutic target for cancer patients, especially those complicated by DVT. Treatment with NF-kB inhibitors may represent a possible strategy to prevent or reduce the risk of DVT in cancer patients.

No MeSH data available.


Related in: MedlinePlus