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Targeting inhibition of extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) suppresses growth and angiogenesis of gastric cancer.

Gao JH, Wang CH, Tong H, Wen SL, Huang ZY, Tang CW - Sci Rep (2015)

Bottom Line: In this study, high p-ERK expression was associated with advanced TNM stage, increased lymphovascular invasion and poor survival.This result was further supported by suppression of tube formation and migration in HUVEC cells after treatment with AZD6244.In conclusions, High p-ERK expression was associated with advanced TNM stage, increased lymphovascular invasion and poor survival.

View Article: PubMed Central - PubMed

Affiliation: Division of Peptides Related with Human Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.

ABSTRACT
AZD6244 (ARRY-142886), a highly selective MAPK-ERK kinase inhibitor, has shown excellent clinical efficacy in many tumors. However, the anti-tumor and anti-angiogenesis efficacy of AZD6244 on gastric cancer has not been well characterized. In this study, high p-ERK expression was associated with advanced TNM stage, increased lymphovascular invasion and poor survival. For absence of NRAS, KRAS and BRAF mutation, SGC7901 and BGC823 gastric cancer cells were relative resistance to AZD6244 in vitro. And such resistance was not attributed to the insufficient inhibition of ERK phosphorylation. However, tumor growth was significantly suppressed in SGC7901 xenografts by blockage of angiogenesis. This result was further supported by suppression of tube formation and migration in HUVEC cells after treatment with AZD6244. Moreover, the anti-angiogenesis effect of AZD6244 may predominantly attribute to its modulation on VEGF through p-ERK - c-Fos - HIF-1α integrated signal pathways. In conclusions, High p-ERK expression was associated with advanced TNM stage, increased lymphovascular invasion and poor survival. Targeting inhibition of p-ERK by AZD6244 suppress gastric cancer xenografts by blockage of angiogenesis without systemic toxicity. The anti-angiogenesis effect afford by AZD6244 may attribute to its modulation on p-ERK - c-Fos - HIF-1α - VEGF integrated signal pathways.

No MeSH data available.


Related in: MedlinePlus

AZD6244 inhibits migration rate, tube formation and cell viability in HUVEC.The migration rate (A,B) and tube length (C,D) were remarkably reduced in AZD6244 (4 μM) treated cells when compared with that in control group. The CCK-8 assay was applied to determine cell viability of HUVEC (E). Inhibition of cell viability was observed in cells treatment with high concentration of AZD6244 for 24 hours (4 μM) and 48 hours (2, 3 and 4 μM) (A). #p < 0.05 vs. control group.
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f6: AZD6244 inhibits migration rate, tube formation and cell viability in HUVEC.The migration rate (A,B) and tube length (C,D) were remarkably reduced in AZD6244 (4 μM) treated cells when compared with that in control group. The CCK-8 assay was applied to determine cell viability of HUVEC (E). Inhibition of cell viability was observed in cells treatment with high concentration of AZD6244 for 24 hours (4 μM) and 48 hours (2, 3 and 4 μM) (A). #p < 0.05 vs. control group.

Mentions: Compared with vehicle treated HUVEC cells, the migration rate was markedly reduced in AZD6244 treated cells (80.8 ± 9.7% vs. 50.9 ± 6.1%, p < 0.001 Fig. 6A,B). Furthermore, the tube length in AZD6244 treated cells was also substantially decreased when compared with that in vehicle treated cells (26.3 ± 3.2 mm vs. 14.2 ± 1.7 mm, p < 0.001 Fig. 6C,D). Interestingly, cell viability was suppressed in HUVEC cells treatment with high concentration of AZD6244 for 24 hours (4 μM) and 48 hours (2, 3 and 4 μM) (Fig. 6E).


Targeting inhibition of extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) suppresses growth and angiogenesis of gastric cancer.

Gao JH, Wang CH, Tong H, Wen SL, Huang ZY, Tang CW - Sci Rep (2015)

AZD6244 inhibits migration rate, tube formation and cell viability in HUVEC.The migration rate (A,B) and tube length (C,D) were remarkably reduced in AZD6244 (4 μM) treated cells when compared with that in control group. The CCK-8 assay was applied to determine cell viability of HUVEC (E). Inhibition of cell viability was observed in cells treatment with high concentration of AZD6244 for 24 hours (4 μM) and 48 hours (2, 3 and 4 μM) (A). #p < 0.05 vs. control group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4644956&req=5

f6: AZD6244 inhibits migration rate, tube formation and cell viability in HUVEC.The migration rate (A,B) and tube length (C,D) were remarkably reduced in AZD6244 (4 μM) treated cells when compared with that in control group. The CCK-8 assay was applied to determine cell viability of HUVEC (E). Inhibition of cell viability was observed in cells treatment with high concentration of AZD6244 for 24 hours (4 μM) and 48 hours (2, 3 and 4 μM) (A). #p < 0.05 vs. control group.
Mentions: Compared with vehicle treated HUVEC cells, the migration rate was markedly reduced in AZD6244 treated cells (80.8 ± 9.7% vs. 50.9 ± 6.1%, p < 0.001 Fig. 6A,B). Furthermore, the tube length in AZD6244 treated cells was also substantially decreased when compared with that in vehicle treated cells (26.3 ± 3.2 mm vs. 14.2 ± 1.7 mm, p < 0.001 Fig. 6C,D). Interestingly, cell viability was suppressed in HUVEC cells treatment with high concentration of AZD6244 for 24 hours (4 μM) and 48 hours (2, 3 and 4 μM) (Fig. 6E).

Bottom Line: In this study, high p-ERK expression was associated with advanced TNM stage, increased lymphovascular invasion and poor survival.This result was further supported by suppression of tube formation and migration in HUVEC cells after treatment with AZD6244.In conclusions, High p-ERK expression was associated with advanced TNM stage, increased lymphovascular invasion and poor survival.

View Article: PubMed Central - PubMed

Affiliation: Division of Peptides Related with Human Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.

ABSTRACT
AZD6244 (ARRY-142886), a highly selective MAPK-ERK kinase inhibitor, has shown excellent clinical efficacy in many tumors. However, the anti-tumor and anti-angiogenesis efficacy of AZD6244 on gastric cancer has not been well characterized. In this study, high p-ERK expression was associated with advanced TNM stage, increased lymphovascular invasion and poor survival. For absence of NRAS, KRAS and BRAF mutation, SGC7901 and BGC823 gastric cancer cells were relative resistance to AZD6244 in vitro. And such resistance was not attributed to the insufficient inhibition of ERK phosphorylation. However, tumor growth was significantly suppressed in SGC7901 xenografts by blockage of angiogenesis. This result was further supported by suppression of tube formation and migration in HUVEC cells after treatment with AZD6244. Moreover, the anti-angiogenesis effect of AZD6244 may predominantly attribute to its modulation on VEGF through p-ERK - c-Fos - HIF-1α integrated signal pathways. In conclusions, High p-ERK expression was associated with advanced TNM stage, increased lymphovascular invasion and poor survival. Targeting inhibition of p-ERK by AZD6244 suppress gastric cancer xenografts by blockage of angiogenesis without systemic toxicity. The anti-angiogenesis effect afford by AZD6244 may attribute to its modulation on p-ERK - c-Fos - HIF-1α - VEGF integrated signal pathways.

No MeSH data available.


Related in: MedlinePlus