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Met tyrosine kinase inhibitor, PF-2341066, suppresses growth and invasion of nasopharyngeal carcinoma.

Zhao Y, Zhang J, Tian Y, Xue C, Hu Z, Zhang L - Drug Des Devel Ther (2015)

Bottom Line: We explored the effect of hepatocyte growth factor (HGF)/Met signaling pathway on nasopharyngeal carcinoma (NPC) cells in vitro and in vivo, and investigated the ability of Met tyrosine kinase inhibitor (TKI) to block HGF-induced biological signaling.Met TKI inhibitor PF-2341066 alone, or in combination with cisplatin, was investigated for its ability to block HGF-induced signaling and biological effects in vitro and in vivo.Met TKI, PF-2341066, showed potent antitumor activity in vivo and in vitro which was enhanced by combination with cisplatin.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China.

ABSTRACT

Purpose: We explored the effect of hepatocyte growth factor (HGF)/Met signaling pathway on nasopharyngeal carcinoma (NPC) cells in vitro and in vivo, and investigated the ability of Met tyrosine kinase inhibitor (TKI) to block HGF-induced biological signaling.

Experimental design: Met TKI inhibitor PF-2341066 alone, or in combination with cisplatin, was investigated for its ability to block HGF-induced signaling and biological effects in vitro and in vivo. HGF/Met expression and activation of signaling in NPC cells were detected by using Western blot and immunohistochemistry. Biological evaluation, including wound healing, cell proliferation, and invasion of NPC cells, was also examined, and the correlation between HGF/Met expression of primary and metastatic tumor in NPC patients and clinical prognosis were also analyzed.

Results: Met TKI inhibitor, PF-2341066, inhibited growth of NPC cells in vivo with half maximal inhibitory concentration of 0.79±0.21 μmol/L, and suppressed invasion and migration of NPC cells; also, the inhibition of PF-2341066 was synergized with cisplatin treatment. Compared with the control group, Met TKI inhibited metastasis of transplanted NPC in nude mice (the number of live metastases [mean ± SD]: 5.8±2.2 versus 11.8±2.2, P=0.03; the number of lung metastases: 2.3±1.5 versus 5.3±0.9, P=0.06). HGF was widely expressed in both primary and metastatic lesions while Met expression of metastatic lesions was higher than that of primary lesions (primary lesions: 24.7%; liver metastases: 40%; lung metastases: 29%; lymph node metastases: 29%, P<0.05), and overall survival of NPC patients with higher expression of Met was shorter (P=0.13).

Conclusion: Our results demonstrated that HGF/Met signaling promoted NPC growth, further resulting in metastasis and poor prognosis. Met TKI, PF-2341066, showed potent antitumor activity in vivo and in vitro which was enhanced by combination with cisplatin. Our study implied that HGF/Met signaling was the potential therapeutic target in NPC, and blockage of the signaling could prevent growth and metastasis of NPC and derive clinical benefit.

No MeSH data available.


Related in: MedlinePlus

The antitumor effect of PF-2341066 in vivo.Notes: NPC cells (two ×106) were injected into nude mice, and 7 days later tumors were measured and divided into four groups randomly and kept for 3 weeks. The PF-2341066 group was given 50 mg/kg/d PF-2341066 by oral gavages; the DDP group was injected intraperitoneally with 1 mg/kg/d DDP; the combination group was given both PF-2341066 and DDP in the above concentrations; the control group was given gavages with sterile water and injected with normal saline. (A) PF-2341066 inhibited NPC xenograft growth. (B) PF-2341066 had little effect on mice weight loss. (A and B) Tumor volume and mice weights were measured every 2 days. The inhibition rate is highest in the combination group (P=0.03) while there was no statistical difference in weight loss (P=0.77). (C) Western blot of Met signaling pathway in xenograft. PF-2341066 not only inhibited the phosphorylation of Met, AKT, and ERK, but also enhanced inhibition of HGF/Met signaling pathway of DDP treatment.Abbreviations: DDP, cisplatin; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; NPC, nasopharyngeal carcinoma.
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f4-dddt-9-4897: The antitumor effect of PF-2341066 in vivo.Notes: NPC cells (two ×106) were injected into nude mice, and 7 days later tumors were measured and divided into four groups randomly and kept for 3 weeks. The PF-2341066 group was given 50 mg/kg/d PF-2341066 by oral gavages; the DDP group was injected intraperitoneally with 1 mg/kg/d DDP; the combination group was given both PF-2341066 and DDP in the above concentrations; the control group was given gavages with sterile water and injected with normal saline. (A) PF-2341066 inhibited NPC xenograft growth. (B) PF-2341066 had little effect on mice weight loss. (A and B) Tumor volume and mice weights were measured every 2 days. The inhibition rate is highest in the combination group (P=0.03) while there was no statistical difference in weight loss (P=0.77). (C) Western blot of Met signaling pathway in xenograft. PF-2341066 not only inhibited the phosphorylation of Met, AKT, and ERK, but also enhanced inhibition of HGF/Met signaling pathway of DDP treatment.Abbreviations: DDP, cisplatin; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; NPC, nasopharyngeal carcinoma.

Mentions: In in vivo test, PF-2341066 inhibited HNE-1 tumor xenograft growth in nude mice with 50 mg/kg/d, and inhibition rate was highest in the combination group (P=0.03), while weight loss was almost the same (P=0.77) (Figure 4A and B). Also, it was further confirmed that PF-2341066 inhibited not only the phosphorylation of Met, AKT, and ERK, but also enhanced inhibition of HGF/Met signaling pathway of cisplatin treatment (Figure 4C).


Met tyrosine kinase inhibitor, PF-2341066, suppresses growth and invasion of nasopharyngeal carcinoma.

Zhao Y, Zhang J, Tian Y, Xue C, Hu Z, Zhang L - Drug Des Devel Ther (2015)

The antitumor effect of PF-2341066 in vivo.Notes: NPC cells (two ×106) were injected into nude mice, and 7 days later tumors were measured and divided into four groups randomly and kept for 3 weeks. The PF-2341066 group was given 50 mg/kg/d PF-2341066 by oral gavages; the DDP group was injected intraperitoneally with 1 mg/kg/d DDP; the combination group was given both PF-2341066 and DDP in the above concentrations; the control group was given gavages with sterile water and injected with normal saline. (A) PF-2341066 inhibited NPC xenograft growth. (B) PF-2341066 had little effect on mice weight loss. (A and B) Tumor volume and mice weights were measured every 2 days. The inhibition rate is highest in the combination group (P=0.03) while there was no statistical difference in weight loss (P=0.77). (C) Western blot of Met signaling pathway in xenograft. PF-2341066 not only inhibited the phosphorylation of Met, AKT, and ERK, but also enhanced inhibition of HGF/Met signaling pathway of DDP treatment.Abbreviations: DDP, cisplatin; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; NPC, nasopharyngeal carcinoma.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4555972&req=5

f4-dddt-9-4897: The antitumor effect of PF-2341066 in vivo.Notes: NPC cells (two ×106) were injected into nude mice, and 7 days later tumors were measured and divided into four groups randomly and kept for 3 weeks. The PF-2341066 group was given 50 mg/kg/d PF-2341066 by oral gavages; the DDP group was injected intraperitoneally with 1 mg/kg/d DDP; the combination group was given both PF-2341066 and DDP in the above concentrations; the control group was given gavages with sterile water and injected with normal saline. (A) PF-2341066 inhibited NPC xenograft growth. (B) PF-2341066 had little effect on mice weight loss. (A and B) Tumor volume and mice weights were measured every 2 days. The inhibition rate is highest in the combination group (P=0.03) while there was no statistical difference in weight loss (P=0.77). (C) Western blot of Met signaling pathway in xenograft. PF-2341066 not only inhibited the phosphorylation of Met, AKT, and ERK, but also enhanced inhibition of HGF/Met signaling pathway of DDP treatment.Abbreviations: DDP, cisplatin; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; NPC, nasopharyngeal carcinoma.
Mentions: In in vivo test, PF-2341066 inhibited HNE-1 tumor xenograft growth in nude mice with 50 mg/kg/d, and inhibition rate was highest in the combination group (P=0.03), while weight loss was almost the same (P=0.77) (Figure 4A and B). Also, it was further confirmed that PF-2341066 inhibited not only the phosphorylation of Met, AKT, and ERK, but also enhanced inhibition of HGF/Met signaling pathway of cisplatin treatment (Figure 4C).

Bottom Line: We explored the effect of hepatocyte growth factor (HGF)/Met signaling pathway on nasopharyngeal carcinoma (NPC) cells in vitro and in vivo, and investigated the ability of Met tyrosine kinase inhibitor (TKI) to block HGF-induced biological signaling.Met TKI inhibitor PF-2341066 alone, or in combination with cisplatin, was investigated for its ability to block HGF-induced signaling and biological effects in vitro and in vivo.Met TKI, PF-2341066, showed potent antitumor activity in vivo and in vitro which was enhanced by combination with cisplatin.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China.

ABSTRACT

Purpose: We explored the effect of hepatocyte growth factor (HGF)/Met signaling pathway on nasopharyngeal carcinoma (NPC) cells in vitro and in vivo, and investigated the ability of Met tyrosine kinase inhibitor (TKI) to block HGF-induced biological signaling.

Experimental design: Met TKI inhibitor PF-2341066 alone, or in combination with cisplatin, was investigated for its ability to block HGF-induced signaling and biological effects in vitro and in vivo. HGF/Met expression and activation of signaling in NPC cells were detected by using Western blot and immunohistochemistry. Biological evaluation, including wound healing, cell proliferation, and invasion of NPC cells, was also examined, and the correlation between HGF/Met expression of primary and metastatic tumor in NPC patients and clinical prognosis were also analyzed.

Results: Met TKI inhibitor, PF-2341066, inhibited growth of NPC cells in vivo with half maximal inhibitory concentration of 0.79±0.21 μmol/L, and suppressed invasion and migration of NPC cells; also, the inhibition of PF-2341066 was synergized with cisplatin treatment. Compared with the control group, Met TKI inhibited metastasis of transplanted NPC in nude mice (the number of live metastases [mean ± SD]: 5.8±2.2 versus 11.8±2.2, P=0.03; the number of lung metastases: 2.3±1.5 versus 5.3±0.9, P=0.06). HGF was widely expressed in both primary and metastatic lesions while Met expression of metastatic lesions was higher than that of primary lesions (primary lesions: 24.7%; liver metastases: 40%; lung metastases: 29%; lymph node metastases: 29%, P<0.05), and overall survival of NPC patients with higher expression of Met was shorter (P=0.13).

Conclusion: Our results demonstrated that HGF/Met signaling promoted NPC growth, further resulting in metastasis and poor prognosis. Met TKI, PF-2341066, showed potent antitumor activity in vivo and in vitro which was enhanced by combination with cisplatin. Our study implied that HGF/Met signaling was the potential therapeutic target in NPC, and blockage of the signaling could prevent growth and metastasis of NPC and derive clinical benefit.

No MeSH data available.


Related in: MedlinePlus