Limits...
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

PF-2341066 alone or combination with cisplatin inhibited the proliferation of HNE-1 cells in vitro.Notes: (A) PF-2341066 alone or in combination with DDP inhibited the proliferation of HNE-1 cells. The half maximal inhibitory concentration of PF-2341066 alone is 0.79±0.21 μmol/L, while in combination with DDP is 0.41±0.13 μmol/L. (B) PF-2341066 showed a synergistic effect in combination with DDP. The inhibition rate increased by 23.4% and showed certain synergistic effects by using CalcuSyn.Abbreviations: CI, confidence interval; DDP, cisplatin; SD, standard deviation.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4555972&req=5

f1-dddt-9-4897: PF-2341066 alone or combination with cisplatin inhibited the proliferation of HNE-1 cells in vitro.Notes: (A) PF-2341066 alone or in combination with DDP inhibited the proliferation of HNE-1 cells. The half maximal inhibitory concentration of PF-2341066 alone is 0.79±0.21 μmol/L, while in combination with DDP is 0.41±0.13 μmol/L. (B) PF-2341066 showed a synergistic effect in combination with DDP. The inhibition rate increased by 23.4% and showed certain synergistic effects by using CalcuSyn.Abbreviations: CI, confidence interval; DDP, cisplatin; SD, standard deviation.

Mentions: PF-2341066 alone or combination with cisplatin inhibited the proliferation of HNE-1 cells in vitro. We tested cell viability by CCK-8 kit. The half maximal inhibitory concentration of PF-2341066 alone is 0.79±0.21 μmol/L, while combination with cisplatin is 0.41±0.13 μmol/L. The inhibition rate increased by 23.4% and showed certain synergistic effects (Figure 1A and B).


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)

PF-2341066 alone or combination with cisplatin inhibited the proliferation of HNE-1 cells in vitro.Notes: (A) PF-2341066 alone or in combination with DDP inhibited the proliferation of HNE-1 cells. The half maximal inhibitory concentration of PF-2341066 alone is 0.79±0.21 μmol/L, while in combination with DDP is 0.41±0.13 μmol/L. (B) PF-2341066 showed a synergistic effect in combination with DDP. The inhibition rate increased by 23.4% and showed certain synergistic effects by using CalcuSyn.Abbreviations: CI, confidence interval; DDP, cisplatin; SD, standard deviation.
© Copyright Policy
Related In: Results  -  Collection

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

f1-dddt-9-4897: PF-2341066 alone or combination with cisplatin inhibited the proliferation of HNE-1 cells in vitro.Notes: (A) PF-2341066 alone or in combination with DDP inhibited the proliferation of HNE-1 cells. The half maximal inhibitory concentration of PF-2341066 alone is 0.79±0.21 μmol/L, while in combination with DDP is 0.41±0.13 μmol/L. (B) PF-2341066 showed a synergistic effect in combination with DDP. The inhibition rate increased by 23.4% and showed certain synergistic effects by using CalcuSyn.Abbreviations: CI, confidence interval; DDP, cisplatin; SD, standard deviation.
Mentions: PF-2341066 alone or combination with cisplatin inhibited the proliferation of HNE-1 cells in vitro. We tested cell viability by CCK-8 kit. The half maximal inhibitory concentration of PF-2341066 alone is 0.79±0.21 μmol/L, while combination with cisplatin is 0.41±0.13 μmol/L. The inhibition rate increased by 23.4% and showed certain synergistic effects (Figure 1A and B).

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