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Paeoniflorin Potentiates the Inhibitory Effects of Erlotinib in Pancreatic Cancer Cell Lines by Reducing ErbB3 Phosphorylation

View Article: PubMed Central - PubMed

ABSTRACT

Blockade of the epidermal growth factor receptor (EGFR) by EGFR tyrosine kinase inhibitors is insufficient for effective anti-tumor activity because the reactivation of the ErbB3 signaling pathway significantly contributes to activating the consequent phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. Combinatorial therapies including ErbB3 targeting may ameliorate tumor responses to anti-EGFR therapies. In the present study, we found that in BxPC-3 and L3.6pl cells, which highly expressed the ErbB3 receptor, significant reduction in cell viability, induction of apoptosis were observed when treated with a combination of erlotinib and PF compared to either agent alone. Moreover, in ErbB3-expressing BxPC-3, L3.6pl and S2VP10 cell lines, the inhibition of ErbB3/PI3K/Akt phosphorylation were observed when treated with PF. Most strikingly, both EGFR/MAPK/Erk and ErbB3/PI3K/Akt activitions were substantially suppressed when treated with the combination of PF and erlotinib. However, in the ErbB3-deficient cell line MIAPaCa-2, no such effects were observed with similar treatments. Most importantly, these in vitro results were replicated in nude mouse transplanted tumor models. Taken together, our findings show that PF enhances the effect of erlotinib in ErbB3-expressing pancreatic cancer cells by directly suppressing ErbB3 activation, and PF in combination with erlotinib is much more effective as an antitumor agent compared with either agent alone.

No MeSH data available.


Related in: MedlinePlus

PF Augmented in Vivo Therapeutic Effects of Erlotinib on the BxPC-3 Transplanted Tumors.(A) Representative image of excised tumors (B) Effects of erlotinib, PF or Combination treatment on tumor volume and weight. The volume curve shows the change in tumor volume, and the left histogram shows the final tumor volume. On the 40th day, the implanted tumors were excised and weighted (right histogram). (C) Expression of phosphorylated ErbB3 in tumor tissues. Left, images are shown with phosphorylated ErbB3 positive areas (400×). (D) Effect of erlotinib, PF or combination on mouse weight.
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f4: PF Augmented in Vivo Therapeutic Effects of Erlotinib on the BxPC-3 Transplanted Tumors.(A) Representative image of excised tumors (B) Effects of erlotinib, PF or Combination treatment on tumor volume and weight. The volume curve shows the change in tumor volume, and the left histogram shows the final tumor volume. On the 40th day, the implanted tumors were excised and weighted (right histogram). (C) Expression of phosphorylated ErbB3 in tumor tissues. Left, images are shown with phosphorylated ErbB3 positive areas (400×). (D) Effect of erlotinib, PF or combination on mouse weight.

Mentions: Treatment with erlotinib or PF alone induced significant growth delay of the BxPC-3 xenografted tumor compared to untreated controls, as shown in the Fig. 4A,B. The tumor weight was reduced by 46.0% and 32.15% in the PF-treated and erlotinib-treated groups, respectively. The combination drastically and effectively suppressed tumor growth compared to either drug alone with the tumor weight being reduced by 61.46% (P < 0.001 for both). Next, phosphorylation of ErbB3 in tumor xenografts was assessed. Consistent with the in vitro observations, p-ErbB3 was reduced by PF treatment. Furthermore, the combination of PF and erlotinib led to a more drastic reduction of p-ErbB3 compared to either drug alone (Fig. 4C).


Paeoniflorin Potentiates the Inhibitory Effects of Erlotinib in Pancreatic Cancer Cell Lines by Reducing ErbB3 Phosphorylation
PF Augmented in Vivo Therapeutic Effects of Erlotinib on the BxPC-3 Transplanted Tumors.(A) Representative image of excised tumors (B) Effects of erlotinib, PF or Combination treatment on tumor volume and weight. The volume curve shows the change in tumor volume, and the left histogram shows the final tumor volume. On the 40th day, the implanted tumors were excised and weighted (right histogram). (C) Expression of phosphorylated ErbB3 in tumor tissues. Left, images are shown with phosphorylated ErbB3 positive areas (400×). (D) Effect of erlotinib, PF or combination on mouse weight.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5016851&req=5

f4: PF Augmented in Vivo Therapeutic Effects of Erlotinib on the BxPC-3 Transplanted Tumors.(A) Representative image of excised tumors (B) Effects of erlotinib, PF or Combination treatment on tumor volume and weight. The volume curve shows the change in tumor volume, and the left histogram shows the final tumor volume. On the 40th day, the implanted tumors were excised and weighted (right histogram). (C) Expression of phosphorylated ErbB3 in tumor tissues. Left, images are shown with phosphorylated ErbB3 positive areas (400×). (D) Effect of erlotinib, PF or combination on mouse weight.
Mentions: Treatment with erlotinib or PF alone induced significant growth delay of the BxPC-3 xenografted tumor compared to untreated controls, as shown in the Fig. 4A,B. The tumor weight was reduced by 46.0% and 32.15% in the PF-treated and erlotinib-treated groups, respectively. The combination drastically and effectively suppressed tumor growth compared to either drug alone with the tumor weight being reduced by 61.46% (P < 0.001 for both). Next, phosphorylation of ErbB3 in tumor xenografts was assessed. Consistent with the in vitro observations, p-ErbB3 was reduced by PF treatment. Furthermore, the combination of PF and erlotinib led to a more drastic reduction of p-ErbB3 compared to either drug alone (Fig. 4C).

View Article: PubMed Central - PubMed

ABSTRACT

Blockade of the epidermal growth factor receptor (EGFR) by EGFR tyrosine kinase inhibitors is insufficient for effective anti-tumor activity because the reactivation of the ErbB3 signaling pathway significantly contributes to activating the consequent phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. Combinatorial therapies including ErbB3 targeting may ameliorate tumor responses to anti-EGFR therapies. In the present study, we found that in BxPC-3 and L3.6pl cells, which highly expressed the ErbB3 receptor, significant reduction in cell viability, induction of apoptosis were observed when treated with a combination of erlotinib and PF compared to either agent alone. Moreover, in ErbB3-expressing BxPC-3, L3.6pl and S2VP10 cell lines, the inhibition of ErbB3/PI3K/Akt phosphorylation were observed when treated with PF. Most strikingly, both EGFR/MAPK/Erk and ErbB3/PI3K/Akt activitions were substantially suppressed when treated with the combination of PF and erlotinib. However, in the ErbB3-deficient cell line MIAPaCa-2, no such effects were observed with similar treatments. Most importantly, these in vitro results were replicated in nude mouse transplanted tumor models. Taken together, our findings show that PF enhances the effect of erlotinib in ErbB3-expressing pancreatic cancer cells by directly suppressing ErbB3 activation, and PF in combination with erlotinib is much more effective as an antitumor agent compared with either agent alone.

No MeSH data available.


Related in: MedlinePlus