Xiaoaiping injection combined with gefitinib inhibits resistant non-small cell lung cancer xenografts H460 and H1975
10.3867/j.issn.1000-3002.2016.01.007
- VernacularTitle:消癌平注射液联合吉非替尼对耐药非小细胞肺癌H460和H1975裸鼠移植瘤的抑制作用
- Author:
Shuyan HAN
;
Wenxian ZHENG
;
Xiran HE
;
Can ZHAO
;
Shantong JIANG
;
Lina PANG
;
Xiaohong LI
;
Pingping LI
- Publication Type:Journal Article
- Keywords:
Xiaoaiping injection;
geftinib;
non-small cell lung cancer;
neoplasm transplantation
- From:
Chinese Journal of Pharmacology and Toxicology
2016;(1):44-52
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE To study the antitumor activity and underlying mechanisms of Xiaoaiping injection(Xap)combined with gefitinib(Gef)in nude mice bearing resistant non-small cell lung cancer (NSCLC) cells H460 or H975. METHODS BALB/c nude mice were inoculated with human NSLCL cells H460 or H1975 and the drug treatment did not start until the tumor volume reached 50-100 mm3. The tumor bearing mice were divided into four groups:control group,Xap group(5 g · kg-1,ip),Gef group (50 mg · kg-1,ig),and Xap plus Gef group. All the administration lasted for 21 d continuous. Tumor volumes were measured two or three times per week,and the body weight of animals was re-corded. At the end of the test,tumors were weighed after the sacrifice of mice. Tumor inhibition rate and relative tumor proliferation rate were calculated based on tumor weight and tumor volume. The related biomarkers and proteins in tumor tissues were detected by immunohistochemistry and Western blot assay, respectively. RESULTS Compared with the control group,no significant effect was observed on the growth of H460 and H1975 xenografts in groups of Xap or Gef alone in nude mice. However,the two-drug combination significantly suppressed tumor volume,with (1103 ± 340) versus (3020 ± 450) mm3 for H460 and(487 ± 153)versus(1269 ± 161)mm3 for H1975,respectively(P<0.05). The combined Xap and Gef application also significantly reduced the tumor weight,with(1.20±0.52)versus(2.78± 0.93)g for H460 and(0.52 ± 0.32)versus(0.92 ± 0.42)g for H1975,respectively(P<0.05). The relative tumor proliferation rate and inhibition rate in the combination group was 42.1%and 43.5%for H460(P<0.01),43.0%and 52.5% for H1975(P<0.01). Compared with Xap and Gef drug alone,their combination showed significant difference in reducing tumor weight,suppressing tumor proliferation rate and increasing tumor inhibition rate(P<0.05). Immunohistochemistry results showed that each drug alone had no effect on tumor angiogenesis markers of vascular endothelial growth factor(VEGF)and CD105 expression,or on drug resistance related proteins of p-ERK,p-Akt and p-mTOR,whereas the combination of Xap and Gef obviously reduced the expression of these biomarkers in H460 and H1975 tumor tissues. The decreased drug resistance related proteins of p-PI3K and its downstream molecules p-Akt,p-ERK and p-mTOR by the two-drug combination were also confirmed by Western blot results(P<0.01,compared with control), and showed significant difference compared with each single treatment(P<0.05). CONCLUSION The addition of Xap significantly improves the antitumor activity of Gef in H460 and H1975 xenografts,and this synergistic effect may be ascribed to the inhibition of tumor angiogenesis,the down-regulation of PI3K and its downstream signaling molecules which are associated with drug resistance.
