J Cancer 2019; 10(26):6666-6672. doi:10.7150/jca.30361

Research Paper

The Effects and Mechanisms by which Saikosaponin-D Enhances the Sensitivity of Human Non-small Cell Lung Cancer Cells to Gefitinib

Jian-cai Tang1, Feng Long2, Jia Zhao3, Jia Hang3, Yong-gang Ren1, Jian-ye Chen1✉, Bo Mu1✉

1. Department of Biochemistry, North of Si Chuan Medical College, Nan Chong, Si Chuan, China;
2. Department of Pharmacy, Nan Chong Central Hospital, Nan Chong, Si Chuan, China;
3. School of Pharmacy, North of Si Chuan Medical College, Nan Chong, Si Chuan, China.

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Citation:
Tang Jc, Long F, Zhao J, Hang J, Ren Yg, Chen Jy, Mu B. The Effects and Mechanisms by which Saikosaponin-D Enhances the Sensitivity of Human Non-small Cell Lung Cancer Cells to Gefitinib. J Cancer 2019; 10(26):6666-6672. doi:10.7150/jca.30361. Available from http://www.jcancer.org/v10p6666.htm

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Abstract

Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)-sensitive mutations benefit from epidermal growth factor receptor tyrosine kinase inhibitors (EGFR- TKIs). However, drug resistance is a major cause of therapeutic failure. This study examined whether saikosaponin-d (SSD) enhances the anti-tumor effect of gefitinib in NSCLC cells. Cell Counting Kit-8 (CCK-8) was used to determine cell viability. Cell apoptosis was examined by flow cytometry. Signal transducer and activator of transcription (STAT3), phosphor-STAT3 (P-STAT3), and B-cell lymphoma 2 (Bcl-2) were detected by Western blot. An HCC827/GR tumor model was established to observe the effect of combination therapy in vivo. The combination of SSD with gefitinib had an enhanced inhibitory effect by reducing cell viability and inducing cells apoptosis in NSCLC cells. Furthermore, SSD decreased and increased the expression of P-STAT3 and Bcl-2, respectively. Down-regulated STAT3 promoted the sensitivity of lung cancer cells to gefitinib. The results of animal experiments also showed that SSD enhanced the anti-tumor effect of gefitinib. These results indicated that the combination of SSD with gefitinib had an increased antitumor effect in NSCLC cells and that the molecular mechanisms were associated with the inhibition of STAT3/Bcl-2 signaling pathway. Our findings suggest a promising approach for the treatment of NSCLC patients with EGFR-TKI resistance.

Keywords: Saikosaponin-d, gefitinib resistance, STAT3, Bcl-2