Yang-Yin-Jie-Du decoction overcomes gefitinib resistance in non-small cell lung cancer via down-regulation of the PI3K/Akt signalling pathway

Abstract

Context

Yang-Yin-Jie-Du Decoction (YYJDD) was used to improve gefitinib efficacy in our clinical practice, but its mechanism remains unclear.

Objective

This study explored if YYJDD could reverse gefitinib resistance.

Materials and methods

H1975 cells were exposed to control, 10 μM gefitinib, 3.2 mg/mL YYJDD or combination treatment. Cell viability was detected by MTT during 0–96 h. Apoptosis and the PI3K/Akt proteins were tested by flow cytometry and western-blot at 24 h. LY294002 was applied to further determine the role of the PI3K/Akt. 23 BALB/c nude xenograft mice received normal saline (n = 5), 80 mg/kg gefitinib (n = 6), 2.35 g/kg lyophilised powder of YYJDD (n = 6) or combination treatment (n = 6) by gavage for 4 weeks and submitted to TUNEL, immunohistochemistry, and western-blot.

Results

In vitro, gefitinib (IC₅₀: 20.68 ± 2.06 μM) and YYJDD (IC₅₀: 6.6 ± 0.21 mg/mL) acted in a moderate synergistic way. Combination treatment inhibited cell viability from 100% to 25.66%. Compared to gefitinb (33.23 ± 3.99%), cell apoptosis was increased with combination treatment (54.11 ± 7.32%), accompanied by down-regulation of the PI3K/Akt. LY294002 further inhibited cell viability, increased apoptosis, and down-regulated p-Akt/Akt. In vivo, the tumour sizes in the combination group (1165.13 ± 157.79 mm³) were smaller than gefitinib alone (1630.66 ± 208.30 mm³). The positive rate of TUNEL staining was increased by combination treatment (22.33 ± 2.75%) versus gefitinib (7.37 ± 0.87%), while the PI3K/Akt was down-regulated.

Discussion and conclusion

YYJDD has potential to overcome gefitinib resistance. Future investigations should be focussed on its specific targets.

Keywords:

• Chinese herbal medicine
• epidermal growth factor receptor-tyrosine kinase inhibitor
• lung neoplasm
• drug-resistant

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data that support the findings of this study are available on reasonable request from the corresponding author.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China under Grant [number: 81704013]; Clinical (gastric cancer) Cooperation Pilot Project of Chinese and Western Medicine for Major and Difficult Diseases; The Key Research and Development Projects of Science and Technology Department of Zhejiang Province under Grant [number: 2015C03G2120026]; and Zhejiang Traditional Chinese Medicine of Science and Technology Program under Grant [number: 2020ZA053].