Sodium Butyrate Combined with Docetaxel for the Treatment of Lung Adenocarcinoma A549 Cells by Targeting Gli1

Maojian Chen; Wei Jiang; Chanchan Xiao; Weiping Yang; Qinghong Qin; Anyun Mao; Qixing Tan; Bin Lian; Changyuan Wei

doi:10.2147/OTT.S252323

Sodium Butyrate Combined with Docetaxel for the Treatment of Lung Adenocarcinoma A549 Cells by Targeting Gli1

Onco Targets Ther. 2020 Sep 4:13:8861-8875. doi: 10.2147/OTT.S252323. eCollection 2020.

Authors

Maojian Chen^#¹, Wei Jiang^#², Chanchan Xiao³, Weiping Yang⁴, Qinghong Qin¹, Anyun Mao¹, Qixing Tan¹, Bin Lian¹, Changyuan Wei¹

Affiliations

¹ Department of Breast Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, People's Republic of China.
² Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, People's Republic of China.
³ Department of Microbiology and Immunology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, People's Republic of China.
⁴ Department of Ultrasound Diagnosis, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, People's Republic of China.

^# Contributed equally.

Abstract

Purpose: This study is aimed to investigate the combined treating efficacy of sodium butyrate and docetaxel on proliferation and apoptosis of the lung adenocarcinoma A549 cell line based on Gli1 regulation in vitro and in vivo.

Materials and methods: RNA interference method was used to overexpress Gli1 in A549 cells. Cells were treated with varying concentrations of sodium butyrate, docetaxel or both in combination. CCK-8, colony formation assay, Hoechst 33258 staining, flow cytometry and TUNEL assay were employed to detect proliferation, cell cycle and apoptosis. qRT-PCR and Western blot analysis were applied to detect the mRNA and protein expression of Gli1. In vivo tumorigenicity was detected by tumor transplantation in nude mice. Downstream protein levels of Gli1 were detected using Western blot assay.

Results: It was found that sodium butyrate or docetaxel alone, respectively, inhibited proliferation and promoted apoptosis of A549 cells in vitro and in vivo, while the combination of the two generated significantly higher responses, which were also effective in another lung adenocarcinoma cell line H1299. Furthermore, the combined therapy had an additive effect in suppressing Gli1 expression and regulating the expression of its downstream proteins that involve in proliferation, cell cycle and apoptosis of A549 cells in vitro and in vivo, including decreased protein expression of Ki-67, CDK1, CDK2, Cyclin D1, Bcl-2 and Survivin, and increased protein expression of Cyclin A, p21, Bax and cleaved-Caspase 3. On the other hand, Gli1 overexpression perceptibly reversed the above-mentioned additive effect in vitro and in vivo.

Conclusion: This study demonstrates that the combined therapy of sodium butyrate and docetaxel additively inhibits proliferation and promotes apoptosis of A549 lung adenocarcinoma cells via suppressing Gli1 expression in vitro and in vivo. Targeting Gli1 by the combined therapy may provide new insights into the therapeutic management of patients with lung adenocarcinoma.

Keywords: A549; Gli1; docetaxel; lung adenocarcinoma; sodium butyrate.

Grants and funding

This work was supported by the foundation of the National Natural Science Foundation of China (No. 81360396), the International Communication of Guangxi Medical University Graduate Education, the Science and Technology Infrastructure Project of Guangxi (No.15-235-05) and the Innovation Project of Guangxi Graduate Education (No. YCSW2017108).