Shenmai injection enhances cisplatin-induced apoptosis through regulation of Mfn2-dependent mitochondrial dynamics in lung adenocarcinoma A549/DDP cells.

Yushi Chen,Ye Sun,Chun Wang,Chunying Liu,Qiuyu Zhao

doi:10.20517/cdr.2021.94

Abstract

Aim: Chemoresistance is the biggest obstacle in cancer treatment. Our previous study demonstrated that Shenmai injection (SMI), a Chinese herbal medicine, enhanced the antitumor effect of cisplatin via glucose metabolism reprogramming. This study aimed to further determine whether the SMI sensitizes the non-small cell lung cancer (NSCLC) cells to cisplatin through regulation mitochondrial dynamics. Methods: The Kaplan-Meier Plotter database was used to investigate the relationship between mRNA expression of mitofusin-2 (Mfn2) and the survival analysis of NSCLC patients. The protein expression of Mfn2 in a lung adenocarcinoma tissue chip was detected by immunohistochemistry staining. The expression of Mfn2 and ATAD3A were compared between cisplatin-sensitive A549 and cisplatin-resistant A549/DDP cells. Additionally, A549/DDP cells were co-treated with cisplatin and SMI to detect mitochondrial morphology by fluorescent staining, apoptosis-related protein expression with Western blotting, and mitochondrial membrane potential (ΔΨm) with flow cytometry analysis. Results: The mean survival time of the Mfn2low group was significantly lower than that of the Mfn2high group by Kaplan-Meier Plotter database analysis, and the Mfn2 protein expression level was lower in cancer tissues than in adjacent tissues. The combination of SMI and cisplatin induced dynamic changes in A549/DDP cells, with increased mitochondrial fusion followed by upregulation of Mfn2 and downregulation of ATAD3A and reduced mitochondrial mass and ΔΨm. Moreover, SMI significantly enhanced cisplatin-induced A549/DDP apoptosis, upregulated Bax and the active subunit of caspase-3, and downregulated Bcl-2 expression, as shown via Hoechst staining and flow cytometry analysis. Conclusion: Our findings suggest SMI enhances cisplatin-induced apoptosis through regulation of Mfn2-dependent mitochondrial dynamics in cisplatin-resistant lung adenocarcinoma cells.

Highlights

Lung cancer is one of the most common malignancies worldwide and has become the leading cause of cancer-related mortality in China
The combination of Shenmai injection (SMI) and cisplatin induced dynamic changes in A549/DDP cells, with increased mitochondrial fusion followed by upregulation of Mfn2 and downregulation of ATAD3A and reduced mitochondrial mass and ΔΨm
Mfn2 was fed into the database, and the survival time of patients with lung adenocarcinoma was analyzed according to the hazard ratio (HR), 95% confidence interval (CI), and log-rank P-value shown in the main panel of the operating system

Summary

Introduction

Non-small cell lung cancer (NSCLC) accounts for approximately 80%85% of all lung cancers[1]. Shenmai injection (SMI), the watersoluble extract of Radix Ginseng Rubra and Radix Ophiopogonis, is derived from a well-known traditional Chinese formula, Shendong Yin, and approved by the China Food and Drug Administration as an injectable treatment[3]. Current clinical practice has shown that SMI is a valid alternative medicine for anti-tumor therapy and alleviates chemotherapy-induced side effects in NSCLC, breast cancer, and pancreatic cancer[7]. Experimental studies have demonstrated the mechanism of reversal of adriamycin and paclitaxel in colorectal cancers[8], as well as enhancing the antitumor effect of cisplatin via glucose metabolism reprogramming in lung adenocarcinoma A549/DDP cells as detected by our previous study[9]

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