Shenmai Injection Supresses Glycolysis and Enhances Cisplatin Cytotoxicity in Cisplatin-Resistant A549/DDP Cells via the AKT-mTOR-c-Myc Signaling Pathway.

Ye Sun,Chun Wang,Yushi Chen,Hai Shang,Chunying Liu,Ming Xu

doi:10.1155/2020/9243681

Abstract

Tumor cells, especially drug-resistant cells, predominately support growth by glycolysis even under the condition of adequate oxygen, which is known as the Warburg effect. Glucose metabolism reprogramming is one of the main factors causing tumor resistance. Previous studies on Shenmai injection (SMI), a Chinese herbal medicine, have shown enhanced efficacy in the treatment of tumors in combination with chemotherapy drugs, but the mechanism is not clear. In this study, we investigated the effect of SMI combined with cisplatin on cisplatin-resistant lung adenocarcinoma A549/DDP cells. Our results showed that cisplatin-resistant A549/DDP cells exhibited increased glucose consumption, lactate production, and expression levels of key glycolytic enzymes, including hexokinase 2 (HK2), pyruvate kinase M1/2 (PKM1/2), pyruvate kinase M2 (PKM2), glucose transporter 1 (GLUT1), and lactate dehydrogenase A (LDHA), compared with cisplatin-sensitive A549 cells. SMI combined with cisplatin in A549/DDP cells, led to significantly lower expression levels of key glycolytic enzymes, such as HK2, PKM1/2, GLUT1, and pyruvate dehydrogenase (PDH). In addition, we found that the combination of SMI and cisplatin could inhibit cell proliferation and promote apoptosis by reducing the expression levels of p-Akt, p-mTOR, and c-Myc, and then, it reduced the glycolysis level. These results suggest that SMI enhances the antitumor effect of cisplatin via glucose metabolism reprogramming. Therefore, the combination of SMI and cisplatin may be a potential therapeutic strategy to treat cisplatin-resistant nonsmall cell lung cancer.

Highlights

The antitumor activities of cisplatin, such as induction of DNA damage and mitochondrial apoptosis, have been widely used in chemotherapy for many kinds of tumors, especially for advanced lung cancer [1]
We first evaluated the difference in glycolysis metabolism between cisplatin sensitive cells and cisplatin-resistant cells (A549/DDP cells), and subsequently, we explored the antitumor mechanism of Shenmai injection (SMI) in reversing cisplatin resistance in A549/DDP cells
We assessed the level of glucose metabolism, as shown in Figure 1(b); glucose consumption in A549/DDP cells was increased compared with that in A549 cells (P < 0:05)

Summary

Introduction

The antitumor activities of cisplatin, such as induction of DNA damage and mitochondrial apoptosis, have been widely used in chemotherapy for many kinds of tumors, especially for advanced lung cancer [1]. Shenmai injection (SMI) is derived from Shengmai San, the well-known Chinese medicine prescription, which consists of Radix Ginseng Rubra and Radix Ophiopogonis [4]. SMI is used to improve myocardial function and enhance immunity; recently, it has been found to increase the therapeutic effect combined with chemotherapy drugs in antitumor treatment [5, 6]. Liu reported that SMI enhances the cytotoxicity of chemotherapy drugs against colorectal cancer by improving the distribution of drugs in cells [7]. SMI has an obvious inhibitory effect on various tumors in mice, which effectively prolongs the survival time

Methods

Results

Conclusion