Cordycepin enhances the chemosensitivity of esophageal cancer cells to cisplatin by inducing the activation of AMPK and suppressing the AKT signaling pathway

Ying Gao,Dan-Lei Chen,Jia-Xing Zhang,Sheng Huang,Zhou-San Zheng,Xiao-Zhong Liao,Mei-Fang He,Mi Zhou

doi:10.1038/s41419-020-03079-4

Abstract

Although cisplatin (cDDP), is a first-line chemotherapy drug for esophageal cancer, it still has the potential to develop drug resistance and side effects. There is increasing evidence that cordycepin can work synergistically with other chemotherapy drugs. Therefore, we investigated whether combination therapy of cordycepin and cDDP may enhance the therapeutic effect of cDDP. We performed a series of functional tests to study the effect of medical treatment on esophageal cancer cells. We then used GO analysis to examine the pathways affected by treatment with cordycepin and cDDP. Next, we observed changes in the abundance of the selected pathway proteins. The in vivo animal model supported the results of the in vitro experiments. Co-treatment with cordycepin and cDDP inhibited cell growth, migration, and metastasis, as well as induced apoptosis. Cordycepin was found to effectively enhance activation of AMPK and inhibited activity of AKT. In all treatment groups, the expression levels of p-PI3K, p-Akt, p-p70S6K, Caspase-3, and Bcl-2 were significantly reduced, while the expression levels of p-AMPK, cleaved Caspase-3, and Bax increased, and the total levels of Akt, PI3K, and p70S6K levels remained unchanged. Overall, cordycepin was found to enhance the chemical sensitivity of esophageal cancer cells to cisplatin by inducing AMPK activation and inhibiting the AKT signaling pathway. Combination therapy of cordycepin and cisplatin represent a novel potential treatment of esophageal cancer.

Highlights

Esophageal cancer is one of the most common types of cancer in the world[1], and only 20% of patients have esophageal cancer that can be treated with surgery
The results showed that cordycepin and cDDP (CI < 1) had a synergistic effect on esophageal cancer cell proliferation inhibition after 48 h of treatment (Fig. 2B, D, F, H)
We found that the protein expression levels of p-AMPK, cleaved Caspase-3, and Bax were upregulated in cells treated with monotherapy and combination therapy, while the levels of pPI3K, p-Akt, Caspase-3, and Bcl-2 were down-regulated, and the total Akt, PI3K and GAPDH levels remained unchanged

Summary

Introduction

Esophageal cancer is one of the most common types of cancer in the world[1], and only 20% of patients have esophageal cancer that can be treated with surgery. Cordycepin, a nucleoside analogue, is the main biologically active ingredient found, isolated, and purified in Cordyceps militaris. It has effects on several biological processes including regulation of the inflammatory response[3], platelet aggregation[4], and steroid production[5]. The main anti-cancer mechanism of cDDP is through its interaction with purine bases in DNA, leading to the formation of DNA-protein and DNA-DNA inter- and intra-strand cross-links that result in tumor cell proliferation inhibition and apoptosis[11]. The role of cDDP and cordycepin in combination therapy for treatment of esophageal cancer is largely unknown

Methods

Results

Conclusion