Antrodin C, an NADPH Dependent Metabolism, Encourages Crosstalk between Autophagy and Apoptosis in Lung Carcinoma Cells by Use of an AMPK Inhibition-Independent Blockade of the Akt/mTOR Pathway.

Hairui Yang,Yanfang Liu,Zhendong Liu,Yingying Wu,Jingsong Zhang,Chuanhong Tang,Yan Yang,Wenhan Wang,Wei Jia,Henan Zhang,Xu Bai

doi:10.3390/molecules24050993

Abstract

The current study aims to explore the possible anti-lung carcinoma activity of ADC as well as the underlying mechanisms by which ADC exerts its actions in NSCLC. Findings showed that ADC potently inhibited the viability of SPCA-1, induced apoptosis triggered by ROS, and arrested the cell cycle at the G2/M phase via a P53 signaling pathway. Interestingly, phenomena such as autophagosomes accumulation, conversion of the LC3-I to LC3-II, etc., indicated that autophagy could be activated by ADC. The blockage of autophagy-augmented ADC induced inhibition of cell proliferation, while autophagy activation restored cell death, indicating that autophagy had a protective effect against cell death which was induced by ADC treatment. Meanwhile, ADC treatment suppressed both the Akt/mTOR and AMPK signaling pathways. The joint action of both ADC and the autophagy inhibitor significantly increased the death of SPCA-1. An in vitro phase I metabolic stability assay showed that ADC was highly metabolized in SD rat liver microsomes and moderately metabolized in human liver microsomes, which will assist in predicting the outcomes of clinical pharmacokinetics and toxicity studies. These findings imply that blocking the Akt/mTOR signaling pathway, which was independent of AMPK inhibition, could activate ADC-induced protective autophagy in non-small-cell lung cancer cells.

Highlights

According to the report, 1.8 million people globally are diagnosed with lung cancer, and 1.6 million people died from this cancer in 2012 [1]
Antrodin C (ADC) was incubated with SPCA-1 cells for 72 h, after which the cell proliferation rate was reduced in a dose-dependent manner (Figure 1A)
At a concentration of 300 μM, ADC treatment could lead to a 71.41% decrease in cell proliferation when compared with untreated cells

Summary

Introduction

1.8 million people globally are diagnosed with lung cancer, and 1.6 million people died from this cancer in 2012 [1]. The mortality of lung cancer ranks first and second among men and women, respectively [1]. Chemotherapy is one of the major treatments for cancer, it is known to have strong side effects [4]. Multi-drug resistance and dose limiting adverse reactions are the main reasons for the failure of chemotherapy in NSCLC [5]. Those from medicinal mushrooms, have been considered to have major potential in this field, due to their attractive anticancer effect and hypotoxicity [6,7,8]

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Results

Conclusion