Linalool Prevents Cisplatin Induced Muscle Atrophy by Regulating IGF-1/Akt/FoxO Pathway.

Linlin Chen,Cheng Guo,Lili Wan,Xipeng Sun,Hong Zhang,Quanjun Yang,Mengyi Chi

doi:10.3389/fphar.2020.598166

Abstract

Skeletal muscle atrophy is an important feature of cancer cachexia, which can be induced by chemotherapy, and affects the survival and quality of life of cancer patients seriously. No specific drugs for cancer cachexia have been applied in clinical practice. This study explored the therapeutic effect of linalool (LIN) on cisplatin (DDP) induced skeletal muscle atrophy. In vivo, LIN can improve skeletal muscle weight loss, anorexia, muscle strength decline and other cachexia symptoms caused by cisplatin treatment in a Lewis lung cancer tumor bearing mouse model, and cause no adverse effects on the anti-tumour effect. LIN treatment decreased the expression of muscle RING-finger protein-1 (MuRF1) and Atrogin1(MAFbx) in muscle, and the activation of insulin-like growth factor-1 (IGF-1)/protein kinase B (Akt)/forkhead box O (FoxO) pathway was observed. In vitro, LIN alleviated DDP induced C2C12 myotube atrophy, and IGF-1 receptor inhibitor Picropodophyllin (PIC), which had no adverse effect on C2C12 myotube cells, could reverse the protective effect of LIN. These results indicate that LIN down-regulates the expression of Atrogin1 and MuRF1 through the IGF-1/Akt/FoxO pathway, alleviating DDP-induced muscle atrophy and improving cachexia symptoms. LIN has the potential to be developed as a drug against cancer cachexia.

Highlights

Linalool (LIN, C10H18O, molecular weight: 154.25 g mol−1) is a monoterpene with multiple pharmacological effects and is derived from many fruits, aromatic plants and Chinese herbal medicines, such as Citrus reticulata peel, Linderae Radix and Amomum aurantiacum
In order to explore the effect of LIN on Lewis Lung cancer (LLC) tumor bearing mice treated with DDP, 5-week-old C57BL/6 mice were treated with DDP (4 mg kg−1·3 days−1, i. p.) and divided into groups treated with LIN (5, 20 mg kg−1 d−1, i. p.) for 12 days (Figure 1A)
The tumor size in the group receiving DDP treatment was smaller than that in the Group LLC significantly, and there was no significant difference in the tumor size between the groups receiving LIN treatment and Group LLC + DDP (Figure 1C)

Summary

Introduction

Linalool (LIN, C10H18O, molecular weight: 154.25 g mol−1) is a monoterpene with multiple pharmacological effects and is derived from many fruits, aromatic plants and Chinese herbal medicines, such as Citrus reticulata peel, Linderae Radix and Amomum aurantiacum. LIN has an inhibitory effect on colon cancer, glioma and liver cancer cells (Iwasaki et al, 2016; Cheng et al, 2017; Rodenak-Kladniew et al, 2018) and can enhance the curative effect of anthracyclines in the treatment of breast cancer (Ravizza et al, 2008). LIN has anti-inflammatory effects (Huo et al, 2013; Kim et al, 2019), inhibiting inflammation of the respiratory tract, and can reduce inflammation-related pain (Berliocchi et al, 2009). LIN can protect nerves and reduce cerebral ischemic injury (Park et al, 2016; Sabogal-Guáqueta et al, 2019). Clinical studies have shown that patients with lung cancer will experience weight loss, BMI decrease, and sarcopenia after chemotherapy

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