Inhibition of Non-Small Cell Lung Cancer Proliferation and Survival by Rosemary Extract Is Associated with Activation of ERK and AMPK

Eric J O’Neill,Evangelia Litsa Tsiani,Jessy Moore,Joon Song

doi:10.3390/life12010052

Abstract

Non-small cell lung cancer (NSCLC) represents an aggressive form of lung cancer which often develops resistance to chemo- and radiotherapy emphasizing a need to identify novel treatment agents to combat it. Many plants contain compounds with anti-inflammatory, antimicrobial, antidiabetic, and anticancer properties and some plant-derived chemicals are used in the treatment of cancer. A limited number of in vitro and in vivo animal studies provide evidence of anticancer effects of rosemary (Rosmarinus officinalis) extract (RE); however, no studies have explored its role in H1299 NSCLC cells, and its underlying mechanism(s) of action are not understood. The current study examined the effects of RE on H1299 cell proliferation, survival, and migration using specific assays. Additionally, immunoblotting was used to investigate the effects of RE treatment on signalling molecules implicated in cell growth and survival. Treatment with RE dose-dependently inhibited H1299 proliferation with an IC50 value of 19 µg/mL. Similarly, RE dose-dependently reduced cell survival, and this reduction correlated with increased levels of cleaved poly (ADP-ribose) polymerase (PARP), a marker of apoptosis. RE was also able to inhibit cell migration as assessed with a wound healing assay. These cellular effects of RE were associated with an increase in phosphorylated levels of extracellular signal-regulated kinase (ERK), AMP-activated protein kinase (AMPK), and its downstream targets ACC, the mTORC1 protein raptor, and decreased p70S6K phosphorylation. More studies are required to fully examine the effects of RE against NSCLC.

Highlights

Lung cancer was the leading cause of cancer-related death in 2020, and non-small cell lung cancer (NSCLC) accounts for 80–85% of all lung cancer cases in North America [1,2].NSCLC is very aggressive with fewer than 20% of diagnosed individuals surviving five years despite the use of aggressive chemo- and radiation therapies [2]
Downstream of AMPK, acetyl CoA carboxylase (ACC) phosphorylation/inactivation increased with Rosemary extract (RE) treatment as did phosphorylation/inactivation of the mTOR complex 1 (mTORC1) protein raptor
MTORC1 inhibition was confirmed by decreased levels of phosphorylated p70 S6 kinase (p70 S6K). These data suggest that RE possesses significant anticancer properties and that the mechanism of action of RE may involve activation of extracellular signal-regulated kinase (ERK) and AMPK signalling, and inhibition of mTORC1 (Figure 10)

Summary

Introduction

Lung cancer was the leading cause of cancer-related death in 2020, and non-small cell lung cancer (NSCLC) accounts for 80–85% of all lung cancer cases in North America [1,2].NSCLC is very aggressive with fewer than 20% of diagnosed individuals surviving five years despite the use of aggressive chemo- and radiation therapies [2]. Many plants have been the source for isolation of compounds that are used in the treatment of cancer. Extracts of European (Taxus baccata) and pacific (Taxus brevifolia) yew are the sources of docetaxel and paclitaxel, which are common chemotherapeutic drugs used in the treatment of breast, lung, and ovarian cancers [3,4]. Rosemary extract (RE) has been shown to exhibit anticancer properties including inhibition of cancer cell proliferation and survival, and enhanced apoptotic activity in vitro and in vivo in colon, breast, prostate, and leukemic cancers, among others [5,6]. Foods/plants rich in polyphenols have promising chemotherapeutic potential and further investigation of polyphenol-rich plant extracts, such as rosemary, may lead to the discovery of molecules with potent anticancer properties and improve knowledge of their anticancer mechanisms

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