Stemness-Suppressive Effect of Bibenzyl from Dendrobium ellipsophyllum in Human Lung Cancer Stem-Like Cells.

Pornchanok Taweecheep,Anirut Hlosrichok,Pithi Chanvorachote,Boonchoo Sritularak,Chatchai Chaotham,Eakachai Prompetchara,Gea Abigail Uy Ecoy,Hnin Ei Ei Khine,Eun Jung Sohn

doi:10.1155/2021/5516655

Abstract

Cancer stem-like cells (CSCs) are key mediators driving tumor initiation, metastasis, therapeutic failure, and subsequent cancer relapse. Thus, targeting CSCs has recently emerged as a potential strategy to improve chemotherapy. In this study, the anticancer activity and stemness-regulating capacity of 4,5,4′-trihydroxy-3,3′-dimethoxybibenzyl (TDB), a bibenzyl extracted from Dendrobium ellipsophyllum, are revealed in CSCs of various human lung cancer cells. Culture with TDB (5–10 μM) strongly abolished tumor-initiating cells in lung cancer H460, H23, and A549 cells in both anchorage-dependent and anchorage-independent colony formation assays. Through the 3D single-spheroid formation model, attenuation of self-renewal capacity was observed in CSC-enriched populations treated with 1–10 μM TDB for 7 days. Flow cytometry analysis confirmed the attenuation of %cell overexpressing CD133, a CSC biomarker, in TDB-treated lung cancer spheroids. TDB at 5–10 μM remarkably suppressed regulatory signals of p-Akt/Akt, p-GSK3β/GSK3β, and β-catenin corresponding to the downregulated mRNA level of stemness transcription factors including Nanog, Oct4, and Sox2. Moreover, the antiapoptosis Bcl-2 and Mcl-1 proteins, which are downstream molecules of Akt signaling, were evidently decreased in CSC-enriched spheroids after culture with TDB (1–10 μM) for 24 h. Interestingly, the diminution of Akt expression by specific siAkt effectively reversed suppressive activity of TDB targeting on the CSC phenotype in human lung cancer cells. These findings provide promising evidence of the inhibitory effect of TDB against lung CSCs via suppression of Akt/GSK3β/β-catenin cascade and related proteins, which would facilitate the development of this bibenzyl natural compound as a novel CSC-targeted therapeutic approach for lung cancer treatment.

Highlights

Lung cancer has been recognized as one of the most common cancers worldwide, accounting for a large proportion of cancer deaths [1]
Primary antibodies specific to Akt, phosphorylated Akt (p-Akt) (Ser 473), GSK3β, phosphorylated GSK3β (p-GSK3β) (Ser 9), β-catenin, Bcl-2 (B-cell lymphoma 2), Mcl-1, GAPDH, and horseradish peroxidase (HRP) labeled secondary antibody were obtained from Cell Signaling Technology (Danvers, MA, USA)
After 24 h of treatment at 0–50 μM, TDB reduced viability in human lung cancer H460, H23, and A549 cells in a dosedependent manner (Figure 1(b)). e relatively nontoxic effect of TDB was noted at 1–5 μM, whereas a significant reduction of %cell viability was observed at 10–50 μM compared with the untreated control cells

Summary

Introduction

Lung cancer has been recognized as one of the most common cancers worldwide, accounting for a large proportion of cancer deaths [1]. Comprising approximately 80% of all cases, non-small-cell lung cancer (NSCLC) is the predominant type, the majority of which are diagnosed at an advanced or metastatic stage [2]. Despite the progress in cancer research, there is still a low five-year survival rate among lung cancer patients [3, 4]. Recurrence of tumor lesions resulting in high mortality rates indicates a failure of available therapeutic regimens for lung cancer [5, 6]. Chemotherapy, especially when combined with other remedies such as surgery or radiation, has been shown to offer a survival advantage to NSCLC patients [7, 8]. Key barriers in chemotherapy such as innate or developed chemoresistance and high incidence of cancer relapse after completion of therapeutic regimens have been consistently reported [9, 10]

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