Aloe-emodin (AE) nanoparticles suppresses proliferation and induces apoptosis in human lung squamous carcinoma via ROS generation in vitro and in vivo

https://doi.org/10.1016/j.bbrc.2017.06.084 Get rights and content

Highlights

  • Aloe-emodin nanoparticles (NanoAE) displayed significant anti-tumor effect in lung squamous carcinoma.

  • NanoAE inhibited cell proliferation and induced apoptosis in squamous carcinoma cells.

  • NanoAE up-regulated ROS levels in apoptosis and cell proliferation process.

  • NanoAE suppresses the growth of human squamous carcinoma mice in vivo.

Abstract

Human lung squamous cell carcinoma is a deadly cancer for which present therapeutic strategies are inadequate. And traditional chemotherapy results in severe systemic toxicity. Compounds from living organisms often exert a biological activity, triggering several targets, which may be useful for the improvement of novel pharmaceuticals. Aloe-emodin (AE), a well-known natural compound, is a primary component of anthraquinones in Aloe vera and exhibits anti-proliferative and apoptotic effects on various tumor cells. However, the translational and clinical use of AE has been limited owing to its rapid degradation and poor bioavailability. To improve its efficacy, a poly (lactic-co-glycolic acid) based AE nanoparticle formulation (NanoAE) was prepared. Our study indicated that compared to the free AE, nanoAE significantly suppressed cancer cell proliferation, induced cell cycle arrest and apoptosis, evidenced by high cleavage of Caspase-3, poly (ADP-ribose) polymerase (PARP), Caspase-8 and Caspase-9. NanoAE enhanced reactive oxygen species (ROS) production, along with Mitogen-activated protein kinases (MAPKs) activation and PI3K/AKT inactivation. Cell proliferation, apoptosis and MAPKs and PI3K/AKT were dependent on ROS production in nanoAE-treated groups. In vivo, nanoAE exhibited inhibitory effects on the tumor growth with little toxicity. Together, our results indicated that nanoAE might be an effective treatment for human lung squamous cell carcinoma.

Introduction

Lung squamous cell carcinoma (SCC) is a common type of non-small-cell lung cancer (NSCLC) and the second leading cause of death associated with lung cancer [1], [2]. There are not yet any approved targeted therapies for SCC and few advances have resulted in better therapeutic options for SCC [3]. Thus, finding effective therapeutic strategy is urgently necessary for preventing SCC.

Aloe-emodin (AE, 1,8-dihydroxy-3-hydroxymethyl-anthraquinone) is a bioactive anthraquinone, derived from both Aloe vera and Rheum officinale, and recently has been suggested to have various pharmacological activities [4]. AE has attracted much attention for its remarkable antineoplastic activity on different tumor cells, including lung, hepatic and colon cancers, through multi-channel molecular mechanisms, such as the induction of apoptosis, disruption of cell cycle, anti-metastasis, and enhancement of immune function [5], [6]. However, the toxicity, pharmacokinetic behavior, and molecular mechanisms of this drug have not been fully understood so far. Additionally, AE plays as a sensitizer for chemotherapy and radiation in cancer therapy [7]. Unfortunately, due to its hydrophobic property, it is not convenient to carry out intravascular administration of AE, exhibiting poor pharmacokinetics, low bioavailability and bad absorption [8]. Hence, looking for effective methods to attenuate these limitations is required for obtaining better efficacy of AE for cancer treatment.

Recently, novel drug delivery systems have shown superior advances in improving drugs' efficacy as well as patients' compliance [9]. Nanoparticle technology supplies an effective method to deliver anti-cancer drugs into tumors [10]. To circumvent AE's inherent issues, AE nanoparticles formulation (NanoAE) were prepared according to poly (lactic-co-glycolic acid) (PLGA). The formulation has been suggested to be effective for improving therapeutic effects in cancer cells [11]. Here, we attempted to implement nanoAE formulation to obtain improved anti-cancerous effects on SCC. We found that nanoAE effectively suppressed the growth of SCC cells, arrested cell cycle in the G1/S and G2/M transition phase, triggered apoptosis, associated with elevated ROS generation. NanoAE might be a beneficial treatment for the overall management of SCC.

Section snippets

Cells culture

Human SCC cell lines of H520, H226, SK-MES-1 and H1299, as well as human bronchial epithelial cell of BEAS-2B were all obtained from American Type Culture Collection (ATCC, USA) and maintained in RPMI-1640 or DMEM medium (Gibco, USA) with 10% fetal bovine serum in a humidified CO2 incubator under 5% CO2 for further study.

Cell viability analysis

2 × 104 cells/well were seeded on plates and incubated at 37 °C overnight under an atmosphere of 95% air and 5% CO2, and treated with various concentration of nanoAE for 24 h.

The preparation of aloe-emodin nanoparticles (NanoAE) and its effects on the cell proliferation of human lung squamous carcinoma

In order to calculate the AE's role in preventing human lung squamous carcinoma, the AE nanoparticles were formulated (NanoAE), which was based on PLGA (Fig. 1A). The transmission electron microscopy (TEM) was used to observe the morphology of AE nanoparticles (Fig. 1B). The particle size distribution of freshly-prepared nanoAE was 42 nm, which revealed the narrow particle size distribution of nanoAE (Fig. 1C). As shown in Fig. 1D, the zeta potential of nanoparticles was −21.2 mv. Fluorescent

Discussion

Conventional cytotoxic chemotherapy and radiation therapy to patients with squamous non-small-cell lung cancer are limited due to eventual development of systemic toxicity and drug resistance [5]. Thus, it is required to implement biologically safe and effective natural components as anti-tumor and chemo-preventive drugs, widely applied in human. Aloe-emodin (AE) is a novel anthraquinone compound, derived from traditional Chinese medicine plants, and has been suggested to have anticancer

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