Elsevier

Food and Chemical Toxicology

Volume 58, August 2013, Pages 459-466
Food and Chemical Toxicology

Feruloyl-l-arabinose attenuates migration, invasion and production of reactive oxygen species in H1299 lung cancer cells

https://doi.org/10.1016/j.fct.2013.05.019Get rights and content

Highlights

  • Ferulic acid (FAA) exerts good water solubility and an antioxidant effect.

  • FAA reduces intracellular reactive oxygen species (ROS) effectively.

  • FAA attenuates the migration of lung cancer cells without inducing cytotoxicity.

Abstract

Ferulic acid (FA), a phenolic compound, is an abundant dietary antioxidant and exerts the mitogenic effect on cells. Recently, we isolated an active FA derivative, namely feruloyl-l-arabinose (FAA), from coba husk. The aim of this study was to investigate the effects of FAA on the proliferation, migration and invasion of H1299 human lung cancer cells. Our results showed a strong antioxidant potential of FAA. Additionally, FAA inhibited the migration and invasion ability, while causing a significant accumulation of G2/M-population, of H1299 tumor cells in a dose-dependent manner, whereas no significant change on cell proliferation was observed. Results from the wound healing assay revealed that cell migration ability was markedly inhibited by FAA treatments. Similarly, results of gelatin zymography study showed that FAA treatments significantly decreased the activities of matrix metalloproteinase (MMP)-2 and MMP-9, suggesting that FAA-mediated inhibition on migration and invasion of lung cancer cells may be achieved by the down-regulation of the MMPs activities. Taken together, our present work provides a new insight into the novel inhibitory function of FAA on cell migration in H1299 cells, suggesting its promising role in the chemoprevention of lung cancer.

Introduction

Lung cancer is the leading cause of death in the world. The human non-small cell lung cancer (NSCLC) accounts for 80–85% of lung cancer cases. More than one of three patients with NSCLC is surgically unavailable (Pirker and Minar, 2010). Until now, chemotherapy is still the major approach in clinical NSCLC treatment (Ettinger et al., 2010, O’Rourke et al., 2010, Pirker and Minar, 2010, Wagner and Yang, 2010). Despite the continuing efforts on improving the current therapies and developing new regimens to treat lung cancers, both poor prognosis at the advanced stage of NSCLC and chemotherapeutic resistance contribute to the low survival rate of NSCLC patients (Wagner and Yang, 2010). Nowadays, numerous anticancer agents derived from natural products (Chiu et al., 2011, Liu, 2011, Wang and Yi, 2008) have been shown to exhibit improved chemopreventive effects against lung cancer, and this may shed the light on the efficacy of lung cancer therapy.

Ferulic acid (FA), or 4-hydroxy-3-methoxycinnamic acid (Fig. 1A), is an abundant aromatic natural constituent found in plant cell walls (Buanafina et al., 2010, Srinivasan et al., 2007). FA is known to exert potent effects on scavenging reactive oxygen species (ROS) and inhibiting lipid peroxidation, and thus has been approved as food additive to prevent lipid peroxidation in certain countries (Srinivasan et al., 2007). Recently, water-soluble FA sugar esters from wheat bran had been reported to stimulate the growth of Bifidobacterium bifidum (Yuan et al., 2005a), and effectively protect normal rat erythrocytes against AAPH-induced oxidative damage (Yuan et al., 2005b). In in vitro studies, water-soluble FA sugar esters were found to possess effective antioxidant activity towards low-density lipoproteins oxidation and exhibit better scavenging activity on 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radicals than FA (Ohta et al., 1997). In addition, water-soluble FA sugar esters exhibited protection capacity against oxidative damage due to diabetes (Ou et al., 2007). Additionally, the major site of FA absorption is the colon, free FA and feruloyl-glucuronide could be efficiently transported through an in vitro model for the colonic epithelium consisting of co-cultured Caco-2 and mucus-producing HT29-MTX cells (Poquet et al., 2008). Based on these observations, FA and water soluble FA sugar esters demonstrated potential to be used as food additive for atherosclerosis prevention or other applications involving its antioxidant capacity.

Previous studies have shown that FA exhibited anti-proliferative effects on colon cancer cells (Janicke et al., 2011, Jayaprakasam et al., 2006), increased the radiosensitizing effects on cervical cancer cells (Karthikeyan et al., 2011) and showed the protective effects against chemical-induced DNA damages and/or carcinogenesis in various model systems (Stagos et al., 2005, Tanaka et al., 1993). In another study however, FA was shown to enhance proliferation of MCF7 and BT20 human breast cancer cells (Chang et al., 2006), indicating the possibility that FA might exhibit different biological effects depending upon cancer cell types it interacts with. However, the antioxidant activity of identified FA sugar esters in a cell model has not yet to be reported. Although FA and its various derivatives have been shown to exhibit the antioxidant effects in vitro and in vivo, they seem to possess diverse pharmacological functions, with some of which still remaining unknown. Therefore, the roles of FA derivatives in cancer cells remained to be fully investigated. To date, studies performed to investigate the direct effects of FA and its derivatives on lung cancer cells have been limited.

In the current study, we purified a FA derivative, feruloyl-l-arabinose (FAA) (Fig. 1B) from coba husk of plant Zizania latifolia, and examined its antioxidant ability on the lung cancer H1299 cell line as many cancers are known to possess elevated ROS levels that enhance their mobility, invasiveness and metastatic capabilities. H1299 cell is a large cell carcinoma, one subtype of non-small cell lung cancer cells, and has been reported to exhibit a high invasiveness compared to other lung cancer cells (Seo et al., 2009, Shatz et al., 2010). We hypothesized that FAA possesses anti-oxidant properties, causing the reduction of intracellular ROS that leads to decreased proliferation, altered cell cycle and reduced mobility in H1299 lung cancer cells. In addition, other effects of FAA, such as the scavenging ability of endogenous ROS, and influence on cellular invasion and proliferatory capacities, on H1299 cells were also examined.

Section snippets

Preparation of FAA

Zizania latifolia coba husk was collected from local farm in Pu-Li, Taiwan. After washed and oven-dried at 60 °C for overnight, samples were milled and passed through a 0.5 mm sieve. Samples were defatted immediately using n-hexane with the Soxhlet apparatus. The dry defatted sample was then used for insoluble dietary fiber (IDF) preparation according to a previously published protocol (Bunzel et al., 2001). The mixtures of phenolic acid sugar esters were prepared from IDF of coba husk by

Radical-scavenging activity of FAA

To evaluate the radical scavenging activity of FAA, the DPPH assay was performed. The antioxidant activity of FAA was measured by assessing the capacity of FAA to scavenge DPPH. The absorbance in solution decreases upon accepting hydrogen atoms from an antioxidant. As shown in Fig. 2B and Supplementary Fig. 2, all concentrations (0.01, 0.03, 0.06, 0.15, 0.3 and 0.6 mM) of FA and FAA tested exhibited significant radical-scavenging activity as compared with the blank control. In addition, higher

Discussion

In our current study, we investigated the ability of FAA, an active FA derivative, to affect migration of lung cancer H1299 cells. Many chemopreventive and anti-cancer agents suffer from poor water-solubility, and therefore their further development in clinical therapeutics is limited. Similarly, the poor water solubility of FA (Maegawa et al., 2007), like other polyphenolic compounds, leads to its reduced bioavailability and may pose practical difficulties in its potential pharmacological

Conflict of Interest

The authors declare that there is no conflict of interest.

Acknowledgements

This work was supported by the grants from ChiMei-KMU Joint Research Project (101-CM-KMU-11), Kaohsiung Medical University, Taiwan (M098007), Kaohsiung Medical University Research Foundation (KMUER-004), NSYSU-KMU Joint Research Project (NSYSUKMU 101-01, 101-14 and 102-28) and the National Science Council, Taiwan (NSC101-2313-B-037-001, NSC101-2622-B-037-002-CC3, NSC101-2320-B-037-046-MY3 and NSC101-2313-B-037-002).

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