Molecular and cellular pharmacologyThe effects of caffeic, coumaric and ferulic acids on proliferation, superoxide production, adhesion and migration of human tumor cells in vitro
Introduction
Reactive oxygen species (ROS) are usually known as cytotoxic, mutagenic and linked to tumor progression. Reactive oxygen species are well-known mediators of various biological responses. Recently, new homologs of the catalytic subunit of NADPH oxidase have been discovered in non-phagocytic cells. These new homologs (Nox1–Nox5) produce low levels of superoxides compared to the phagocytic homolog Nox2/gp91phox (Sadok et al., 2008). Most anticancer drugs kill their target cells, at least in part, through the generation of elevated amounts of intracellular reactive oxygen species (Benhar et al., 2001, Jackson and Loeb, 2001, Tobiume et al., 2001). Redox homeostasis of the cell is greatly dependent on prooxidant and antioxidant enzymes. Reactive oxygen species, such as superoxide anions () and hydrogen peroxide (H2O2) are produced by mitochondria, peroxisome, cytochrome P-450 and NADPH oxidase (D'Autreaux and Toledano, 2007) and have been shown to play a role in proliferation, apoptosis, differentiation and migration (Abid et al., 2000, Finkel, 1999). The acquisition of cell motility and the capacity to invade basement membranes and adjacent tissues plays a central role in the complex multistep process of metastasis. Cell migration results in dynamic interactions between the cell, the extracellular matrix (ECM) and the cytoskeleton. These interactions are partly mediated by integrins, a family of cell surface adhesion receptors composed by the non covalent association of α and β subunits (Humphries, 2000). Integrins connect the ECM proteins outside to the actin cytoskeleton within the cell, allowing the traction required for cell migration (Geiger et al., 2001, Small et al., 1999). In addition to regulating cell adhesion, integrins relay molecular cues regarding the cellular environment that influence cell shape, survival, proliferation and gene transcription. Integrins therefore play a pivotal role during tumor progression (Hood and Cheresh, 2002, Parise et al., 2000). Currently, the search for biological antitumor agents from plants has revealed many molecules that block the growth, progression, and spread of cancer. As cancer treatments generally being preventive rather than curative (Lemjabbar-Alaoui et al., 2015), we looked for molecules that could intervene to prevent the spread of a tumorigenisation process already started by inhibiting or reducing the adhesion and migration of cancer cells as they are two early stages participating in the spread of a tumor. The present study shows, for the first time to our knowledge, that caffeic, coumaric and ferulic acids are potent inhibitors of superoxide anion and act by influencing the adhesion and migration of human lung (A549) and colon (HT29-D4) cancer cell lines, two preliminary steps to the tumor spread, as colorectal and lung cancers were the most common causes of cancer death in Europe for more than 50% of all cancer incidence and mortality (Znaor et al., 2013).
Section snippets
Chemicals and reagents
The phenolic acids, caffeic, ferulic and p-coumaric acids were purchased from Extrasynthèse (Genay, France) unless otherwise noted and were of the highest available purity. All phenolic acids were dissolved in DMSO first and then diluted with buffer (1:199, v/v).
Dulbecco's modified Eagle’s medium (DMEM) and RPMI 1640 medium were purchased from Lonza (Levallois- Perret, France). Penicillin and streptomycin were purchased from GIBCO (Cergy-Pontoise, France). Fetal bovine serum (FBS),
Phenolic acids affect cell viability
We first evaluated the cytotoxicity of caffeic, coumaric and ferulic acids (50–1000 µM) after 24 h of incubation on different cancer cell lines (A549 and HT29-D4) using MTT assay. As illustrated in Fig. 1, the three phenolic acids significantly inhibited the proliferation of both A549 and HT29-D4 cells in a concentration-dependent manner.
Phenolic acids decrease superoxide production
Dysregulated reactive oxygen species level plays a critical role in cancer development. Excessive elevated ROS level confers cancer cells a susceptibility to
Discussion
It is well known that many compounds from natural plants have chemopreventive and chemotherapeutic efficacy in human cancers (Eggler et al., 2008, Shen et al., 2014, Surh, 2003). The discovery of phytomedicinal plants as well as elucidation of their underlying mechanisms in anticancer activity is important. Caffeic, coumaric and ferulic acids, the major representative of phenolic acids, are present in many natural plants (Pan and Ho, 2008), and they have been shown to suppress tumor growth
Conclusion
To summarize, we provide evidence that caffeic, coumaric and ferulic acids are potentially useful antioxidant agents in the treatment of human lung carcinoma and colon adenocarcinoma, suggesting that these compounds should participate to the development of therapeutic drugs for cancer diseases.
Disclosure of interest
The authors declare that they have no conflicts of interest concerning this article.
Acknowledgments
We acknowledge the “Ministère de l׳enseignement supérieur, de la recherche scientifique et des technologies de l׳information et de la communication, Tunisia (UR12ES12), INSERM, France (Institut National de la Santé et de la Recherche Médicale), U911 (CRO2) and ARCUS (Action en Région de Coopération Universitaire et Scientifique) (UR12ES12) for the financial support of this study.
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