Anti-cancer effects of 3,5-dimethylaminophenol in A549 lung cancer cells

Pinar Erkekoglu,Yu-Chen Chen,Pei-Ying Lin,Ming-Wei Chao,Chin-Hung Lin,Yu-Jung Chang,Chia-Yi Tseng

doi:10.1371/journal.pone.0205249

Pinar Erkekoglu, Yu-Chen Chen + Show 5 more

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https://doi.org/10.1371/journal.pone.0205249

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Abstract

Exposure to 3,5-dimethylaminophenol (3,5-DMAP), the metabolite of the 3-5-dimethylaniline, was shown to cause high levels of oxidative stress in different cells. The aim of the present work was to observe whether this metabolite can lead to cytotoxicity, oxidative stress, DNA damage and cell cycle changes in non-small cell lung cancer A549 cells. 3,5-DMAP caused a dose-dependent increase in cytotoxicity, generation of superoxide (O2-.), inductions in the enzyme activities orchestrating cellular antioxidant balance, increases in lipid peroxidation as well as DNA damage. However, 3,5-DMAP showed significantly lower cytotoxicity towards human lung fibroblast (HLF) cells. 3,5-DMAP also led to molecular events, like inducing apoptotic markers (ie. p53, Bad, Bax and cytochrome c); decreasing anti-apoptotic proteins (Bcl-2) and alterations in cell cycle. Our findings indicate that the cytotoxicity caused by this particular alkylaniline metabolite led to initiation of caspase 3-mediated apoptosis. Furthermore, 3,5-DMAP attenuated carcinogenic properties like migration capacity of A549 cells and eventually inhibited growth of A549 cells in an in vivo mouse model. Tumor sections showed that 3,5-DMAP down-regulated c-Myc expression but up-regulated p53 and cytochrome c, all of which might result in tumor growth arrest. Co-treatment with N-acetylcysteine provided reductions in cytotoxicity and positively modulated genetic events induced by 3,5-DMAP in A549 cells. In conclusion, our findings demonstrate 3,5-DMAP may be a potential anti-cancer drug in cancer, due to its self redox cycling properties.

Highlights

10,000 new lung cancer cases occur each year, and 7000 people annually die from lung cancer in Taiwan [1]
We used the MTS test to detect the effects 3,5-DMAP had on the viability of human lung fibroblast HLF cells, and A549 lung cancer cells
The median inhibitory concentrations (IC50) for both cells were achieved at 75 μM of 3,5-DMAP for HLF cells and 45 μM for A549 cells

Summary

Introduction

10,000 new lung cancer cases occur each year, and 7000 people annually die from lung cancer in Taiwan [1]. The incidence of lung cancer is greater than combined incidences of colorectal, cervical, breast, prostate, and stomach cancers throughout the globe. The number of cases continue to grow rapidly each year [2,3,4]. Symptoms of this particular cancer are not always obvious [5,6,7,8].

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