Copper (II) and 2,2'-bipyridine complexation improves chemopreventive effects of naringenin against breast tumor cells.

Júlio César Conceição Filho,Jaqueline Raquel Batalhão,Angelina Maria Fuzer,Caio Marcio Paranhos Da Silva,André Lúcio Franceschini Sarria,Márcia Regina Cominetti,Rose Maria Carlos,Paulo Cezar Vieira,João Batista Fernandes,Amanda Blanque Becceneri,Arun Rishi

doi:10.1371/journal.pone.0107058

Abstract

Cancer is the second leading cause of death worldwide and there is epidemiological evidence that demonstrates this tendency is emerging. Naringenin (NGEN) is a trihydroxyflavanone that shows various biological effects such as antioxidant, anticancer, anti-inflammatory, and antiviral activities. It belongs to flavanone class, which represents flavonoids with a C6-C3-C6 skeleton. Flavonoids do not exhibit sufficient activity to be used for chemotherapy, however they can be chemically modified by complexation with metals such as copper (Cu) (II) for instance, in order to be applied for adjuvant therapy. This study investigated the effects of Cu(II) and 2,2′-bipyridine complexation with naringenin on MDA-MB-231 cells. We demonstrated that naringenin complexed with Cu(II) and 2,2′-bipyridine (NGENCuB) was more efficient inhibiting colony formation, proliferation and migration of MDA-MB-231 tumor cells, than naringenin (NGEN) itself. Furthermore, we verified that NGENCuB was more effective than NGEN inhibiting pro-MMP9 activity by zymography assays. Finally, through flow cytometry, we showed that NGENCuB is more efficient than NGEN inducing apoptosis in MDA-MB-231 cells. These results were confirmed by gene expression analysis in real time PCR. We observed that NGENCuB upregulated the expression of pro-apoptotic gene caspase-9, but did not change the expression of caspase-8 or anti-apoptotic gene Bcl-2. There are only few works investigating the effects of Cu(II) complexation with naringenin on tumor cells. To the best of our knowledge, this is the first work describing the effects of Cu(II) complexation of a flavonoid on MDA-MB-231 breast tumor cells.

Highlights

Cancer is the second leading cause of death and there are epidemiological evidences demonstrating that this tendency is emerging worldwide
The (6)-Naringenin (NGEN), bipyridine, CuCl2 complex (NGENCuB) was synthesized in good yield (79.0%), its structure was characterized by FT-IR (Figure S1), HRMS (Figure S2), UV (Figure S3), TGA (Figures S4 and S5) measurements and its purity was .99% as described in the experimental
The stability of NGENCuB complex (Figure S4) and naringenin without complexation (Figure S5) in the dark at room temperature and in the concentrations of 1 to 100 mM was proved by the absence of changes in the electronic absorption spectra in methanol and in DMEM medium over a period of 24 hours

Summary

Introduction

Cancer is the second leading cause of death and there are epidemiological evidences demonstrating that this tendency is emerging worldwide. Almost 1.4 million women were diagnosed with breast cancer worldwide in 2008 with approximately 459,000 deaths recorded [1]. Breast cancer is the third most frequent cancer and one of the most common malignant diseases in women worldwide. In developing countries, it is the second highest cause of death in women after cervical cancer [2]. Breast cancer is the most common malignancy among women, accounting for nearly 1 in 3 cancers diagnosed among women in the United States [3]. The number of cancer-related deaths is expected to increase 45% between 2007 and 2030, influenced in part by population growth and global aging

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