From GC-rich DNA binding to the repression of survivin gene for quercetin nickel (II) complex: implications for cancer therapy

Abstract

The DNA binding and cleavage properties of quercetin nickel (II) complex have been studied, but little attention has been devoted to the relationship between antitumor activity of this complex and DNA-binding properties. In the present study, we report that quercetin nickel (II) complex showed significant cytotoxicity against three tumor cell lines (HepG2, SMMC7721 and A549). Hoechst33258 and AO/EB staining showed HepG2 cells underwent the typical morphologic changes of apoptosis characterized by nuclear shrinkage, chromatin condensation, or fragmentation after exposure to quercetin nickel (II) complex. We also demonstrate that the levels of survivin and bcl-2 protein expression in HepG2 cells decreased concurrently, and the levels of p53 protein increased significantly after treatment with quercetin nickel (II) complex by immunocytochemistry analysis. The relative activity of caspase-3 and caspase-9 increased significantly after treatment with the complex. Furthermore, fluorescence measurements and molecular modeling were performed to learn that the complex could be preferentially bound to DNA in GC region. These results imply that quercetin nickel (II) complex may intercalate into the GC-rich core promoter region of survivin, down-regulating survivin gene expression and promoting tumor cells apoptosis. So our results suggest that antitumor activity of quercetin nickel (II) complex might be related to its intercalation into DNA and DNA-binding selectivity, and that the complex may be a promising agent for cancer therapy.

Cytotoxic action of methylquercetins in human lung adenocarcinoma cells

“…As A549 line has been widely used as a model system to study human alveolar carcinoma, cytotoxic profile of flavonoids in these cells was previously characterized with the results very similar to those measured in our work. Indeed, the IC 50 value of 72.2 µM for quercetin is close to the inhibitory constants published by Loizzo et al (26), Tan et al (27)(28)(29), Robaszkiewicz et al (30), and Chan et al (31); and IC 50 values more than 100 µM were previously reported for fisetin (32), hesperetin (33-35), luteolin (32,36), chrysin (35), baicalein (34), daidzein (37), and genistein (38). Based on our results presented in this article, cytotoxic activity profiles of flavonoids were rather similar for both A549 and HCC-44 lung cancer lines, despite the gender difference of initial origin of these cells.…”

Molecular aspects on the interaction of quercetin and its metal complexes with DNA

“…This suggests that the Cu(II) considerably change the chemical properties of the quercetin [13]. Also antitumor activity of nickel(II) quercetin complex has been reported by Tan et al they believe that anti-tumor activity of this complex might be related to its intercalation into DNA and DNA-binding selectivity [17].…”

Cytotoxic effect of inositol hexaphosphate and its Ni(II) complex on human acute leukemia Jurkat T cells

“…However, studies on the antitumoral activity for Ni(II) complexes with other ligands are available in the literature (Tan et al, 2010;Milenković et al, 2013). Tan et al (2010) observed that quercetin-Ni(II) complex induced apoptosis in dose-dependent cell lines of liver carcinoma (HepG2), human hepatoma (SMMC7721) and lung adenocarcinoma (A549). According to the authors, the antitumoral activity consisted of the selective binding of the complex with DNA, triggering a series of events that led to cell death.…”

“…The activity of some metal complexes against tumors using both in vitro and in vivo protocols is already known and recognized worldwide (Immel et al, 2011;Côrte-Real et al, 2013;Palanimuthu et al, 2013;Tan et al, 2010;Milenković et al, 2013). Studies have reported the characterization and stability of some InsP 6 complexes with transition metal ions, including Ni(II) (De Carli et al, 2006Quirrenbach et al, 2009).…”