Curcumin and Its Derivatives Induce Apoptosis in Human Cancer Cells by Mobilizing and Redox Cycling Genomic Copper Ions

Abstract

Turmeric spice contains curcuminoids, which are polyphenolic compounds found in the Curcuma longa plant’s rhizome. This class of molecules includes curcumin, demethoxycurcumin, and bisdemethoxycurcumin. Using prostate cancer cell lines PC3, LNCaP, DU145, and C42B, we show that curcuminoids inhibit cell proliferation (measured by MTT assay) and induce apoptosis-like cell death (measured by DNA/histone ELISA). A copper chelator (neocuproine) and reactive oxygen species scavengers (thiourea for hydroxyl radical, superoxide dismutase for superoxide anion, and catalase for hydrogen peroxide) significantly inhibit this reaction, thus demonstrating that intracellular copper reacts with curcuminoids in cancer cells to cause DNA damage via ROS generation. We further show that copper-supplemented media sensitize normal breast epithelial cells (MCF-10A) to curcumin-mediated growth inhibition, as determined by decreased cell proliferation. Copper supplementation results in increased expression of copper transporters CTR1 and ATP7A in MCF-10A cells, which is attenuated by the addition of curcumin in the medium. We propose that the copper-mediated, ROS-induced mechanism of selective cell death of cancer cells may in part explain the anticancer effects of curcuminoids.

Soy Isoflavones Induce Cell Death by Copper-Mediated Mechanism: Understanding Its Anticancer Properties

“…Despite this, there are plenty of available pieces of evidence showing that elevated copper levels contribute to tumor angiogenesis [ 26 , 48 ]. Our experimental hypothesis [ 24 , 25 ] suggests that plant polyphenols interact with copper within the cell and trigger oxidative DNA breakage has recently been confirmed by using a wide range of experiments and a variety of polyphenols [ 40 , 49 , 50 , 51 , 52 ]. The results of the current investigation provide even more support for the ideas we have generated as a result of our prior research.…”

“…As shown in Figure 8 , HPrEC cells are more sensitive to isoflavone-induced growth suppression (inhibition of cell proliferation) when CTR1 and ATP7A are expressed. CTR1 and ATP7A proteins promote copper uptake in cells [ 40 ]. The silencing of the copper transporters CTR1 / ATP7A compromised the sensitivity of HPrEC cells to genistein/and daidzein in the copper-enriched medium.…”

“…The immortalized non-transformed prostate cell line HPrEC and the prostate cancer cell lines LNCaP and DU145 were obtained from ATCC (Manassas, VA, USA) and maintained following the protocol as described previously [ 40 ]. The stock solutions of genistein and daidzein were prepared in DMSO, whereas the stock solutions of metal chelators were prepared in PBS.…”

“…The stock solutions of genistein and daidzein were prepared in DMSO, whereas the stock solutions of metal chelators were prepared in PBS. A normal prostate epithelial cell line, HPrEC, was propagated using the protocol described earlier [ 40 ]. HPrEC-Cu cells are HPrEC cells that were cultivated in their standard culture media with additional supplementation of CuCl 2 (25 µM) for thirty days.…”

“…The MTT experiment was carried out exactly as stated previously [ 40 ]. LNCaP and DU145 cells were seeded at a density of 2 × 10 3 cells per well on 96-well microtiter culture plates.…”