Organic cadmium complexes as proteasome inhibitors and apoptosis inducers in human breast cancer cells

Abstract

Although cadmium (Cd) is a widespread environmental contaminant and human carcinogen, our studies indicate an organic Cd complex to be a potent inhibitor of proteasomal chymotrypsin-like (CT-like) activity, further capable of inducing apoptosis in a cancer cell-specific manner. It has been reported that the ligands indole-3-butyric acid (L1) and indole-3-propionic acid (L2) have cancer-fighting effects when tested in a rat carcinoma model. In addition, 3, 5-diaminobenzoic acid o-vanillin Schiff bases (L3) have high antimicrobial activity and a large number of Schiff base complexes have been reported to have proteasome-inhibitory activity. We therefore hypothesized that synthetic forms of Cd in combination with L1, L2 and L3 may have proteasome-inhibitory and apoptosis-inducing activities, which would be cancer cell-specific. To test this hypothesis, we have synthesized three novel Cd-containing complexes: [Cd2(C12H12O2N)4(H2O)2]·2H2O (Cd1), [Cd2(C11H10O2N)4(H2O)2]·2H2O (Cd2) and [Cd(C7H4N2O2)(C8H6O2)2]·2H2O (Cd3), by using these three ligands. We sought out to characterize and assess the proteasome-inhibitory and anti-proliferative properties of these three Cd complexes in human breast cancer cells. Cd1, Cd2 and Cd3 were found to effectively inhibit the chymotrypsin-like activity of purified 20S proteasome with IC50 values of 2.6, 3.0 and 3.3 μM, respectively. Moreover, inhibition of cancer cell proliferation also correlated with this effect. As a result of proteasomal shutdown, the accumulation of ubiquitinated proteins and the proteasome target IκB-α protein as well as induction of apoptosis were observed. To account for the cancer specificity of this effect, immortalized, non-tumorigenic breast MCF10A cells were used under the same experimental conditions. Our results indicate that MCF10A cells are much less sensitive to the Cd1, Cd2 and Cd3 complexes when compared to MDA MB 231 breast cancer cells. Therefore, our study suggests that these Cd organic complexes are capable of inhibiting tumor cellular proteasome activity and consequently induce cancer cell-specific apoptotic death.

l-Ornithine Schiff base–copper and –cadmium complexes as new proteasome inhibitors and apoptosis inducers in human cancer cells

“…4c, 5c, 6c, 7c). We found that Cd-coordinating compounds were relatively more potent in their ability to inhibit MDA-MB-231, breast cancer cell proliferation [3].…”

“…The molar conductivities (Λm) of Cu2, Cd1 and Cd2 in DMSO were 9.42, 12.13, 8.32 and 13.48 S cm 2 mol −1 , respectively. As the molar conductivities were less than 35 S cm 2 mol −1 [29], these complexes are considered to be nonelectrolytes and are quite stable in culture media [3,35,36]. This data suggest that the active species are metal complexes.…”

“…Metal complexes have been the research interest of our lab and we have previously synthesized and tested various metal complexes [3,28,35,36]. The synthesis routes of complexes Cu1, Cd1, Cu2 and Cd2 that are discussed here are shown in the Scheme 1.…”

“…Thus, UPS plays a critical role in normal health and disease states [1,2]. Importantly, as UPS plays a key role in carcinogenesis and tumor progression, it has therefore been extensively studied as a novel molecular target for the development of new anticancer agents [3,4].…”

Anticancer activity and computational modeling of ternary copper (II) complexes with 3-indolecarboxylic acid and 1,10-phenanthroline

“…Thus, after some minor modifications and energy optimization, this bovine 20S proteasome structure could be directly used as receptor of docking studies. We previously reported that some metal complexes possess the ability to inhibit the CT-like activity of proteasome and induce cancer cell death in human cancer cells (22)(23)(24)(25). However, the involved mechanism is unknown.…”