Cadmium chloride enhances cisplatin sensitivity in osteosarcoma cells by reducing FOXM1 expression.

Osteosarcoma is a highly malignant disease and is associated with a poor patient prognosis and a high mortality rate. Disease prognosis significantly correlates with chemotherapeutic responses. Cadmium is a heavy metal with specific effects on bone, but its benefits for osteosarcoma treatment have not been characterized. In the present study, cadmium chloride was used to treat MG63 osteosarcoma cells, and their gene expression profiles were assessed by GeneChip technology. We found that forkhead box protein M1 (FOXM1) was downregulated by cadmium chloride, and lentiviral­mediated silencing of FOXM1 confirmed a role for this factor in the cisplatin resistance of MG63 cells. In nude mice, cadmium chloride enhanced the sensitivity of osteosarcoma to cisplatin, an effect mediated by FOXM1. Collectively, these data indicate that cadmium chloride can alter the sensitivity of osteosarcoma cells to cisplatin through FOXM1, highlighting it as a potential therapeutic target and prognostic factor for osteosarcoma.

Enhancement of antiproliferative and proapoptotic effects of cadmium chloride combined with hSmac in hepatocellular carcinoma cells.

BACKGROUND: To study the effects of cadmium chloride (CdCl(2)) combined with hSmac on the proliferation and apoptosis of hepatocellular carcinoma cells, i.e. SMMC-7721. METHODS: SMMC-7721 cells were transfected with pcDNA3.1(+)-hSmac using a lipofectamine-mediated method, and then cell viability was detected by MTT assay after exposure to 10, 20, and 30 µmol/l CdCl(2). Apoptosis was determined by both acridine orange-ethidium bromide staining and flow cytometry, and expressions of caspase-3, caspase-9, and cytochrome c by Western blot. RESULTS: CdCl(2) had cytotoxicity to SMMC-7721 cells, and it could inhibit proliferation in a dose-dependent manner and induce apoptosis; hSmac could inhibit proliferation and induce apoptosis independently in SMMC-7721 cells. Furthermore, cotreatment with CdCl(2) and hSmac could enhance antiproliferative and proapoptotic effects in SMMC-7721 cells. CONCLUSIONS: hSmac could enhance the cytotoxicity of CdCl(2).

Effects of cadmium on cardiac metallothionein induction and ischemia-reperfusion injury in rats.

Myocardial ischemia-reperfusion injury is associated with an imbalance between the formation and the scavenging of reactive oxygen species. In this context, the protective role of the antioxidant metallothionein, a thiol-rich protein that is induced in different organs in response to heavy metals and oxidative conditions, has mainly been investigated in metallothionein-knockout mice or metallothionein-overexpressing mice. The aim of this study was to evaluate whether the administration of cadmium has a protective effect against cardiac ischemia-reperfusion injury and whether this is associated with induction of in vivo cardiac metallothionein. Forty-eight hours after an injection of 0, 1, or 2 mg/kg cadmium, isolated perfused rat hearts were submitted to 30 min of total global ischemia and 30 min of reperfusion. The ischemia-reperfusion sequence was associated with a significant decrease in cardiac metallothionein levels. Pretreatment with cadmium at a dose of 2 mg/kg (i) prevented this decrease and (ii) improved the postischemic recuperation of the coronary flow, the ventricular developed pressure, and therefore, the global postischemic functional recovery. These results showed that pretreatment of rats with 2 mg/kg cadmium induced cardioprotection against ischemia-reperfusion injuries, perhaps through an in vivo metallothionein induction that may be related to a metal activation of antioxidant systems.

Heme oxygenase-1 and cardiovascular disease.

Heme oxygenase (HO)-1 is the inducible isoform of the first and rate-controlling enzyme of heme degradation. HO-1 is up-regulated by a host of oxidative stress stimuli and has potent cytoprotective and anti-inflammatory functions via decreasing tissue levels of the prooxidant heme along with production of bilirubin and the signaling gas carbon monoxide. This review deals with recent findings that highlight the emerging significance of HO-1 in cardiovascular disease. Evidence is presented on how heme and various oxidative stress stimuli may cause endothelial cell dysfunction and how HO-1 may counteract the detrimental effects of oxidative stress in the endothelium. Recent advances in the understanding of the role of endothelial HO-1 for the regulation of the inflammatory response are summarized, including the modulation of leukocyte recruitment and transmigration through the endothelial barrier. Furthermore, experimental evidence from various cell culture and animal models is discussed which suggests an association of HO-1 with the complex sequence of events that cause atherosclerosis. In the second part of the review we present potential strategies that apply HO-1 as a therapeutic target in the treatment of cardiovascular disease. Specific inducers of HO-activity which may ultimately lead to the development of clinically relevant pharmacological applications are introduced.

Effects of metal salts on the oral production of volatile sulfur-containing compounds (VSC).

BACKGROUND/AIM: Halitosis, mainly caused by bacteria located on the posterior dorsum of the tongue and in periodontal pockets, is due to formation of volatile sulfur compounds (VSC). The hypothesis to be tested was that the affinity of a metal for sulfur determines its anti-VSC activity. METHOD: Clinical tests were carried out on 12 subjects who rinsed with cysteine to induce halitosis (baseline) before rinsing with 7.34 mM ZnCl2, SnF2 and CuCl2. Mouth air VSC analyses were repeated following cysteine rinses at 1 h, 2 h and 3 h using a gas chromatograph. In vitro experiments tested toxic metals Hg2+, Pb2+ and Cd2+. 10-microl aliquots of metal salts were added to 1-ml aliquots of human whole saliva from 30 subjects. Samples were incubated overnight at 37oC and saliva headspace was analyzed for VSC in a gas chromatograph. CLINICAL RESULTS: Cu2+>Sn2+>Zn2+ (supports hypothesis). Zn2+ had significantly less anti-VSC effect compared with Cu2+ and Sn2+ at 1, 2 and 3 h. In vitro results indicated that Hg2+, Cu2+ and Cd2+ had close to 100% anti-VSC effect, and that Pb2+ was less effective and Cd2+ more effective than expected in inhibiting VSC. CONCLUSIONS: Apart from Hg2+ and Cu2+, the metals had a significantly greater effect on H2S than on CH3SH. Cu2+ and Hg2+ have well-known antibacterial activity and may presumably also operate by this mechanism.

Cadmium-induced inhibition of the growth and metastasis of human lung carcinoma xenografts: role of apoptosis.

Our previous studies indicate that cadmium in mice can inhibit the formation of chemically induced and spontaneously occurring tumors in the liver and lung. Cadmium is an effective anti-tumor agent when given at non-toxic doses and even when given well after tumor formation, implying a unique sensitivity in certain tumor cells. The present studies tested the ability of cadmium to inhibit growth and progression of transplanted human pulmonary tumor xenografts. Male athymic nude mice were inoculated with either H460 cells, originally derived from a non-small cell pulmonary carcinoma, or DMS 114 cells, originally derived from a small cell lung carcinoma, under the left renal capsule. Starting 1 week later mice received 0, 125 or 250 p.p.m. cadmium in the drinking water, levels without effect on host animal growth or survival, and were observed over the next 4 weeks (H460 cells) or 100 days (DMS 114 cells). An additional experiment gave cadmium as an i.v. loading dose (20 micromol/kg) 4 days after renal inoculation with H460 cells and 200 p.p.m. cadmium in the drinking water from 7 days onward, with an observation period of 28 days. Cadmium caused dose-related reductions in the growth of tumors resulting from the inoculation of either H460 or DMS 114 cells of up to 83%. Additionally, cadmium reduced the rate of tumor metastasis to the lung by up to 58%. Cadmium treatment had no effects on either Bcl-2 or Bax protein expression in tumor xenografts, indicating that apoptotic pathways probably do not contribute to this anti-neoplastic effect. These studies show cadmium can effectively reduce growth and progression of human lung carcinoma xenografts in a fashion that is probably independent of apoptosis.