Antitumor effects of cadmium against diethylnitrosamine‑induced liver tumors in mice

Abstract

Cadmium (Cd) has been reported to exhibit antitumor effects against chemically induced liver tumors. However, the antitumor effects of Cd are not completely understood. Metallotherapy, the use of a toxic metal to attack liver tumors, could be a viable strategy. In the present study, 8-week old, male, C57BL/6 mice were administered injections of diethylnitrosamine (DEN) (90 mg/kg, and then 50 mg/kg 2 weeks later), followed by liver tumor promotion with carbon tetrachloride. Cadmium chloride was administered in the drinking water (1000 ppm) from 21–40 weeks after DEN initiation. Body weights were recorded and liver tumor formation was monitored via ultrasound. At the end of experiments, livers were removed, weighed, and the tumor incidence, tumor numbers and tumor size scores were recorded. Liver histology and metallothionein (MT) immunostaining were performed. After DEN injection, animal body weight decreased, and then slowly recovered with time. Cd treatment did not affect animal body weight gain. Ultrasound analysis detected liver tumors 35 weeks after DEN injection, and the mice were necropsied at 40 weeks. Liver/body weight ratios increased in the DEN and DEN + Cd groups. Cd treatment decreased the tumor incidence (71 vs. 17%), tumor numbers (15 vs. 2) and tumor scores (22 vs. 3) when compared with the DEN only group. Histopathology showed hepatocyte degeneration in all groups, and immunohistochemistry showed MT-deficiency in the liver tumors, while MT staining was intensified in the surrounding tissues. Reverse transcription-quantitative PCR showed increases in α-fetoprotein level in DEN-treated livers, and increases in MT-2 and tumor necrosis factor α (TNFα) levels in Cd-treated livers. Thus, it was concluded that Cd is effective in the suppression of DEN-induced liver tumors, and that the mechanisms may be related to MT-deficiency in tumors and the induction of TNFα to kill tumor cells.

In Vivo Anti-Hepatocellular Carcinoma Effects of the Chloroform Root Extract of Clausena excavata Burm

“…The Histological assay was performed using methods described by Nie et al . 7 Briefly, liver tissues of the treated and untreated mice were fixed in 10% formalin at room temperature for about 48 h. The tissue sections were embedded in paraffin at 60 °C, cut into thin sections (3.5 µm) using a microtome (Reichert-Jung, UK) and treated successively with xylene and then 100, 95, 85 and 75% (v/v) of ethanol. Thereafter, the histological sections were stained with hematoxylin and eosin (H & E) at room temperature and sections were viewed under light microscope (Olympus, Japan).…”

Relevance of Carcinogen-Induced Preclinical Cancer Models

“…DEN-induced liver tumors are highly heterogeneous and can be classified into different histological subtypes, such as trabecular, pseudoglandular, and scirrhous. DEN-induced liver tumors can also metastasize to other organs, such as the lung, spleen, and lymph nodes, as demonstrated in Figure 4 A. DEN is one of the most widely used chemical carcinogens to induce mouse models of HCC, as it can partially mimic the molecular and pathological features of human HCC [ 34 ]. DEN can induce HCC via two mechanisms: through direct DNA damage or by facilitating tumor formation after initiation through a hepatotoxic compound that promotes clonal expansion.…”