Study of the antitumor mechanisms of apiole derivatives (AP-02) from Petroselinum crispum through induction of G0/G1 phase cell cycle arrest in human COLO 205 cancer cells.

BACKGROUND: Apiole was isolated from the leaves of various plants and vegetables and has been demonstrated to inhibit human colon cancer cell (COLO 205 cells) growth through induction of G0/G1 cell cycle arrest and apoptotic cell death. This study further explored the antitumor effects of apiole derivatives AP-02, 04, and 05 in COLO 205 cancer cells. METHODS: Human breast (MDA-MB-231, ZR75), lung (A549, PE089), colon (COLO 205, HT 29), and hepatocellular (Hep G2, Hep 3B) cancer cells were treated with apiole and its derivatives in a dose-dependent manner. Flow cytometry analysis was subsequently performed to determine the mechanism of AP-02-induced G0/G1 cell cycle arrest. The in vivo antitumor effect of AP-02 (1 and 5 mg/kg, administered twice per week) was examined by treating athymic nude mice bearing COLO 205 tumor xenografts. The molecular mechanisms of AP-02-induced antitumor effects were determined using western blot analysis. RESULTS: AP-02 was the most effective compound, especially for inhibition of COLO 205 colon cancer cell growth. The cytotoxicity of AP-02 in normal colon epithelial (FHC) cells was significantly lower than that in other normal cells derived from the breast, lung or liver. Flow cytometry analysis indicated that AP-02-induced G0/G1 cell cycle arrest in COLO 205 cells but not in HT 29 cells (< 5 µM for 24 h, **p < 0.01). Tumor growth volume was also significantly inhibited in AP-02 (> 1 mg/kg)-treated athymic nude mice bearing COLO 205 tumor xenografts compared to control mice (*p < 0.05). Furthermore, G0/G1 phase regulatory proteins (p53 and p21/Cip1) and an invasion suppressor protein (E-cadherin) were significantly upregulated, while cyclin D1 was significantly downregulated, in AP-02-treated tumor tissues compared to the control group (> 1 mg/kg, *p < 0.05). CONCLUSIONS: Our results provide in vitro and in vivo molecular evidence of AP-02-induced anti-proliferative effects on colon cancer, indicating that this compound might have potential clinical applications.

The apple polyphenol phloretin inhibits breast cancer cell migration and proliferation via inhibition of signals by type 2 glucose transporter.

Human triple-negative breast cancer (TNBC) is the most aggressive and poorly understood subclass of breast cancer. Glucose transporters (GLUTs) are required for glucose uptake in malignant cancer cells and are ideal targets for cancer therapy. To determine whether the inhibition of GLUTs could be used in TNBC cell therapy, the apple polyphenol phloretin (Ph) was used as a specific antagonist of GLUT2 protein function in human TNBC cells. Interestingly, we found that Ph (10-150 µM, for 24 h) inhibited cell growth and arrested the cell cycle in MDA-MB-231 cells in a p53 mutant-dependent manner, which was confirmed by pre-treatment of the cells with a p53-specific dominant-negative expression vector. We also found that Ph treatment (10-150 µM, for 24 h) significantly decreased the migratory activity of the MDA-MB-231 cells through the inhibition of paxillin/FAK, Src, and alpha smooth muscle actin (α-sMA) and through the activation of E-cadherin. Furthermore, the anti-tumorigenic effect of Ph (10, 50 mg/kg or DMSO twice a week for six weeks) was demonstrated in vivo using BALB/c nude mice bearing MDA-MB-231 tumor xenografts. A decrease in N-cadherin, vimentin and an increase in p53, p21 and E-cadherin were detected in the tumor tissues. In conclusion, inhibition of GLUT2 by the apple polyphenol Ph could potentially suppress TNBC tumor cell growth and metastasis.

Effects of environmental lead exposure on T-helper cell-specific cytokines in children.

Lead (Pb) may alter T-lymphocyte reactivity in situ by preferentially enhancing the development of T-helper 2 (T(H)2)- and inhibiting T(H)1-lymphocyte development. These effects could result in dysregulation of the presence/availability of T(H)1- and T(H)2-associated cytokines. The aim of this study was two-fold, that is, to assess whole blood Pb levels in schoolchildren from Taiwanese communities that varied in degree of potential for Pb exposure and then ascertain if there were relationships between Pb exposure and changes in levels of key T(H)1 and T(H)2 cytokines. Grades 5 and 6 students were selected from four different community schools, i.e., one from: urban area with new homes; urban area with old homes; rural site with old homes; and area located near an oil refinery. Students at each site were further divided into healthy and respiratory allergy subgroups. Blood was collected and whole blood Pb levels and serum interferon (IFN)-γ, interleukin (IL)-12, -4, and -5 levels were determined. The results indicate no differences in whole blood Pb levels (<4 µg/dl) among students from urban and rural sites; these values were similar in the healthy and allergic subjects. Serum T(H)1 and T(H)2 cytokine levels also did not differ among/within the groups. In contrast, refinery children had significantly increased Pb levels (5.2-8.8 µg/dl) relative to any of the other sets' levels. Of these, children with allergies had serum T(H)2 cytokine levels significantly higher and T(H)1 cytokine levels significantly lower than their healthy counterparts. Oddly, though having elevated Pb levels, healthy refinery students did not display altered T(H)1 or T(H)2 cytokine levels relative to control student values. From this, we conclude that substantively increased whole blood Pb levels may promote T(H) cell dysregulation and alter the availability of key T(H)1 and T(H)2 cytokines, effects that could ultimately contribute to development of pulmonary allergic diseases.