Differential inhibition of human cancer cell proliferation by citrus limonoids

Limonoids have been shown to inhibit the growth of estrogen receptor-negative and -positive human breast cancer cells in culture. The primary objective of this study was to test the antiproliferative activity of limonoids (obacunone 17beta-D-glucopyranoside, nomilinic acid 17beta-D-glucopyranoside, limonin, nomilin, and a limonoid glucoside mixture), found in high concentrations in mandarin (Citrus reticulata Blanco), against a series of human cancer cell lines. The human cancer cell lines included leukemia (HL-60), ovary (SKOV-3), cervix (HeLa), stomach (NCI-SNU-1), liver (Hep G2), and breast (MCF-7). The growth-inhibitory effects of the four limonoids and the limonoid glucoside mixture against MCF-7 cells were significant, and the antiproliferative activity of the different citrus limonoids was also dose and time dependent. No significant effects were observed on growth of the other cancer cell lines treated with the four individual limonoids at 100 mug/ml At 100 mug/ml, the limonoid glucoside mixture demonstrated a partial inhibitory effect on SKOV-3 cancer cells. With use of flow cytometry, it was found that all the limonoid samples could induce apoptosis in MCF-7 cells at relatively high concentrations (100 mug/ml). Considering the high concentration needed to induce apoptosis, it is unlikely that this is the primary mechanism of action for the cytotoxic effects seen with limonoids in this study. Further work is needed in this area to establish the mechanism of action of citrus limonoids on human breast cancer cells.