Apoptosis and Cell-Cycle Arrest in Human and Murine Tumor Cells Are Initiated by Isoprenoids

Abstract

Diverse classes of phytochemicals initiate biological responses that effectively lower cancer risk. One class of phytochemicals, broadly defined as pure and mixed isoprenoids, encompasses an estimated 22,000 individual components. A representative mixed isoprenoid, gamma-tocotrienol, suppresses the growth of murine B16(F10) melanoma cells, and with greater potency, the growth of human breast adenocarcinoma (MCF-7) and human leukemic (HL-60) cells. beta-Ionone, a pure isoprenoid, suppresses the growth of B16 cells and with greater potency, the growth of MCF-7, HL-60 and human colon adenocarcinoma (Caco-2) cells. Results obtained with diverse cell lines differing in ras and p53 status showed that the isoprenoid-mediated suppression of growth is independent of mutated ras and p53 functions. beta-Ionone suppressed the growth of human colon fibroblasts (CCD-18Co) but only when present at three-fold the concentration required to suppress the growth of Caco-2 cells. The isoprenoids initiated apoptosis and, concomitantly arrested cells in the G1 phase of the cell cycle. Both suppress 3-hydroxy-3-methylglutaryl CoA reductase activity. beta-Ionone and lovastatin interfered with the posttranslational processing of lamin B, an activity essential to assembly of daughter nuclei. This interference, we postulate, renders neosynthesized DNA available to the endonuclease activities leading to apoptotic cell death. Lovastatin-imposed mevalonate starvation suppressed the glycosylation and translocation of growth factor receptors to the cell surface. As a consequence, cells were arrested in the G1 phase of the cell cycle. This rationale may apply to the isoprenoid-mediated G1-phase arrest of tumor cells. The additive and potentially synergistic actions of these isoprenoids in the suppression of tumor cell proliferation and initiation of apoptosis coupled with the mass action of the diverse isoprenoid constituents of plant products may explain, in part, the impact of fruit, vegetable and grain consumption on cancer risk.

β‐Ionone suppresses mammary carcinogenesis, proliferative activity and induces apoptosis in the mammary gland of the Sprague‐Dawley rat

“…Physiological functions attributed to b-ionone include the inhibition of the growth of fungi 7 and the regulation of the synthesis of mevalonate-derived constituents. 8 In previous studies, b-ionone inhibited the growth of breast-, gastric-, colon-and HL-60-cancer cells in a dosedependent manner, [9][10][11][12][13] affected the MAPK pathway of MDA MB 435 cells, 14 and induced apoptosis of SGC-7901 gastric cancer cells and B16 murine tumor cells. 10,12 In addition, b-ionone could also affect metastasis in B16 and SGC-7901 cancer cell lines.…”

“…8 In previous studies, b-ionone inhibited the growth of breast-, gastric-, colon-and HL-60-cancer cells in a dosedependent manner, [9][10][11][12][13] affected the MAPK pathway of MDA MB 435 cells, 14 and induced apoptosis of SGC-7901 gastric cancer cells and B16 murine tumor cells. 10,12 In addition, b-ionone could also affect metastasis in B16 and SGC-7901 cancer cell lines. 11,12,15 Dietary studies reveal the chemopreventive 16 and antitumor 17 activities of b-ionone.…”

“…Discussion b-Ionone, a pure isoprenoid, has been shown to possess potent antiproliferative activity 9,13,17 and to induce apoptosis 10,12 in cancer cells. Liu's study 9 reported that b-ionone at doses of 25-200 lmol/l inhibited cell proliferation and DNA synthesis in human mammary cancer MCF-7 cells in a dose-dependent manner.…”

“…14 In another study, b-ionone also suppressed the growth of other cancer cells-human colon fibroblasts CCD18Co cells, HL-60 cells, and human colon adenocarcinoma Caco-2 cells. 12 Apoptosis morphology was observed in SGC-7901 cells induced by b-ionone using transmission electron microscopy and hoechst-33258 staining. Apoptosis was induced in SGC-7901 cells at doses of 25-200lmol/l of b-ionone using the TUNEL assay and showed a dose-and time-dependent response.…”

“…10,12 In addition, b-ionone could also affect metastasis in B16 and SGC-7901 cancer cell lines. 11,12,15 Dietary studies reveal the chemopreventive 16 and antitumor 17 activities of b-ionone.This study confirms and extends observations of the chemopreventive impact of, and actions triggered, by dietary b-ionone during DMBA-initiated mammary carcinogenesis in Sprague-Dawley rats. …”