Epidemiological evidence indicates that Brassica vegetables protect against colorectal cancer. Brassicas contain glucosinolates, the breakdown products of which exert antiproliferative effects against cancer cells. We have examined the effects of allyl-isothiocyanate (AITC), a major breakdown product of the glucosinolate sinigrin, on proliferation and death of colorectal cancer cells. HT-29 colorectal cells were exposed to AITC for 24 h and the number of adherent and detached cells determined. Both populations were analysed for cell-cycle characteristics and examined by light and electron microscopy for features of apoptosis and mitosis. Evidence of apoptosis was also determined by flow cytometric analysis of Annexin V staining in the detached population of cells. AITC-treated cells were also stained for alpha-tubulin. Treatment caused cells to round up after 7 h of exposure and subsequently detach. At 24 h these cells were blocked in mitosis. Detached AITC-treated cells showed no signs of apoptosis as assessed by morphological features or by Annexin V staining but they did show evidence of disrupted tubulin. AITC inhibits proliferation of cancer cells by causing mitotic block associated with disruption of alpha-tubulin in a manner analogous to a number of chemotherapeutic agents.
Glucosinolates are sulfur-containing glycosides found in the Brassica vegetables. Their breakdown products include isothiocyanates, which are produced following exposure to the endogenous plant enzyme myrosinase. Isothiocyanates are pungent, biologically active compounds that suppress carcinogenesis in vivo, and induce apoptosis in vitro. We have shown previously that oral administration of the isolated glucosinolate sinigrin induces apoptosis, and suppresses aberrant crypt foci in the colonic mucosa of rats treated previously with 1,2-dimethylhydrazine (DMH). In this study we explored the effects of both raw and thermally processed Brussels sprout tissue on the modulation of crypt cell apoptosis and mitosis, and the frequency of aberrant crypt foci in the colon. Freeze-dried raw and microwave-cooked Brussels sprouts contained high levels of intact glucosinolates, but they were absent from freshly prepared sprout juice. Oral administration of uncooked Brussels sprouts, whether as a juice, or as a freeze-dried powder, was associated with significantly enhanced levels of apoptosis and reduced mitosis in the colonic crypts. However, this effect was confined to rats previously injected (48 h) with DMH, in which levels of apoptosis and mitosis following DNA damage were already high. There was no effect of treatment in control animals. There was also little evidence of these effects when intact glucosinolates were administered in blanched sprout tissue, which lacked active myrosinase. We conclude that glucosinolate breakdown products derived from Brassica vegetables can exert a profound effect on the balance of colorectal cell proliferation and death in an animal model of colorectal neoplasia.
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