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Article

Dietary Compounds That Induce Cancer Preventive Phase 2 Enzymes Activate Apoptosis at Comparable Doses in HT29 Colon Carcinoma Cells¹

Ward G. Kirlin^*,, Jiyang Cai^*, Mary J. DeLong^**,, Emma J. Patten^**, and Dean P. Jones^*,2

^* Department of Biochemistry and Winship Cancer Center, Emory University, Atlanta, GA 30322; Department of Pharmacology and Toxicology, Morehouse School of Medicine, Atlanta, GA 30310; ^** Division of Environmental and Occupational Health Sciences, School of Public Health, Emory University, Atlanta, GA 30322; Graduate Program in Nutritional Health Sciences, Emory University, Atlanta, GA 30322

²To whom correspondence should be addressed.

Dietary agents that induce glutathione S-transferases and related detoxification systems (Phase 2 enzyme inducers) are thought to prevent cancer by enhancing elimination of chemical carcinogens. The present study shows that compounds of this group (benzyl isothiocyanate, allyl sulfide, dimethyl fumarate, butylated hydroxyanisole) activated apoptosis in human colon carcinoma (HT29) cells in culture over the same concentration ranges that elicited increases in enzyme activity (5–25, 25–100, 10–100, 15–60 µmol/L, respectively). Pretreatment of cells with sodium butyrate, an agent that induces HT29 cell differentiation, resulted in parallel increases in Phase 2 enzyme activities and induction of apoptosis in response to the inducers. Cell death characteristics included apoptotic morphological changes, appearance of cells at sub-G1 phase on flow cytometry, caspase activation, DNA fragmentation and TUNEL-positive staining. The results suggest that dietary Phase 2 inducers may protect against cancer by a mechanism distinct from and in addition to that associated with enhanced elimination of carcinogens. If this occurs in vivo, diets high in such compounds could eliminate precancerous cells by apoptosis at time points well after initial exposure to chemical mutagens and carcinogens.

KEY WORDS: • NAD(P)H:quinone reductase • glutathione S-transferase • butyrate • apoptosis • human colon carcinoma cells

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