β-Carotene 9′,10′ Oxygenase Modulates the Anticancer Activity of Dietary Tomato or Lycopene on Prostate Carcinogenesis in the TRAMP Model

Abstract

The hypothesis that dietary tomato consumption or the intake of the carotenoid lycopene inhibits prostate cancer arose from epidemiologic studies and is supported by preclinical rodent experiments and in vitro mechanistic studies. We hypothesize that variation in activity of carotenoid cleavage enzymes, such as β-carotene 9’,10’-oxygenase (BCO2), may alter the impact of dietary tomato and lycopene on prostate carcinogenesis and therefore examined this relationship in the TRAMP model. Starting at three weeks of age, TRAMP:Bco2+/+ and TRAMP:Bco2−/− mice were fed either AIN-93G control, or semi-purified diets containing 10% tomato powder or 0.25% lycopene beadlets until 18 weeks of age. Both tomato- and lycopene-fed TRAMP:Bco2−/− mice had significantly greater serum concentrations of total, 5-cis, other cis, and all-trans lycopene than TRAMP:Bco2+/+ mice. Tomato- and lycopene-fed mice had a lower incidence of prostate cancer compared to the control-fed mice. While Bco2 genotype alone did not significantly change prostate cancer outcome in the control AIN-93G-fed mice, the abilities of lycopene and tomato feeding to inhibit prostate carcinogenesis were significantly attenuated by the loss of Bco2 (interaction p=0.0004 and p=0.0383, respectively). Overall, dietary tomato and lycopene inhibited the progression of prostate cancer in TRAMP in a Bco2 genotype-specific manner, potentially implicating the anticancer activity of lycopene cleavage products. This study suggests that genetic variables impacting carotenoid metabolism and accumulation can impact anti-cancer activity and that future efforts devoted to understanding the interface between tomato carotenoid intake, host genetics, and metabolism will be necessary to clearly elucidate their interactive roles in human prostate carcinogenesis.

Plasma Metabolomics Reveals Steroidal Alkaloids as Novel Biomarkers of Tomato Intake in Mice

“…As polar extracts of the plasma were analyzed, non‐polar carotenoids were not present in these extracts. We have previously reported blood concentrations of lycopene (25 μM) in mice fed the same red tomato‐ and lycopene‐containing diets …”

“…The tomato and control diets contained placebo beadlets (0.25 %) to match the other components of the lycopene beadlets. The red tomato diet and lycopene diet were formulated to deliver the same amount of lycopene and have demonstrated biological activity in mice . Diets were stored in the dark at ‐20°C to minimize the degradation and oxidation of phytochemicals over the course of the study.…”

“…In the western diet, tomatoes and tomato products are the predominant sources of lycopene, which is absorbed and distributed to various tissues, although large interindividual variation is noted suggesting strong genetic and other factors impacting bioavailability . Studies in preclinical models of carcinogenesis have also demonstrated a protective effect of tomatoes or lycopene . Human intervention studies to prove a causal relationship between tomato or lycopene intake and reduced disease risk have not been conducted.…”

Chemoprevention agents for melanoma: A path forward into phase 3 clinical trials

“…There is evidence from studies in transgenic mouse models of prostate cancer that metabolites similar to bixin are the molecular species responsible for the cancer preventive effects of lycopene. 138 Bixin has an excellent safety record and good systemic bioavailability when orally administered. A team from the Arizona Cancer Center recently reported that intraperitoneal injection of bixin activates the transcription factor Nrf2 and thereby induces an antioxidant response in a mouse model of UVinduced photodamage and inflammation.…”

“…It is used worldwide as a dietary additive and cosmetic ingredient known as annatto. There is evidence from studies in transgenic mouse models of prostate cancer that metabolites similar to bixin are the molecular species responsible for the cancer preventive effects of lycopene 137 . Bixin has an excellent safety record and good systemic bioavailability when administered orally.…”