The diterpene geranylgeraniol (all trans-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraen-1-ol) suppresses the growth of human liver, lung, ovary, pancreas, colon, stomach and blood tumors with undefined mechanisms. We evaluated the growth-suppressive activity of geranylgeraniol in murine B16 melanoma cells. Geranylgeraniol induced dose-dependent suppression of B16 cell growth (IC(50) = 55 ± 13 µmol/L) following a 48-h incubation in 96-well plates. Cell cycle arrest at the G1 phase, manifested by a geranylgeraniol-induced increase in the G1/S ratio and decreased expression of cyclin D1 and cyclin-dependent kinase 4, apoptosis detected by Guava Nexin™ assay and fluorescence microscopy following acridine orange and ethidium bromide dual staining, and cell differentiation shown by increased alkaline phosphatase activity, contributed to the growth suppression. Murine 3T3-L1 fibroblasts were 10-fold more resistant than B16 cells to geranylgeraniol-mediated growth suppression. Geranylgeraniol at near IC(50) concentration (60 µmol/L) suppressed the mRNA level of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase by 50%. The impact of geranylgeraniol on B16 cell growth, cell cycle arrest and apoptosis were attenuated by supplemental mevalonate, the product of HMG-CoA reductase that is essential for cell growth. Geranylgeraniol and d-δ-tocotrienol, a down-regulator of HMG-CoA reductase, additively suppressed the growth of B16 cells. These results support our hypothesis that mevalonate depletion mediates the tumor-specific growth-suppressive impact of geranylgeraniol. Geranylgeraniol may have potential in cancer chemoprevention and/or therapy.

The rate-limiting enzyme of the mevalonate pathway, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, provides essential intermediates for the prenylation of nuclear lamins and Ras and dolichol-mediated glycosylation of growth factor receptors. The diterpene geranylgeraniol downregulates the level of HMG CoA reductase and suppresses the growth of human liver, lung, ovary, pancreas, colon, stomach, and blood tumors. We evaluated the growth-suppressive activity of geranylgeraniol in human prostate carcinoma cells. Geranylgeraniol induced dose-dependent suppression of the viability of human DU145 prostate carcinoma cells (IC50 = 80 ±18 μmol/L, n =5) following 72-h incubations in 96-well plates. Cell cycle was arrested at the G1 phase with a concomitant decrease in cyclin D1 protein. Geranylgeraniol-induced apoptosis was detected by flow cytometric analysis, fluorescence microscopy following acridine orange and ethidium bromide dual staining, and caspase-3 activation. Geranylgeraniol-induced viability suppression was accompanied by concentration-dependent decrease in the level of HMG CoA reductase protein. As a nonsterol molecule that downregulates HMG CoA reductase in the presence of sterols, geranylgeraniol may have potential in the chemoprevention and/or therapy of human prostate cancer.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase is the rate-limiting activity in the mevalonate pathway that provides essential intermediates for posttranslational modification of growth-associated proteins. Assorted dietary isoprenoids found in plant foods suppress HMG CoA reductase and have cancer chemopreventive activity. β-Ionone, a cyclic sesquiterpene and an end-ring analog of β-carotene, induced concentration-dependent inhibition of the proliferation of human DU145 (IC50 = 210 μmol/L) and LNCaP (IC50 = 130 μmol/L) prostate carcinoma cells and PC-3 prostate adenocarcinoma cells (IC50 = 130 μmol/L). Concomitantly, β-ionone-induced apoptosis and cell cycle arrest at the G1 phase in DU145 and PC-3 cells were shown by fluorescence microscopy, flow cytometry, and TUNEL reaction, and downregulation of cyclin-dependent kinase 4 (Cdk4) and cyclin D1 proteins. Growth suppression was accompanied by β-ionone-induced downregulation of reductase protein. A blend of β-ionone (150 μmol/L) and trans, trans-farnesol (25 μmol/L), an acyclic sesquiterpene that putatively initiates the degradation of reductase, suppressed the net growth of DU145 cells by 73%, an impact exceeding the sum of those of β-ionone (36%) and farnesol (22%), suggesting a synergistic effect. β-ionone, individually or in combination with other HMG CoA reductase suppressors, may have potential in prostate cancer chemoprevention and/or therapy.

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The mevalonate pathway provides essential intermediates for the prenylation or dolichylation of growth‐related proteins including nuclear lamins, Ras and growth factor receptors. d‐δ‐Tocotrienol, a vitamin E isomer with farnesyl side chain, and geranylgeraniol, a diterpene, are suppressors of 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG CoA) reductase, the rate‐limiting activity of the mevalonate pathway. We evaluated the impact of d‐δ‐tocotrienol and geranylgeraniol on cell cycle progression and apoptosis in human A375 and A2058 melanoma cells and murine B16 melanoma cells. d‐δ‐Tocotrienol (11–38 μmol/L) and geranylgeraniol (30–90 μmol/L) induced concentration‐dependent cell cycle arrest at the G1 phase and apoptosis as detected by flow cytometry and fluorescence microscopy; the impacts were accompanied by decreased levels of cyclin‐dependent kinase 4 and cyclin D1 proteins and the activation of caspases‐3. d‐δ‐Tocotrienol also suppressed the level of Ras protein in A375 and A2058 cells. Blends of d‐δ‐tocotrienol and geranylgeraniol suppressed the growth of murine B16 melanoma cells to greater extents than the sum of individual impacts, suggesting a synergistic effect. The tocotrienols, geranylgeraniol and other mevalonate suppressors may have potential application in melanoma prevention and therapy. TDA & TWU REP.

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SummaryThe college environment increases risk of weight gain in young adults with overweight/obesity. Behavioural weight loss interventions are proven effective, however, young adults' adherence to such programs is poor. The purpose of the study was to determine weight loss treatment preferences of 2‐ and 4‐year college students for the development of population‐specific interventions. Students with a BMI ≥25, between 18 and 24 years of age, and enrolled in one of four institutions were recruited. A questionnaire was developed to assess students' preferences and was administered via Qualtrics. BMI was calculated from objectively assessed height and weight measurements. Descriptive analyses, chi‐square, Fisher's Exact Test, Mann‐Whitney U test and Cramer's V were performed. Participants (n = 133, age = 20.2 ± 1.8) predominately identified as female (70%), non‐Hispanic (68%) and Black/African American (32%) or White (32%). Fifty‐five percent met criteria for obesity. Most students preferred session length of ≤1 hour (78%), for meetings to be held on a weekday (70%) and for both a peer and a professional to co‐facilitate meetings (61%). Preferences for health outcomes and physical activity monitoring, type of physical activity, frequency of dietary monitoring, physical activity tracking method and interest in financial incentives to promote core treatment components differed between institutions. Heterogeneity in program preferences by college environment should be considered when designing weight loss interventions.

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