Isoprenoids Suppress the Growth of Murine B16 Melanomas In Vitro and In Vivo

Abstract

Sundry mevalonate-derived constituents (isoprenoids) of fruits, vegetables and cereal grains suppress the growth of tumors. This study estimated the concentrations of structurally diverse isoprenoids required to inhibit the increase in a population of murine B16(F10) melanoma cells during a 48-h incubation by 50% (IC50 value). The IC50 values for d-limonene and perillyl alcohol, the monoterpenes in Phase I trials, were 450 and 250 micromol/L, respectively; related cyclic monoterpenes (perillaldehyde, carvacrol and thymol), an acyclic monoterpene (geraniol) and the end ring analog of beta-carotene (beta-ionone) had IC50 values in the range of 120-150 micromol/L. The IC50 value estimated for farnesol, the side-chain analog of the tocotrienols (50 micromol/L) fell midway between that of alpha-tocotrienol (110 micromol/L) and those estimated for gamma- (20 micromol/L) and delta- (10 micromol/L) tocotrienol. A novel tocotrienol lacking methyl groups on the tocol ring proved to be extremely potent (IC50, 0.9 micromol/L). In the first of two diet studies, experimental diets were fed to weanling C57BL female mice for 10 d prior to and 28 d following the implantation of the aggressively growing and highly metastatic B16(F10) melanoma. The isomolar (116 micromol/kg diet) and the Vitamin E-equivalent (928 micromol/kg diet) substitution of d-gamma-tocotrienol for dl-alpha-tocopherol in the AIN-76A diet produced 36 and 50% retardations, respectively, in tumor growth (P < 0.05). In the second study, melanomas were established before mice were fed experimental diets formulated with 2 mmol/kg d-gamma-tocotrienol, beta-ionone individually and in combination. Each treatment increased (P < 0.03) the duration of host survival. Our finding that the effects of individual isoprenoids were additive suggests the possibility that one component of the anticarcinogenic action of plant-based diets is the tumor growth-suppressive action of the diverse isoprenoid constituents of fruits, vegetables and cereal grains.

Induction of cytotoxicity in human lung adenocarcinoma cells by 6‐O‐carboxypropyl‐α‐tocotrienol, a redox‐silent derivative of α‐tocotrienol

“…The potency of tocotrienol isoforms in anticancer activity display a relationship corresponding to ␦-tocotrienol Ͼ ␥-tocotrienol Ͼ T3. 34 Although ␦-tocotrienol and ␥-tocotrienol have strong anticancer potential, these isoforms are highly toxic toward normal cells. 35 Modification of the isoformdependent anticancer properties by blocking antioxidant activity may also cause high toxicity toward normal cells.…”

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

“…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.…”

“…In addition, b-ionone also affected the progression of metastasis in SGC-7901 cells 11 and B16 cells. 12,17 In this study, female Sparague-Dawley rats were fed 3 levels of 9.0 (low), 18.0 (medium) and 36.0 mmol/kg (high) of b-ionone in the AIN-76A diet, starting 2 weeks before DMBA administration and continuing for the 24 weeks until the end of the experiment. The positive control group, given the DMBA, developed mammary tumors with 82.1% tumor incidence during the 24-week study, and no tumors were detected in the negative control group without DMBA.…”

“…possessed chemopreventive activity, which was observed to prevent DNA damage in the initial phases of hepatocarcinogenesis induced in rats by diethylnitrosamine and 2-acetyaminofluorene. 23 He et al 17 reported that 2 mmol/kg b-ionone in the AIN-76A diet prolonged host survival by 30% compared to the control group in a melanoma model of C57BL female mice (p < 0.005). Thus, b-ionone is a potent cancer chemopreventive agent.…”

“…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.…”