Mammalian lignans enterolactone and enterodiol, alone and in combination with the isoflavone genistein, do not promote the growth of MCF‐7 xenografts in ovariectomized athymic nude mice

Abstract

This study determined the effect of the mammalian lignans enterolactone (ENL) and enterodiol (END) alone and in combination with the isoflavone genistein (GEN) on the growth of MCF-7 tumors in ovariectomized nude mice. Ovariectomized athymic nude mice with established MCF-7 tumors were fed a basal diet (AIN-93G) and divided into 5 groups that received daily subcutaneous injections (10 mg/kg body weight (BW)) of ENL, END, GEN, a mixture of these compounds (MIX), or vehicle as a negative control for 22 weeks. A positive control group was implanted with an estradiol pellet in order to establish an estrogenic tumor growth response. In the ENL-and END-treated mice, palpable tumors regressed significantly by 91 and 83%, respectively, resulting in final tumors that were similar to the negative control tumors. However, tumor cell apoptosis was significantly enhanced by the lignans. In the GEN-treated mice, tumors initially regressed significantly by 64% but regression ceased following prolonged treatment, resulting in final tumors that were significantly larger compared to negative control, ENL-, and END-treated mice, in part by increasing tumor cell proliferation. The MIX treatment significantly regressed palpable tumors by 87% similar to negative control group, with no effects on tumor cell apoptosis or proliferation. The isoflavone GEN alone promoted the growth of established MCF-7 human breast cancer xenografts after prolonged treatment while the mammalian lignans ENL and END did not. When these phytoestrogens were given in combination, no tumor growth-promoting effects were observed. ' 2005 Wiley-Liss, Inc.

Flaxseed attenuates the tumor growth stimulating effect of soy protein in ovariectomized athymic mice with MCF‐7 human breast cancer xenografts

“…In many in vitro studies with MCF-7 cells, soy isoflavones have been shown to increase the proliferation of the cells in concentration dependent manner 6,36,37 and to inhibit apoptosis, 38 which agrees with the findings in MCF-7 xenograft model in vivo showing increased tumor growth via increased cell proliferation after consumption of isoflavone-rich diets. 9,11,22 The mammalian lignan metabolites of plant lignans in FS, enterodiol and especially enterolactone, have also been shown to increase the MCF-7 cell proliferation. 39,40 However, these in vitro findings of mammalian lignans are not in agreement with the findings in vivo as no hormone responsive mammary tumor growth stimulating effect of FS 12,13,20 or enterolactone 11,15 has been demonstrated.…”

“…11,12 After injection, tumors were palpated weekly. The tumor surface area was calculated using the formula (length/2 3 width/2) 3 p. When average tumor area reached 35 mm 2 at week 6, the estradiol pellet was removed and all mice were divided into 4 dietary treatment groups: (1) Control group fed with BD, (2) FS diet group, (3) SP diet group and (4) FS 1 SP diet group.…”

“…11 The cells were grown to 70-90% confluence and given fresh medium every 2-3 days, and a day before cell harvest. For cell injections, the cells were trypsinized, resuspended in serum-free medium containing Matrigel (1:1 vol) as previously described, 11,12 and kept on ice. Cell viability after cell injections was confirmed to be at least 85% by trypan blue exclusion assay.…”

“…11 The cell apoptosis index was determined by in-situ terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) assay demonstrating the DNA fragmentation (ApopTag Detection Kit, Intergen, Purchase, NY) and was run based on the manufacturer's instructions as previously described. 11 All slides were read blind to the treatment groups under a light microscope at 4003 magnification. The Ki-67 labeling index was determined by counting the percentage of positive cells over total number of cells (500-1,200) counted from 5-8 fields.…”

“…7,8 Isoflavone and lignan-rich diets are reported to have distinct effects on the growth of estrogen responsive tumors in vivo. After estrogen deprivation, SP and its isoflavone genistein have been shown to increase the growth of the MCF-7 tumors in ovariectomized animals, [9][10][11] while no stimulation of MCF-7 tumor growth has been observed when mice were exposed to FS 12 or its mammalian lignan metabolites, enterodiol and enterolactone. 11 In addition, FS, SDG and enterolactone have been shown to reduce the growth of the dimethylbenzanthracene (DMBA)-induced hormone responsive mammary tumors in nonovariectomized rats, [13][14][15] suggesting a protective role of lignan-rich diets and enterolactone in breast cancer.…”