Conjugated Linoleic Acid Inhibits Proliferation and Induces Apoptosis of Normal Rat Mammary Epithelial Cells in Primary Culture

Ip, Margot M.; Masso-Welch, Patricia A.; Shoemaker, Suzanne F.; Shea-Eaton, Wendy; Ip, Clement

doi:10.1006/excr.1999.4499

Cited by 138 publications

(74 citation statements)

References 47 publications

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“…In apoptotic pathway, the death signal triggers a cascade of various molecular actions resulting in the cleavage of genomic DNA and specific proteins. It has been reported that CLA induces apoptosis in cancer cells such as mammary adenocarcinoma [20], normal rat mammary epithelical cells [21], and human hepatoma [22]. However, the data on isomer specificity has been limited [13].…”

Section: Discussionmentioning

confidence: 99%

Potent inhibitory effect of trans9, trans11 isomer of conjugated linoleic acid on the growth of human colon cancer cells

Beppu

Hosokawa

Tanaka

et al. 2006

The Journal of Nutritional Biochemistry

122

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This study compared the growth inhibitory effects of pure conjugated linoleic acid (CLA) isomers (cis(c)9,c11-CLA, c9,trans(t)11-CLA, t9,t11-CLA, and t10,c12-CLA) on human colon cancer cell lines (Caco-2, HT-29, and DLD-1). When Caco-2 cells were incubated up to 72 h with 200 M each isomer even in the presence of 10% fetal bovine serum (FBS), cell proliferation was inhibited by all CLA isomers in a time dependent manner. The strongest inhibitory effect was shown by t9,t11-CLA, followed by t10,c12-CLA, c9,c11-CLA, and c9,t11-CLA, respectively. The strongest effect of t9,t11-CLA was also observed in other colon cancer cell lines (HT-29 and DLD-1). The order of the inhibitory effect of CLA isomer was confirmed in the presence of 1% FBS. CLA isomers supplemented in the culture medium were readily incorporated into the cellular lipids of Caco-2 and changed their fatty acid composition. The CLA contents in cellular lipids were 26.2+2.7% for t9,t11-CLA, 35.9+0.3% for c9,t11-CLA, and 46.3+0.8% for t10,c12-CLA, respectively. DNA fragmentation was clearly recognized in Caco-2 cells treated with t9,t11-CLA. This apoptotic effect of t9,t11-CLA was dose-and time-dependent. DNA fragmentation was also induced by 9c,11t-CLA and t10,c12-CLA. However, fragmentation levels with both isomers were much lower than that with t9,t11-CLA.t9t11-CLA treatment of Caco-2 cells decreased Bcl-2 levels in association with apoptosis, whereas Bax levels remained unchanged. These results suggest that decreased expression of Bcl-2 by t9t11-CLA might increase the sensitivity of cells to lipid peroxidation and to programmed cell death, apoptosis. AbstractThis study compared the growth inhibitory effects of pure conjugated linoleic acid (CLA) isomers (cis(c)9,c11-CLA, c9,trans(t)11-CLA, t9,t11-CLA, and t10,c12-CLA) on human colon cancer cell lines (Caco-2, HT-29, and DLD-1). When Caco-2 cells were incubated up to 72 h with 200 µM each isomer even in the presence of 10% fetal bovine serum (FBS), cell proliferation was inhibited by all CLA isomers in a time dependent manner. The strongest inhibitory effect was shown by t9,t11-CLA, followed by t10,c12-CLA, c9,c11-CLA, and c9,t11-CLA, respectively. The strongest effect of t9,t11-CLA was also observed in other colon cancer cell lines (HT-29 and DLD-1). The order of the inhibitory effect of CLA isomer was confirmed in the presence of 1% FBS. * Manuscript 2CLA isomers supplemented in the culture medium were readily incorporated into the cellular lipids of Caco-2 and changed their fatty acid composition. The CLA contents in cellular lipids were 26.2+2.7% for t9,t11-CLA, 35.9+0.3% for c9,t11-CLA, and 46.3+0.8% for t10,c12-CLA, respectively. DNA fragmentation was clearly recognized in Caco-2 cells treated with t9,t11-CLA. This apoptotic effect of t9,t11-CLA was doseand time-dependent. DNA fragmentation was also induced by 9c,11t-CLA and t10,c12-CLA. However, fragmentation levels with both isomers were much lower than that with t9,t11-CLA. t9t11-CLA treatment of Caco-2 cells decreased Bcl-2 levels in...

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Section: Discussionmentioning

confidence: 99%

Potent inhibitory effect of trans9, trans11 isomer of conjugated linoleic acid on the growth of human colon cancer cells

Beppu

Hosokawa

Tanaka

et al. 2006

The Journal of Nutritional Biochemistry

122

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“…t10,c12-CLA, ∼98% pure, was obtained from Larodan Fine Chemicals (Malmö, Sweden) and prepared as the sodium salt [13] for use in culture. For each experiment, 5×10 5 cells were plated in 100 mm dishes (5×10 4 cells/ml of medium) and cultured overnight to allow attachment, prior to addition of CLA.…”

Section: Cell Culturementioning

confidence: 99%

Conjugated linoleic acid induces apoptosis of murine mammary tumor cells via Bcl-2 loss

Lisafeld

et al. 2007

Biochemical and Biophysical Research Communications

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Conjugated linoleic acid (CLA) is a powerful anticancer agent in a number of tumor model systems; however, its precise mechanism of action remains elusive. Here, we report that t10,c12 CLA, a component of synthetic CLA supplements, induced apoptosis and G 1 arrest of p53 mutant TM4t murine mammary tumor cells. Furthermore, t10,c12-CLA induced a time-and concentrationdependent cleavage of caspases-3 and -9, and release of cytochrome c from mitochondria to cytosol. Levels of Bcl-2 protein were decreased both in total cellular lysates and in mitochondria after t10,c12-CLA treatment; however, there was no significant change in Bax or Bak. Overexpression of Bcl-2 attenuated apoptosis in response to t10,c12-CLA treatment. These results demonstrate that t10,c12-CLA triggers apoptosis of p53 mutant murine mammary tumor cells through the mitochondrial pathway by targeting Bcl-2.

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“…The c9t11 isomer may be the active form, alone or in combination with other isomers, for the reported results of the mixed isomer preparations on tumorigenesis. [5][6][7]18,25,26 The t10c12 isomer may be the active form affecting energy metabolism, weight gain and body fat deposition in animals, as indicated by the results of two studies in which mice were supplemented with CLA mixtures varying in the ratio of t10c12 and c9t11 isomers. 13,21 Despite the positive antiobesity effect of CLA in animals, the effects of CLA on body weight and composition in humans are inconsistent and less significant than those observed in animals.…”

Section: Introductionmentioning

confidence: 99%

Conjugated linoleic acid and obesity control: efficacy and mechanisms

2004

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Obesity is associated with high blood cholesterol and high risk for developing diabetes and cardiovascular disease. Therefore, management of body weight and obesity are increasingly considered as an important approach to maintaining healthy cholesterol profiles and reducing cardiovascular risk. The present review addresses the effects of conjugated linoleic acid (CLA) on fat deposition, body weight and composition, safety, as well as mechanisms involved in animals and humans. Animal studies have shown promising effects of CLA on body weight and fat deposition. The majority of the animal studies have been conducted using CLA mixtures that contained approximately equal amounts of trans-10, cis-12 (t10c12) and cis-9, trans-11 (c9t11) isomers. Results of a few studies in mice fed CLA mixtures with different ratios of c9t11 and t10c12 isomers have indicated that the t10c12 isomer CLA may be the active form of CLA affecting weight gain and fat deposition. Inductions of leptin reduction and insulin resistance are the adverse effects of CLA observed in only mice. In pigs, the effects of CLA on weight gain and fat deposition are inconsistent, and no adverse effects of CLA have been reported. A number of human studies suggest that CLA supplementation has no effect on body weight and insulin sensitivity. Although it is suggested that the t10c12 CLA is the antiadipogenic isomer of CLA in humans, the effects of CLA on fat deposition are marginal and more equivocal as compared to results observed in animal studies. Mechanisms through which CLA reduces body weight and fat deposition remain to be fully understood. Proposed antiobesity mechanisms of CLA include decreased energy/food intake and increased energy expenditure, decreased preadipocyte differentiation and proliferation, decreased lipogenesis, and increased lipolysis and fat oxidation. In summary, CLA reduces weight gain and fat deposition in rodents, while produces less significant and inconsistent effects on body weight and composition in pigs and humans. New studies are required to examine isomer-specific effects and mechanisms of CLA in animals and humans using purified individual CLA isomers.

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Conjugated Linoleic Acid Inhibits Proliferation and Induces Apoptosis of Normal Rat Mammary Epithelial Cells in Primary Culture

Cited by 138 publications

References 47 publications

Potent inhibitory effect of trans9, trans11 isomer of conjugated linoleic acid on the growth of human colon cancer cells

Potent inhibitory effect of trans9, trans11 isomer of conjugated linoleic acid on the growth of human colon cancer cells

Conjugated linoleic acid induces apoptosis of murine mammary tumor cells via Bcl-2 loss

Conjugated linoleic acid and obesity control: efficacy and mechanisms

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