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Treatment with flaxseed oil induces apoptosis in cultured malignant cells
Alison L. Buckner,a Carly A. Buckner,a,b Sabine Montaut,a,c and Robert M. Lafreniea,b,c,d,∗
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Abstract
Flaxseed oil is widely recognized for its exceptional nutritional value, high concentration of fiber-based lignans and large amounts of ω-fatty acids. It is one of a generic group of functional foods that is often taken by cancer patients as a potential treatment. We have examined the anti-cancer effects of flaxseed oil by studying its direct effects on cancer cell growth in vitro. Treatment of a variety of cancer cell lines with flaxseed oil decreased their growth in a dose-dependent manner while non-malignant cell lines showed small increases in cell growth. Cells treated with a mixture of fatty acids, including α-linolenic acid, docosahexaenoic acid, and eicosapentaenoic acid and lignans including enterodiol and enterolactone was also able to decrease the growth of cancer cells. Treatment of B16-BL6 murine melanoma and MCF-7 breast cancer cells with flaxseed oil induced apoptosis as determined by changes in cell morphology, annexin V staining, DNA fragmentation and/or caspase activation. In addition, treatment with flaxseed oil also disrupted mitochondrial function in B16-BL6 and MCF-7 cells. These results indicate that flaxseed oil can specifically inhibit cancer cell growth and induce apoptosis in some cancer cells and suggests it has further potential in anti-cancer therapy.
Keywords: Cancer research, Cell biology, Cell culture, Cell death, Food science, Natural product, Nutrition, Flaxseed oil, Cancer cells, Cell death, Omega fatty acids
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1. Introduction
Flax (Linum usitatissimum), in the form of seeds or seed-derived oil, is a “functional food” recognized for its nutritional quality, high concentration of fiber-based lignans, and large amounts of ω−fatty acids [1, 2]. Flax was used to treat various health complaints in ancient Greece and Rome and was described in ancient Ayurvedic and Egyptian sources [3]. The recent popularity of flax has been bolstered by a number of studies describing health-promoting benefits such as reducing cardiovascular disease, decreasing cancer risk, inhibiting inflammatory activity, promoting gastrointestinal regularity, and alleviating menopausal symptoms [4, 5, 6]. Studies conducted in aged hens showed a diet rich in whole flaxseed decreased the risk and severity of ovarian cancer by decreasing proinflammatory prostaglandin and estrogen signaling pathways [7, 8]. The growth of estrogen-dependent MCF-7 breast cancer cells in xenotransplanted mice was also inhibited by feeding the mice flaxseed and involved decreasing hormone and growth factor signaling [9, 10]. A meta-analysis of the impact of flax on patients with breast cancer has indicated that regular consumption of flax decreased breast cancer risk, improved symptoms and survival, and was associated with improved mental health among breast cancer patients [11].
Flaxseed is one of the richest plant sources of α-linolenic acid, an ω-3 polyunsaturated fatty acid (PUFA) (49–60%), and contains a modest level of linoleic acid, an ω-6 PUFA (12–17%) [3]. It is suggested that a healthy diet should consist of a 1:4 ratio of ω-3 to ω-6 fatty acids. However, the average western diet which consists of a 1:10 to 1:30 ratio of ω-3 to ω-6 fatty acids has been linked to high levels of chronic disease and cancer [12, 13, 14]. Increasing the ω-3/ω-6 PUFA ratio has been shown to decrease cancer risk [15, 16] while increasing ω-6 PUFA has been shown to increase cancer risk [17, 18] in some human epidemiological studies, although not in all patient cohorts [6]. In vitro experiments and animal models suggest that diets rich in ω-3 PUFA can be protective against several cancers, such as colon or breast cancers [19, 20, 21, 22] while treatment with ω-6 fatty acids can increase cancer cell proliferation [15]. For example, mice fed diets enriched in α-linolenic acid, which increases plasma levels of α-linolenic acid and its metabolites eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), decreases the growth of transplanted prostate, colon, and breast cancer cells [23, 24, 25, 26]. In vitro studies have shown that treatment of cancer cells with ω-3 fatty acids such as α-linolenic acid, DHA and/or EPA can inhibit their growth and promote apoptosis. For example, treatment of cells with α-linolenic acid can inhibit the growth and promote apoptosis of cervical, pancreatic, colon and breast cancer cells [25, 26, 27, 28, 29, 30]. In addition, treatment of colon cancer cells [31] or MCF-7 breast cancer cells [32] with α-linolenic acid, EPA or DHA was able to induce apoptosis through a mitochondrial-mediated pathway. Other experiments have shown that α-linolenic acid, DHA, and EPA can affect cell survival by altering the expression of oxidative response signaling [33], MAP kinase and NF-kB survival pathways [27], or miR-21 expression [34].
Flaxseed is also a rich source of plant lignans, such as secoisolariciresinol diglucoside (SDG), which have been shown to block cell proliferation and reduce tumor growth in experimental models possibly by modulating estrogen receptor- or growth factor-dependent signaling [9, 35]. For example, treatment of breast cancer cells with flaxseed enriched in lignans, including SDG, was able to inhibit cell growth likely by modifying estrogen signaling and downregulating the expression of ERα and ERβ [10, 19]. However, it is thought that the combination of SDG and ω-3 fatty acids is important to mediate the anti-inflammatory and anti-cancer activities [9, 16, 36].
Our experiments investigated the effects of treatment of cultured cells with flaxseed oil in order to investigate the mechanisms underlying changes in cell growth. The results indicate that treatment with flaxseed oil preferentially inhibits the growth of malignant cell cultures and were able to induce apoptosis in treated cancer cells.
Alison L. Buckner,a Carly A. Buckner,a,b Sabine Montaut,a,c and Robert M. Lafreniea,b,c,d,∗
Author information Article notes Copyright and License information Disclaimer
This article has been cited by other articles in PMC.
Go to:
Abstract
Flaxseed oil is widely recognized for its exceptional nutritional value, high concentration of fiber-based lignans and large amounts of ω-fatty acids. It is one of a generic group of functional foods that is often taken by cancer patients as a potential treatment. We have examined the anti-cancer effects of flaxseed oil by studying its direct effects on cancer cell growth in vitro. Treatment of a variety of cancer cell lines with flaxseed oil decreased their growth in a dose-dependent manner while non-malignant cell lines showed small increases in cell growth. Cells treated with a mixture of fatty acids, including α-linolenic acid, docosahexaenoic acid, and eicosapentaenoic acid and lignans including enterodiol and enterolactone was also able to decrease the growth of cancer cells. Treatment of B16-BL6 murine melanoma and MCF-7 breast cancer cells with flaxseed oil induced apoptosis as determined by changes in cell morphology, annexin V staining, DNA fragmentation and/or caspase activation. In addition, treatment with flaxseed oil also disrupted mitochondrial function in B16-BL6 and MCF-7 cells. These results indicate that flaxseed oil can specifically inhibit cancer cell growth and induce apoptosis in some cancer cells and suggests it has further potential in anti-cancer therapy.
Keywords: Cancer research, Cell biology, Cell culture, Cell death, Food science, Natural product, Nutrition, Flaxseed oil, Cancer cells, Cell death, Omega fatty acids
Go to:
1. Introduction
Flax (Linum usitatissimum), in the form of seeds or seed-derived oil, is a “functional food” recognized for its nutritional quality, high concentration of fiber-based lignans, and large amounts of ω−fatty acids [1, 2]. Flax was used to treat various health complaints in ancient Greece and Rome and was described in ancient Ayurvedic and Egyptian sources [3]. The recent popularity of flax has been bolstered by a number of studies describing health-promoting benefits such as reducing cardiovascular disease, decreasing cancer risk, inhibiting inflammatory activity, promoting gastrointestinal regularity, and alleviating menopausal symptoms [4, 5, 6]. Studies conducted in aged hens showed a diet rich in whole flaxseed decreased the risk and severity of ovarian cancer by decreasing proinflammatory prostaglandin and estrogen signaling pathways [7, 8]. The growth of estrogen-dependent MCF-7 breast cancer cells in xenotransplanted mice was also inhibited by feeding the mice flaxseed and involved decreasing hormone and growth factor signaling [9, 10]. A meta-analysis of the impact of flax on patients with breast cancer has indicated that regular consumption of flax decreased breast cancer risk, improved symptoms and survival, and was associated with improved mental health among breast cancer patients [11].
Flaxseed is one of the richest plant sources of α-linolenic acid, an ω-3 polyunsaturated fatty acid (PUFA) (49–60%), and contains a modest level of linoleic acid, an ω-6 PUFA (12–17%) [3]. It is suggested that a healthy diet should consist of a 1:4 ratio of ω-3 to ω-6 fatty acids. However, the average western diet which consists of a 1:10 to 1:30 ratio of ω-3 to ω-6 fatty acids has been linked to high levels of chronic disease and cancer [12, 13, 14]. Increasing the ω-3/ω-6 PUFA ratio has been shown to decrease cancer risk [15, 16] while increasing ω-6 PUFA has been shown to increase cancer risk [17, 18] in some human epidemiological studies, although not in all patient cohorts [6]. In vitro experiments and animal models suggest that diets rich in ω-3 PUFA can be protective against several cancers, such as colon or breast cancers [19, 20, 21, 22] while treatment with ω-6 fatty acids can increase cancer cell proliferation [15]. For example, mice fed diets enriched in α-linolenic acid, which increases plasma levels of α-linolenic acid and its metabolites eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), decreases the growth of transplanted prostate, colon, and breast cancer cells [23, 24, 25, 26]. In vitro studies have shown that treatment of cancer cells with ω-3 fatty acids such as α-linolenic acid, DHA and/or EPA can inhibit their growth and promote apoptosis. For example, treatment of cells with α-linolenic acid can inhibit the growth and promote apoptosis of cervical, pancreatic, colon and breast cancer cells [25, 26, 27, 28, 29, 30]. In addition, treatment of colon cancer cells [31] or MCF-7 breast cancer cells [32] with α-linolenic acid, EPA or DHA was able to induce apoptosis through a mitochondrial-mediated pathway. Other experiments have shown that α-linolenic acid, DHA, and EPA can affect cell survival by altering the expression of oxidative response signaling [33], MAP kinase and NF-kB survival pathways [27], or miR-21 expression [34].
Flaxseed is also a rich source of plant lignans, such as secoisolariciresinol diglucoside (SDG), which have been shown to block cell proliferation and reduce tumor growth in experimental models possibly by modulating estrogen receptor- or growth factor-dependent signaling [9, 35]. For example, treatment of breast cancer cells with flaxseed enriched in lignans, including SDG, was able to inhibit cell growth likely by modifying estrogen signaling and downregulating the expression of ERα and ERβ [10, 19]. However, it is thought that the combination of SDG and ω-3 fatty acids is important to mediate the anti-inflammatory and anti-cancer activities [9, 16, 36].
Our experiments investigated the effects of treatment of cultured cells with flaxseed oil in order to investigate the mechanisms underlying changes in cell growth. The results indicate that treatment with flaxseed oil preferentially inhibits the growth of malignant cell cultures and were able to induce apoptosis in treated cancer cells.
Treatment with flaxseed oil induces apoptosis in cultured malignant cells
Flaxseed oil is widely recognized for its exceptional nutritional value, high concentration of fiber-based lignans and large amounts of ω-fatty acids. It is one of a generic group of functional foods that is often taken by cancer patients as a ...
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