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Cruciferous Vegetables Destroy Cancer Stem Cells
In this month's guest post, my friend Alexa Federico gives us a wholesome, real foods recipe chocked full of sulfur-containing veggies that promote detoxification and hormonal balance.
In fact, researchers out of South Dakota State University recently discovered that phenethyl isothiocyanate (PEITC), a compound found in cauliflower, broccoli, and the nutritional powerhouse featured in Alexa's recipe below---cabbage---may target cancer stem cells (Wang et al., 2014). Impressively, PEITC suppresses cervical cancer stem cell formation in a concentration- and time-dependent manner, causing 75% of stem cells to die within twenty four hours when human cervical cancer stem cells are incubated with PEITC (Wang et al., 2014).
This is essential, since studies have shown that radiation generates therapy-resistant cancer stem cells, leading cancer cells to become more malignant (Printz, 2012). In fact, oftentimes, conventional chemotherapy and radiation enable cancer stem cells to linger, such that secondary, more aggressive cancers emerge years later (Printz, 2012).
Researchers found that PEITC attenuated proliferation of cancer cells and up-regulated expression of death receptions 4 and 5 on cancer stem cells, the activation of which induces cell suicide, or apoptosis, in cancer cell lines (Wang et al., 2014). PEITC likewise stimulated TRAIL (tumor necrotic factor-related apoptosis-inducing ligand) signaling, which selectively invokes programmed cell death in cancer stem cells (Wang et al., 2014).
When the PEITC-treated cancer stem cells were xeno-transplanted into mice, less tumorigenicity and decreased levels of human vascular endothelial growth factor A were observed (Wang et al., 2014). Human vascular endothelial growth factor A is required for vascularization of the tumor with its own blood supply (angiogenesis), a prerequisite for tumor growth (Wang et al., 2014). Further, metastasis, or migration of the cancer to the distant sites, only occurred in the cancer stem cell-injected group that was not subject to PEITC treatment, suggesting that PEITC reduces risk of cancer spreading (Wang et al., 2014).
Another study showed that watercress, another PEITC-containing cruciferous vegetable, decreases the phosphorylation of the translation regulator 4E binding protein 1 (4E-BP1) (Syed Alwi et al., 2010). Decreased phosphorylation of 4E-BP1 reduces activity of the transcription factor hypoxia-inducible factor (HIF), which is a critical positive regulator of angiogenesis (Syed Alwi et al., 2010). Thus, PEITC exerts anti-cancer effects by preventing the tumor from creating its own blood supply. These results were replicated in human subjects, as participants who consumed an 80 gram portion of watercress exhibited significantly reduced 4E-BP1 phosphorylation at six and eight hours after ingesting watercress (Syed Alwi et al., 2010).
In fact, pre-diagnosis adherence to diets that incorporated these cruciferous vegetables significantly favored survival in ovarian cancer (Dolecek et al., 2010). Cruciferous vegetable intake is correlated with reduced susceptibility to cancers, especially those with epithelial histologies (Beecher, 1994; Verhoven et al., 1995).
The Cancer-Fighting, Hormone-Regulating, Detoxification-Promoting Compounds in Cruciferous Vegetables
Importantly, cruciferous or Brassica family vegetables contain glucosinolates, which are enzymatically converted into isothiocyanates, compounds which favorably modify metabolism of carcinogens by inhibiting carcinogen-activating enzymes and inducing detoxification enzymes (Hayes, Kelleher, & Eggleston, 2008; Bones & Rossiter, 1996). In fact, "Indole-3-carbinol, also found in cruciferous vegetables, is thought to affect estrogen metabolism by producing a less-potent estradiol that protects against estrogen-related cancers including ovary" (Dolecek et al., 2010).
Indole-3-carbinole (I3C) is particularly concentrated in broccoli, white cabbage, Brussels sprouts and cauliflower, and its biological effects are attributed to a series of oligomeric products, such as 3,3'-diindolylmethane (DIM), which are formed under acidic conditions. I3C is capable of suppressing division of tumor cells isolated from breast, colon, prostate, and endometrium cancers, and likewise has shown to be chemopreventative for hormone-sensitive breast and cervical cancers, primarily eliciting effects through the PI3K/Akt/mTOR pathways and the aryl hydrocarbon receptor (Popolo et al., 2017).
Some of the isothiocyanates that occur in the cruciferous family, primarily in the form of their glucosinolate precursors, such as sulforaphane and 4-methylsulfinylbutyl isothiocyanate, are likewise very potent inducers of phase 2 detoxification enzymes. These compounds regulate mammalian enzymes of xenobiotic metabolism, promoting toxicant excretion and reducing the toxic burden that is implicated in cancer, autoimmune disease, and cardiovascular disorders.
Phase 2 biotransformation, which transforms more reactive intermediaries into water-soluble, polar, easily excreted compounds, is often deficient in chronic illness. Fahey and colleagues (1997), for instance, state, "Induction of phase 2 detoxication enzymes [e.g., glutathione transferases, epoxide hydrolase, NAD(P)H: quinone reductase, and glucuronosyltransferases] is a powerful strategy for achieving protection against carcinogenesis, mutagenesis, and other forms of toxicity of electrophiles and reactive forms of oxygen" (p. 10367).
Lastly, cruciferous vegetables have been shown to impart protection from breast cancer. Watercress and broccoli, in particular, inhibit over-expression of matrix metalloproteinases, including metalloproteinase-9 (MMP-9), in a dose-dependent manner (Rose et al., 2005). MMPs are associated with invasiveness of breast cancer cell lines (Rose et al., 2005). In other words, isothiocyanates in cruciferous vegetables prevent tumor expansion, a process mediated by MMPs that degrade the extracellular matrix (Rose et al., 2005). The authors conclude, "The inhibitory effects observed in the current study may contribute to the suppression of carcinogenesis by diets high in cruciferous vegetables" (Rose et al., 2005, p. 105).
For optimal protection, include a variety of the following cruciferous vegetables in your diet:
- bok choy
- Brussels sprouts
- collard greens
- mustard greens
Supplemental Options for the Fiber-Intolerant
If you have small intestinal bacteria overgrowth (SIBO), are in the midst of an inflammatory bowel disease flare, require a low-FODMAP diet, or are otherwise intolerant to the fibrous cruciferous vegetables, you can still reap some of the benefits of I3C, DIM, and sulforaphane on hormonal balance by supplementing with them. I3C and its downstream metabolite, DIM, may also support healthy estrogen metabolism in the case of estrogen dominance, and help to restore balance in phase 1 and phase 2 hepatic detoxification. My favorite high quality combination of I3C/DIM and my favorite sulforaphane product, Crucera SGS, are *here* under the heading "Detoxification Support".
Because many autoimmune patients and women with a history of oral contraceptive use, myself included, have high estrogen relative to progesterone, I supplement with I3C/DIM in order to help restore a more balanced ratio between estrogen species and correct hormonal derangements. I use it in concert with the supplements in my shop under "Female Hormone Balance".
DIM may exert anti-cancer effects, since it up-regulates production of interferon gamma by breast cancer cells, which "plays an important role in preventing the development of primary and transplanted tumors" (Xue, Firestone, & Bjeldanes, 2005). DIM and I3C have likewise been shown to elicit cell death in prostate cancer cells (Li, Chinni, & Sarkar, 2005; Nachshon et al., 2003). Further, DIM stimulates cellular stress response pathways in cervical, breast, and prostate cancer cells, replicating a cellular reaction to nutrient deprivation that enhances the cells' vulnerability to destruction (Firestone & Bjeldanes, 2003).
There is similarly evidence that I3C increases metabolism of estradiol down the protective 2-hydroxylase pathway at the expense of the dangerous 16-alpha-hydroxylase pathway (Michnovicz, Adlercruetz, & Bradlow, 1997; Michnovic & Bradlow, 1991; Kall, Vang, & Calusen, 1997). 16-OH are considered proliferative, cancer-promoting estrogen species whereas higher levels of 2-OH estrogen metabolites are more favorable (Muti et al., 2000; Fowke et al., 2003). I3C likewise inhibits formation of another potent estrogen with growth-promoting effects, 4-hydroxyestrogens (Sepkovic, Bradlow, & Bell, 2001).
However, as always, a foods-first, therapeutic nutrition approach reigns supreme. Include a diversity of fiber-rich cruciferous vegetables in your diet for nutrient synergy and bioavailable nutrition. Start with my pal Alexa's three-ingredient, mouth-watering recipe below!
Beecher, C.W. (1994). Cancer preventive properties of varieties of Brassica oleracea: A review. American Journal of Clinical Nutrition, 59(5), 1166-1170.
Bones, A.M., & Rossiter, J.T. (1996). The myrosinase-glucosinolate system, its organisation and biochemistry. Physiology of Plants, 194-208.
Dolecek et al. (2010). Prediagnosis Food Patterns Are Associated with Length of Survival from Epithelial Ovarian Cancer. Journal of the American Dietetic Association, 110(3), 369-382.
Fahey, J.W., Zhang, Y., & Talaylay, P. (1997). Broccoli sprouts: an exceptionally rich source of inducers of enzymes that protect against chemical carcinogens. Proceedings of the National Academy of Sciences USA, 94(19), 10367-10372.
Firestone GL, Bjeldanes LF. Indole-3-carbinol and 3-3’-diindolylmethane antiproliferative signaling pathways control cell-cycle gene transcription in human breast cancer cells by regulating promoter-Sp1 transcription factor interactions. J Nutr. 2003 Jul;133(7 Suppl):2448S-55S.
Fowke et al. (2003). Urinary isothiocyanate levels, brassica, and human breast cancer. Cancer Research, 63(14), 3980-3986.
Hayes, J.D., Kelleher, M.O., & Eggleston, I.M. (2008). The cancer chemopreventive actions of phytochemicals derived from glucosinolates. European Journal of Nutrition, 47(2), 73-88.
Kall, M.A., Vang, O., & Clausen, J. (1997). Effects of dietary broccoli on human drug metabolising activity. Cancer Letters, 114(1-2), 169-170.
Li, Y., Chinni, S.R., & Sarkar, F.H. (2005). Selective growth regulatory and pro-apoptotic effects of DIM is mediated by AKT and NF-kappaB pathways in prostate cancer cells. Frontiers in Bioscience, 10, 236-243.
Michnovicz, J.J., Adlercreutz, H., & Bradlow, H.L. (1997). Changes in levels of urinary estrogen metabolites after oral indole-3-carbinol treatment in humans. Journal of the National Cancer Institute, 89(10), 718-723.
Michnovicz, J.J. (1998). Increased estrogen 2-hydroxylation in obese women using oral indole-3-carbinol. International Journal of Obesity and Related Metabolic Disorders, 22(3), 227-229.
Muti et al. (2000). Estrogen metabolism and risk of breast cancer: a prospective study of the 2:16alpha-hydroxy-estrone ratio in premenopausal and postmenopausal women. Epidemiology, 11(6), 635-640.
Nachshon-Kedmi, M., Yannai, S., Haj, A., & Fares, F.A. (2003). Indole-3-carbinol and 3,3’-diindolylmethane induce apoptosis in human prostate cancer cells. Food Chemistry and Toxicology, 41(6), 745-752.
Popolo et al. (2017). Two likely targets for the anti-cancer effect of indole derivatives from cruciferous vegetables: PI3K/Akt/mTOR signalling pathway and the aryl hydrocarbon receptor. Seminal Cancer Biology, [Epub ahead of print].
Printz, C. (2012). Radiation treatment generates therapy-resistant cancer stem cells from less aggressive breast cancer cells. Cancer, 118(13), 3225.
Rose et al. (2005). Broccoli and watercress suppress matrix metalloproteinase-9 activity and invasiveness of human MDA-MB-231 breast cancer cells. Toxicology and Applied Pharmacology, 209(2), 105-113.
Sepkovic, D.W., Bradlow, H.L., & Bell, M. (2001). Quantitative determination of 3,3’-diindolylmethane in urine of individuals receiving indole-3-carbinol. Nutrition and Cancer, 41(1-2), 57-63.
Syed Alwi et al. (2010). In vivo modulation of 4E binding protein 1 (4E-BP1) phosphorylation by watercress: a pilot study. British Journal of Nutrition, 104(9), 1288-1296.
Verhoeven et al. (1996). Epidemiological studies on Brassica vegetables and cancer risk. Cancer Epidemiology and Biomarkers Prevention, 5, 733-748.
Wang et al. (2014). Phenethyl isothiocyanate upregulates death receptors 4 and 5 and inhibits proliferation in human cancer stem-like cells. BMC Cancer, 14(591), 1-12.
Xue, L., Firestone, G.L., & Bjeldanes, L.F. (2005). DIM stimulates IFNgamma gene expression in human breast cancer cells via the specific activation of JNK and p38 pathways. Oncogene, 24(14), 2343-2353.
Alexa Federico is a lover of real food, bulletproof coffee, and good books. She was diagnosed with Crohn’s disease at a young age, which inspired her blog, Girl in Healing, where she shares recipes and tips that promote healing for those with IBD and other autoimmune illnesses. You can also connect with her on Instagram, Facebook, Pinterest and Twitter.
Is there really a better way to consume vegetables than cooking them in high-quality animal fats? In my opinion, no, there is not.
Years ago, I would have tossed the fat that ends up in the pan from cooking bacon. Now, I realize that it is a precious commodity included in the price of good bacon!
To avoid the addition of antibiotics, hormones, preservatives, and GMO corn and soy that is provided as feed for factory-farmed animals, pasture-raised bacon is the best option when available to you. Toxins accumulate in the fat of the animals, so when cooking with bacon fat this is especially important.
Sadly, years of false science have touted man-made vegetable oils as health foods while animal fats have been demonized and blamed for cancers, chronic illnesses, heart disease, obesity, and more. The myth that saturated fats cause these health issues has disproven, and Ali’s post defending coconut oil says it all.
Another thing to look out for: sugar. Most conventional bacon on the market is full of some scary ingredients you will want to leave out.
1 package of paleo bacon
1 head of green cabbage
1 yellow onion
On medium heat, lay half of the slices of bacon in a large frying pan. You will need to cook the bacon in two batches.
When the first batch is cooked all the way through, transfer to a paper-towel lined tray to drain the excess fat and pour the rendered fat into a bowl for later use. Then, cook the second batch.
While the bacon is cooking, slice the cabbage and yellow onion. Leave out the tough pieces of the cabbage from the core.
Once the second batch of bacon is done, remove from the pan add the reserved bacon fat back in. Add the cabbage and onions and sauté on medium heat until they become translucent and golden brown, about 20-25 minutes.
Cut the bacon into 1” pieces and add to a large bowl with the veggies. Toss altogether and enjoy!
If you’re not a super fan of cabbage yet, this is a great recipe to get your started! What’s your favorite use for high-quality bacon fat?