Flavonoids are a class of compounds found in fruits, vegetables, seeds, and cereals, and some beverages that have antioxidant, anti-inflammatory, antimutagenic, and anticarcinogenic properties.1,2 In plants, flavonoids play an important role in multiple functions including pigments, attraction of pollinators, growth and development of seedlings, and protection against injury and microorganisms.1,2 Research has suggested that the molecular functions of flavonoids may also impart many health benefits to humans including modulating disease activity, mitigating antibiotic resistance, and downregulating inflammation.1 One area of such research is the potential effect of flavonoids on the risk of developing cancer.
Mechanisms of Anticancer Activity
The anticancer activity of flavonoids is related to their modulation of signal transduction pathways within cancer cells.3 As a result, flavonoids can inhibit cell proliferation, angiogenesis, and metastasis, while also promoting apoptosis.
The classes of flavonoids include isoflavones, flavones, flavonols, flavanones, anthocyanins, and chalcones—and compounds within the classes can have different anticancer properties.1,4 However, the majority of compounds promote apoptosis, induce cell cycle arrest, and promote cellular differentiation.
Dietary flavonoids may also improve treatment response.5 Multiple in vitro studies have shown that flavonoids can reverse treatment resistance. Multidrug resistance is a major challenge during cancer treatment. Although multidrug resistance can occur as a result of different mechanisms, the end result is that drug absorption is inhibited. Flavonoids have been found to target many of the underlying mechanisms that cause multidrug resistance, thus leading to its reversal.
Reducing Cancer Risk
Epidemiological studies have evaluated whether dietary intake of flavonoids can reduce the risk of developing different cancers. For example, meta-analyses of observational cohort and case-control studies suggest that high intake of dietary flavonoids can reduce the risk of aerodigestive tract cancers, breast cancer, ovarian cancer, esophageal cancer, and colorectal cancer.6-10 These studies provide indirect evidence for a potential association, and are hypothesis-generating, but do not establish causality.
In aerodigestive tract cancers, a meta-analysis of 35 studies encompassing over 1 million patients found that total dietary flavonoid intake significantly decreased the risk of developing a smoking-related cancer (odds ratio [OR], 0.82; 95% CI, 0.72-0.93).6 This association remained for aerodigestive tract cancers and lung cancer. The decrease in smoking-related cancers was strongest among individuals who smoked compared with non-smokers.
A meta-analysis of 12 studies including more than 190,000 patients found that ingesting high levels of flavonoids was associated with a significantly decreased risk for developing breast cancer.7 A reduction in breast cancer risk was noted with high intake of flavonols (relative risk [RR], 0.88; 95% CI, 0.80-0.98) and flavones (RR, 0.83; 95% CI, 0.76-0.91).
For ovarian cancer, a meta-analysis of 12 studies that included more than 400,000 patients found that ingesting flavonoids significantly decreased the risk of ovarian cancer (RR, 0.82; 95% CI, 0.68-0.98).8
A meta-analysis that evaluated the effect of dietary flavonoid intake on esophageal cancer included 7 studies of 483,822 patients.9 High levels of intake of specific types of flavonoid significantly reduced the risk of esophageal cancer risk compared with the lowest level of intake for anthocyanidins (OR, 0.60; 95% CI, 0.49-0.74), flavanones (OR, 0.65; 95% CI, 0.49-0.86), and flavones (OR, 0.78; 95% CI, 0.64-0.95). However, overall flavonoid intake was not associated with decreased risk (OR, 0.78; 95% CI, 0.59-1.04).
A meta-analysis of 12 studies that included over 750,000 patients found that high intake of flavonoids significantly decreased the risk of developing colorectal cancer compared with low intake levels, specifically with flavonols (OR, 0.70; 95% CI, 0.54-0.90), flavones (OR, 0.79; 95% CI, 0.83-0.99), and anthocyanidins (OR, 0.78; 95% CI, 0.64-0.95).10
However, another meta-analysis of 23 studies found no association between high flavonoid intake and the risk of esophageal, colorectal, or gastric cancer.11 This highlights that although many studies suggest that high flavonoid intake may reduce the risk of developing different types of cancer, the data remain mixed.
Stronger Evidence for Anticancer Activity
Randomized controlled trials (RCT) are the gold standard for establishing causality. Multiple RCTs have been conducted evaluating a specific flavonoid or food/beverage-containing flavonoids on the effect of cancer prevention or treatment. Many of these trials have not found that these flavonoid interventions prevent cancer, cancer progression, or lower markers of cancer risk. Some examples are described below.
For example, in prostate cancer, an RCT evaluated tomato-based products high in the flavonoid lycopene compared with a control diet for 3 weeks.12 At the end of the 3 weeks, there was no difference in prostate-specific antigen (PSA) values between the groups. Another an RCT assigned 97 men at high risk of developing prostate cancer to 1 year of polyphenon E, a mixture of flavonoids found in green tea, or placebo.13 There was no difference in the incidence of prostate cancer at 12 months between the groups, but there was a decrease in prostate-specific antigen (PSA) levels. An RCT studied the same polyphenon E derived from green tea in healthy menopausal women for 12 months.14 At the end of the study, there was no difference in mammographic density — an established marker for an increased risk of breast cancer — between the patients in the flavonoid and placebo groups.
However, a recent study evaluated the addition of the flavonoid flavopiridol to cytarabine and mitoxantrone compared with cytarabine plus daunorubicin in patients with newly diagnosed acute myeloid leukemia.15 The aim of the study was to determine the complete remission rates after 1 cycle of treatment. The flavonoid combination resulted in higher rates of complete remission (70%) compared with the cytarabine/daunorubicin regimen (46%; P =.003). These results have led to the development of a phase 3 trial.
Extensive in vitro data suggest that many types of flavonoids have anticancer properties and effectively induce apoptosis, decrease cell proliferation, lower the risk of metastasis.1 Many epidemiologic studies support this; many meta-analyses demonstrate that high dietary flavonoid intake can reduce the risk of several different cancer types. However, RCTs have been less successful in demonstrating that specific flavonoids or flavonoid-containing diets or foods/beverages are effective in preventing cancer, cancer progression, or reducing known high-risk markers. However, the research that currently exists suggests that the addition of flavonoids to conventional anticancer treatment could be beneficial, although further research is warranted.
- Panache AN, Diwan AD, Chandra SR. Flavonoids: an overview. J Nutr Sci. 2016;5:1-15.
- Rodriguez-García C, Sánchez-Quesada C, Gaforio JJ. Dietary flavonoids as cancer chemopreventive agents: an updated review of human studies. Antioxidants (Basel). 2019;8(5):137.
- Abotaleb M, Samuel SM, Varghese E, et al. Flavonoids in cancer and apoptosis. Cancers (Basel). 2019;11(1):28.
- Koosha S, Alshawsh MA, Looi CY, Seyedan A, Mohamed Z. An association map on the effect of flavonoids on the signaling pathways in colorectal cancer. Int J Med Sci. 2016;13(5):374-385.
- Ye Q, Liu K, Shen Q, et al. Reversal of multidrug resistance in cancer by multi-functional flavonoids. Front Oncol. 2019;9:487.
- Woo HD, Kim J. Dietary flavonoid intake and smoking-related cancer risk: a meta-analysis. PLoS One. 2013;8(9):e75604.
- Hui C, Qi X, Qianyong Z, Xiaoli P, Jundong Z, Mantian M. Flavonoids, flavonoid subclasses and breast cancer risk: a meta-analysis of epidemiologic studies. PLoS One. 2013;8(1):e54318.
- Hua X, Yu L, You R, et al. Association among dietary flavonoids, flavonoid subclasses and ovarian cancer risk: a meta-analysis. PLoS One. 2016;11(3):e0151134.
- Cui L, Liu X, Tian Y, et al. Flavonoids, flavonoid subclasses, and esophageal cancer risk: a meta-analysis of epidemiologic studies. Nutrients. 2016;8(6):350.
- Chang H, Lei L, Zhou Y, Ye F, Zhao G. Dietary flavonoids and the risk of colorectal cancer: an updated meta-analysis of epidemiological studies. Nutrients. 2018;10(7):950.
- Bo Y, Sun J, Wang M, Ding J, Lu Q, Yuan L. Dietary flavonoid intake and the risk of digestive tract cancers: a systematic review and meta-analysis. Sci Rep. 2016;6:24836.
- Paur I, Lilleby W, Bøhn SK, et al. Tomato-based randomized controlled trial in prostate cancer patients: effect on PSA. Clin Nutr. 2017;36(3):672-679.
- Kumar NB, Pow-Sang J, Egan KM, et al. Randomized, placebo-controlled trial of green tea catechins for prostate cancer prevention. Cancer Prev Res (Phila). 2015;8(10):879-887.
- Samavat H, Ursin G, Emory TH, et al. A randomized controlled trial of green tea extract supplementation and mammographic density in postmenopausal women at increased risk of breast cancer. Cancer Prev Res (Phila). 2017;10(12):710-718.
- Zeidner JF, Foster MC, Blackford AL, et al. Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia. Haematologica. 2015;100(9):1172-1179.