Antioxidant Effects of Isoflavones Flavones Flavonols and other Phenols

Phenolic compounds, including isoflavones, flavones, and flavonols, can act as antioxidants due to the hydrogen-donating capacity of their phenolic groups and, in some cases, their metal-chelating potential. The latter may block the generation of copper- and iron-induced free radicals. Table 19.1 ranks various phenolics and other antioxidants in comparison to vitamin C in their ability to scavenge aqueous free radicals in vitro. As seen, most flavonoids are more active than vitamins C and E.

Some phenolic compounds that normally act as anti-oxidants can also act as prooxidants under the right circumstances (see Chapter 15). For example, some in-vitro conditions are adequate to auto-oxidize quercetin, and the prooxidant effect produced may account for some of quercetin's ability to cause gene mutations in vitro. In one study that tested 55 flavonoids, quercetin was the most mutagenic.74 Other flavonoids in Table 19.1 do not appear to auto-oxidize as readily or tend to be mutagenic in vitro; apigenin may actually inhibit mutagenesis under some circumstances.75-78 Even in the presence of copper, which is a catalyst for oxidation, apigenin was much less apt than quercetin to induce DNA damage.79,80 Still, at moderate doses in vivo, it is likely that quercetin and the other flavonoids produce an antioxidant, rather than prooxidant effect. For one thing, most of the flavonoids found in the plasma occur in the conjugate form, which is less reactive. Indeed, a recent study of men with chronic prostatitis suggested that even a high dose of quercetin produces an antioxidant effect in vivo.81 In this study, a dose of 500 milligrams was given twice per day. Potential carcinogenic effects of quercetin are covered again later in this chapter.

In-vitro Cytotoxicity of Flavones, Flavonols, and Isoflavones

Apigenin, luteolin, quercetin, daidzein, and genistein produce cytotoxic effects in vitro at concentrations of 1 to 100 pM, although the IC50 is often in the range of 10 to 30 pM. Data on their cytotoxicity against various cell lines is presented in Appendix K. Flavones, flavonols, and isoflavones can induce cell death through many possible means. Quite likely, the active means vary between cell lines. The potential anticancer actions of apigenin, luteolin, quercetin, and genistein are listed in Table 19.2.

In-vivo Antitumor Effects of Flavones, Flavonols, and Isoflavones

Unfortunately, very few animal antitumor studies have been conducted on flavones and fla-vonols. As discussed previously, one study on luteolin reported that it inhibited growth of human breast cancer cells in mice. Another mouse study found that intraperitoneal administration of 25 and 50 mg/kg apigenin inhibited growth and metastasis of transplanted melanoma cells.26 The equivalent human oral dose is about 1.2 and 2.5 grams per

TABLE 19.2 POTENTIAL ANTICANCER ACTIONS OF API LUTEOLIN (L), QUERCETIN (Q), AND GENISTEIN

GENIN (A), (G)

ACTIVITY

KNOWN EFFECTS

AS ANTIOXIDANTS, MAY:

AS PTK INHIBITORS, MAY:

AS PKC INHIBITORS, MAY:

AS NF-kB INHIBITORS, MAY:

AS EICOSANOID INHIBITORS, MAY:

AS INVASION ENZYME INHIBITORS, MAY:

Chapter 2: Mutations, Gene Expression, and Proliferation

Act as an antioxidant

x

Inhibit topoisomerases

x

Chapter 3: Results of Therapy at the Cellular Level

Induce differentiation

x

Induce apoptosis

x

x

x

Chapter 4: Growth Factors and Signal Transduction

Inhibit PTK

x

Inhibit PKC

A,L,Q

Induce p21 or p27 activity

A,G

Inhibit ras cascade

A,Q,G

x

x

Chapter 5: Transcription Factors and Redox Signaling

Support p53 function

x

x

Inhibit NF-kB/AP-1 activity

x

x

x

x

x

Chapter 6: Cell-to-Cell Communication

Affect CAMs

x

x

x

x

x

Improve gap junction communication

A,G

x

x

x

Chapters 7 and 8: Angiogenesis

Inhibit angiogenesis

A,L,G

x

x

x

x

x

x

Inhibit bFGF effects

x

Reduce lactic acid

x

Inhibit histamine effects

x

x

x

x

Inhibit eicosanoid effects

x

x

x

Inhibit TNF effects

G

x

x

x

x

Inhibit VEGF effects

G

x

x

x

x

Inhibit insulin resistance

G

x

Chapters 9 and 10: Invasion and Metastasis

Inhibit invasion

x

x

Inhibit hyaluronidase, collagenase, or elastase

A,L, G,Q

x

x

x

Inhibit GAG synthesis

x

Inhibit cell migration

x

x

x

x

Inhibit metastasis

x

x

Inhibit platelet aggregation

x

x

Chapters 11 and 12: Immune System

Inhibit tumor-induced immunosuppression

G

x

x

Chapter 19: Flavonoids

Affect type II estrogen receptors

A,L,Q

day. Moreover, apigenin inhibited the initiation and promotion phases of cancer in animal experiments.76,82

Four animal studies examined the antitumor effects of quercetin:

• A low oral dose (the human equivalent of 290 milligrams) did not affect metastasis of melanoma cells in mice (the same dose of curcumin was inhibitory).32

• Intraperitoneal administration of 20 to 80 mg/kg slightly but not significantly increased the life span of mice injected with lympholeukemia ascites cancer cells.33 The equivalent human oral dose is 1.2 to 4.9 grams.

• Intraperitoneal administration of 20 to 800 mg/kg dramatically inhibited growth of human head and neck squamous cell carcinoma implanted into chambers in rats.34 The 800-mg/kg dose only moderately increased inhibition compared to the 20-mg/kg doses. The human oral equivalent of 20 mg/kg is about 2.1 grams.

• Intraperitoneal administration of 25 and 50 mg/kg inhibited growth and metastasis of transplanted melanoma cells in mice.26 The equivalent human oral dose is about 1.5 and 3.1 grams per day.

In addition to these, one animal study examined the effects of quercetin chalcone, a proprietary, water-soluble form of quercetin. Given orally to mice at a daily dose of 310 and 620 milligrams it reduced the growth of transplanted colon cancer cells by 29 and 65 percent, respectively.83

One human phase I study has also been completed using intravenously administered quercetin. Although phase I trials are designed for determining safe doses rather than inducing an anticancer effect, evidence of tumor inhibition was seen in a few patients in the study.

In contrast to flavones and flavonols, many more in-vivo studies have been conducted on isoflavones. As mentioned above, soy is a natural source of the isofla-vones genistein and daidzein. Epidemiological studies indicate that soy consumption may be responsible for the decreased incidence of a number of cancers in Chinese and Japanese populations. Some of these studies were mentioned above in relation to the estrogenic effects of isoflavones. In another study, Japanese men consuming high quantities of soy products exhibited a low mortality rate from prostate cancer.84

Risk reduction is also seen in animals. In approximately 70 percent of the 30 or so animal studies conducted, soy administration in the diet produced a cancer preventive effect. The effect was generally an increase in latency, suggesting that soy delays the appearance and growth of new tumors.85,86,87 However, soy components other than isoflavones could have been responsible for some of the cancer preventive effects.88

A number of rodent studies have suggested that soy or isolated isoflavones could also inhibit progression of established cancers in vivo. Again, in studies on soy, additional components may have been active. In one study, a large dose of a soybean protein isolate (10 to 20 percent of diet) inhibited metastasis formation and reduced tumor growth in mice injected with melanoma cells.89 In a second one, large doses of soy (33 percent of diet) inhibited growth of transplanted prostate cells in rats.90 In a third, a low-fat diet containing a soy isofla-vone concentrate (about 220 mg/kg) and soy protein (about 24 g/kg) inhibited growth of human prostate cancer cells injected into mice.91

Several studies have been done on genistein, daidzein, or isoflavonoid-rich soy extracts. Based on those listed below, we can conclude that genistein and daidzein may inhibit growth or progression of many types of cancers in vivo, although not necessarily estrogen-dependent cancers. The average dose in all the successful oral, intraperitoneal, and subcutaneous studies on genistein discussed below is about 2.3 grams (range of 250 milligrams to 9.9 grams, all as scaled to human oral equivalents):

• Administration of about 1.2 g/kg of an isoflavone-rich soy concentrate in the diet inhibited the growth of transplanted human prostate cancer cells in mice by 30 percent, as well as angiogenesis. The actual isoflavone dose was about 200 mg/kg, approximately half of which was from genistein and half from daidzein.12 The equivalent human isoflavone dose is about 1.9 grams per day.

• Genistein (at about 180 mg/kg in diet) inhibited the growth of human prostate cancer cells in mice. A soy isoflavone concentrate (at 600 mg/kg in diet) and a diet rich in soy protein but depleted of isoflavones also inhibited tumor growth.13 The human equivalent of a 180-mg/kg dose is about 1.7 grams per day.

• Genistein (at about 40 mg/kg in diet) inhibited growth of transplanted melanoma cells in mice by about 50 percent.11 The equivalent human dose is about 380 milligrams per day.

• Genistein (at about 120 and 240 mg/kg in diet) reduced metastasis of melanoma cells in mice and reduced tumor growth. A 30-mg/kg dose was not effective.92 The equivalent human dose is about 1.2 and 2.4 grams per day.

• Oral administration of 54 mg/kg of genistein inhibited lung metastasis by 54 percent in mice with

TABLE 19.3 ESTIMATED THERAPEUTIC AND LOAEL DOSES FOR ISOFLAVONES, FLAVONES,

AND FLAVONOLS*

DESCRIPTION

GENISTEIN DOSE (g/day)

APIGENIN DOSE (g/day)

LUTEOLIN DOSE (g/day)

QUERCETIN DOSE (g/day)

Required dose as scaled from animal antitumor studies

0.25 to 9.9 (average 2.3)

1.2 to 2.5

1.1 to 3.4

1.2 to 4.9

Required dose as scaled from animal anti-inflammatory studies

none

0.66 to 4.1

0.66 to 4.1

1 to 4

Required dose as estimated from pharmacokinetic calculations

0.72

0.93

2.9

5.2

Target dose based on an average from animal antitumor studies and pharmacokinetic calculations

1.5

1.5

2.5

3.8

Minimum required antitumor dose assuming 15-fold synergistic benefits

0.1

0.1

0.17

0.25

Commonly prescribed human dose in noncancerous conditions

0.05

0.01

uncertain

1

Estimated LOAEL dose

1.6

3.2

4.4

6.5

Tentative dose recommendation for further research

0.1 to 1.1*

0.1 to 1.5

0.17 to 1.8*

0.25 to 1.8*

Minimum degree of synergism required

1.4-fold potency increase

none

1.4-fold potency increase

2.1-fold potency increase

See Appendix J for details. ^ Upper value based on daidzein LOAEL.

* Upper value based on the general linear bioavailability limit of 1.8 grams per day.

transplanted human melanoma cells, but daidzein was not effective.93 The equivalent human dose is about 520 milligrams per day.

• Oral administration of 22 mg/kg of genistein per day to rats with transplanted prostate cancer reduced tumor-associated macrophage numbers, angiogenesis, and tumor volume.94 The equivalent human dose is about 360 milligrams per day.

In addition to the oral studies, genistein also inhibited the growth, metastasis, and/or angiogenesis of a variety of tumors in mice and rats after intraperitoneal or subcutaneous administration.9,10,95-98 Daidzein has also been reported effective. Intraperitoneal administration of 25 to 50 mg/kg daidzein reduced tumor volume by more than 50 percent and induced differentiation of leukemia cells held in chambers in mice.99 The equivalent human oral dose is about 1.1 to 2.3 grams per day.

Lastly, at least two studies found that genistein was not effective; one of these, on rats, used very low doses in the drinking water (0.07 to 0.285 mg/kg). In this study, genistein did not inhibit the growth of transplanted human prostate cancer cells. The equivalent human dose is about 1.1 to 4.6 milligrams per day.15 In the other study, oral administration of about 90 mg/kg of genistein in the diet did not inhibit growth of new or established estrogen-independent breast cancer cells transplanted into mice.14 The equivalent human dose is about 870 milligrams per day.

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