As mentioned in Chapter 7, the rate-limiting step in angiogenesis seems to be increased vascular permeability, and vascular endothelial growth factor (VEGF), one of the most potent inducers of permeability known, plays a key role in angiogenesis. Not surprisingly, some studies have reported that plasma concentrations of VEGF are predictive of recurrence and survival in cancer patients.1 In addition to increased angiogenesis, high concentrations of VEGF have also been associated with increased metastasis of a variety of cancers.2, 3 4 Increased metastasis is likely a byproduct of increased angiogenesis, since metastasis will not happen until an-giogenesis has occurred.
There are two conceivable means to reduce VEGF-mediated angiogenesis. The first is to reduce VEGF production, and the second is to reduce the end effect of VEGF, which is increased vascular permeability itself.
VEGF is produced in response to hypoxic (low-oxygen) conditions, which are prevalent within tumors. It is also produced secondarily in response to the production of other growth factors, such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), tumor necrosis factor (TNF), and transforming growth factor-beta (TGF-beta).5-10 Indeed, one study reported that wound fluid stimulated tumor growth and angiogenesis in vivo, and that PDGF and EGF contained in the fluid were apparently responsible for the effect.11 Most likely, PDGF and EGF stimulated the production of VEGF, which led to angiogenesis. Thus by inhibiting the production or activity of PDGF, EGF, TNF, or TGF-beta, it may be possible to decrease production of VEGF and its stimulating effect on angiogenesis.
A major source of PDGF, EGF, and TNF within solid tumors is macrophages. The production of these and other growth factors by macrophages is discussed later in this chapter, as well as the effects of hypoxia on macrophages and VEGF production, but note here that antioxidants, PTK inhibitors, PKC inhibitors, and leu-kotriene inhibitors may all reduce production of VEGF by macrophages or other cells in response to growth factors or hypoxia. In addition, inhibitors of AP-1 may also block VEGF production, as has been reported for curcumin.12
Reduced production of VEGF has been reported, for example, with genistein, a PTK inhibitor, and EPA, a PKC inhibitor, in vitro and ex vivo.1318, a Reduced production of VEGF has been reported in vivo with selenium, a PKC inhibitor. In one study, oral administration of about 3.6 milligrams of selenium per day (as scaled to humans) for seven weeks reduced angiogenesis in rats with breast cancer.19 VEGF concentrations in tumor tissue were reduced, presumably due to reduced production by macrophages. In support of the types of syner-gistic combinations discussed in this book, recent evidence suggests that combinations of VEGF inhibitors, for example, PTK and PKC inhibitors, may be more effective than single therapies at reducing VEGF
It should come as no surprise that PTK inhibitors would reduce the stimulatory effects of growth factors such as EGF and PDGF on VEGF production. Recall from Table 4.1 that receptors for most growth factors, including EGF and PDGF, are protein tyrosine kinases. Indeed, PTK inhibitors such as EGCG, curcumin, CAPE, and genistein have been reported to reduce EGF and PDGF signaling in a variety of cells.21-27
a In ex-vivo studies, compounds are administered in vivo, then the blood or blood cells are withdrawn and tested in vitro.
TABLE 8.1 NATURAL COMPOUNDS THAT INHIBIT INCREASED VASCULAR PERMEABILITY
Anthocyanidins Butcher's broom Centella asiatica Horse chestnut Proanthocyanidins
Note: See Table F. 1 in Appendix F for details and references.
Some studies have looked specifically at the anti-angiogenic properties of genistein. Genistein (at 13 pM) is an effective inhibitor of endothelial cell proliferation (vascular cells are endothelial cells).28 Also, genistein was identified as the most potent compound in the an-giogenesis-inhibiting urine of healthy humans who consumed a plant-based diet.29,30 At least three animal studies have reported that genistein can inhibit angio-genesis and tumor growth in vivo.31,32,33 One, an oral study, also reported that genistein reduced the number of tumor-associated macrophages.32 It is likely this effect played a role in reducing angiogenesis, since this would reduce the source of many angiogenic factors. In another in-vivo study, a combination of genistein (at 100 mg/kg intraperitoneal) and an antiangiogenic drug (TNP-470), along with a variety of cytotoxic chemotherapy drugs and radiotherapy, was more effective at inhibiting tumor growth in mice with implanted lung tumors than either genistein or TNP-470 used separately with chemotherapy or radiotherapy. Even without TNP-470, genistein reduced angiogenesis in the tumors by about 35 to 51 percent.34,3 The human oral equivalent of the genistein dose is about 4.5 grams per day.
Other flavonoids, which are also PTK inhibitors, may be as potent as genistein. At 10 pM, genistein, luteolin, and apigenin inhibited in-vitro angiogenesis by 60 to 75 percent. The IC50 for inhibition of endothelial cell proliferation was about 2 to 7 mM.36
As with PTK inhibitors, it is not surprising that PKC inhibitors would reduce the stimulatory effects of growth factors such as EGF and PDGF on VEGF production. As discussed in Chapter 4 (see Figure 4.3), signal transduction cascades tend to be interrelated. For example, stimulation of a PTK receptor on the cell surface (such as the EGF or PDGF receptor) can later stimulate PKC within the cell. Thus inhibitors of PKC can block some effects of PTK receptor activity. For example, EPA reduced EGF and PDGF signaling and
reduced angiogenesis in vitro. , -
PKC and PTK inhibitors may also act through other means to reduce angiogenesis, apart from decreasing
VEGF production, since PKC and PTK signaling control many aspects of cell behavior. For example, PKC inhibitors may reduce angiogenesis in part by lowering production of collagenases, which are enzymes involved in tumor invasion (discussed in Chapter 9).41 Other types of collagenase inhibitors also reduce angiogene-sis.42,43 They are effective because both invasion and angiogenesis have some events in common (vascular cells must invade through tissues during angiogene-sis).44,45 Lastly, PKC inhibitors may also reduce angio-genesis by decreasing histamine release by mast cells and by lowering insulin resistance, as is discussed below.
Before leaving this discussion on VEGF and the growth factors that stimulate its production, note that some natural compounds may directly interfere with growth factors or their receptors. For example, EGCG inhibited the binding of EGF to its receptors, and high-molecular-weight polysaccharides such as PSK inhibited the binding of TGF-beta to its receptors.24,46 In addition, EPA inhibited the binding of PDGF to its recep-
A second possible method to reduce VEGF-induced angiogenesis is to minimize the primary effect of VEGF: increased vascular permeability. Again, increased vascular permeability at tumor sites facilitates inflammation and the release or eventual production of angiogenic compounds. Numerous natural compounds have been reported to decrease vascular permeability in animals and humans. Some of these compounds are listed in Table 8.1. Although this approach of normalizing vascular permeability seems reasonable, it has not been investigated in any depth; this book is one of the first to suggest it may be useful.
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