Collagenases and Their Inhibitors

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Collagenases are a family of enzymes that digest collagen, the fibrous protein found in connective tissue. Collagen is derived from the Greek words kolla (glue), and gennan (to produce), reflecting its role in "gluing" cells together. Collagen accounts for approximately 30 percent of the body's total protein store. Each type of collagenase degrades a specific type of collagen. For example, the basement membrane around capillaries contains type IV collagen, and therefore type IV collagenase is a particularly important enzyme in tumor invasion and metastasis. One specific group of collagenases

TABLE 9.2 NATURAL COMPOUNDS THAT AFFECT COLLAGEN

COMPOUND

STABILIZE COLLAGEN

INCREASE COLLAGEN SYNTHESIS

INHIBIT COLLAGENASE

Anthocyanidins and proanthocyanidins

x

x

x

Centella asiatica

x

x

EGCG

x

x

x

EPA

x

Leukotriene inhibitors (see Table 8.2)

x

Curcumin

x

Emodin

x

Genistein

x

Luteolin and quercetin

x

PSK and other mushroom polysaccharides

x

Vitamin A (ATRA)

x

Vitamin C

x

Note: See Table G.2 in Appendix G for details and references.

of interest are matrix metalloproteinases (MMPs), a family of at least 15 zinc-dependent enzymes that collectively can degrade all components of the ECM. MMPs are inhibited by tissue inhibitors of metalloproteinases (TIMPs). TIMPs are being studied for their ability to inhibit tumor invasion and angiogenesis, although their use as chemotherapeutic agents is hampered by their rapid degradation in vivo.41,42,43 Compounds that stimulate TIMP production in vivo may be more suitable than administration of TIMPs themselves.

Natural compounds that affect collagen or collagenase are listed in Table 9.2. Some of these also stimulate TIMP production (see Table G.2 for details). In addition, the table lists natural compounds that stabilize collagen or increase its production. These compounds may inhibit invasion by making collagen more resistant to destruction or by producing fresh collagen to replace degraded material. Some compounds that increase the stability of collagen do so by facilitating the cross-linking of collagen fibers. This approach has received little research but seems promising, especially when used as one part of a more complex anticancer strategy.

There is some concern that compounds that stimulate collagen synthesis might also increase angiogenesis in vivo. For example, vitamin C, which increases collagen production, was reported to increase angiogenesis in vitro; it is uncertain, however, whether this effect would occur in vivo. At least in some animal studies, vitamin C produced an anti- rather than a protumor effect (discussed in Chapter 15). Moreover, the other compounds listed that increase collagen synthesis also inhibit colla-genases, an effect that may limit their ability to facilitate tumor angiogenesis in vivo. Additional in-vivo studies are warranted on vitamin C and other compounds that increase collagen synthesis.

Note that many of the compounds discussed in Table 9.2 are antioxidants. Free radicals by themselves may degrade collagen or otherwise stimulate invasion. Oxygen radicals increased the invasive potential of mouse liver cancer cells, possibly by altering their plasma membrane or by altering signal transduction or both.44

The pathology of varicose veins bears some resemblance to cancer invasion, and in considering the resemblance, we find suggestions for compounds that may be useful in cancer treatment. In both cases, intermittent blood stasis causes tissue hypoxia and reperfusion, which leads to free radical generation. The free radicals then degrade collagen in the ECM and basement membrane. In addition, collagenases are produced, which further degrade collagen. At the same time, a dysregula-tion of normal matrix production occurs in both diseases, and GAG synthesis, primarily of hyaluronic acid, is excessively stimulated.45,46 This leads to a maldevel-oped ECM and basement membrane that is collagen-poor and GAG-rich.

Proanthocyanidins and other compounds such as Centella and boswellic acid inhibit GAG synthesis and collagen degradation, and/or stimulate collagen production in vitro. In fact, proanthocyanidins are reportedly useful in vivo for increasing capillary resistance in diseases such as varicose veins (see Table F.1 in Appendix F). This suggests they might also be useful in cancer treatment.

TABLE 9.3 EFFECTS OF NATURAL COMPOUNDS ON CELL MIGRATION

COMPOUND

INHIBIT CANCER CELL MIGRATION

INHIBIT IMMUNE CELL MIGRATION

1,25-D3 (vitamin D3)

x

x

Apigenin, luteolin, quercetin

x

Bromelain and other proteolytic enzymes

x

EPA/DHA

x

x

Boswellic acid

x

Genistein

x

x

Hyaluronidase inhibitors (see Table 9.1)

x

x

Melatonin

x

Panax ginseng

x

PKC inhibitors (see Table 4.3)

x

PSK

x

PTK inhibitors (see Table 4.2)

x

x

Note: See Table G.3 in Appendix G for details and references.

variants may act as an indicator of tumor burden and

variants may act as an indicator of tumor burden and

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