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Antiangiogenic Steroids in Human Cancer Therapy.

Pietras RJ, Weinberg OK - Evid Based Complement Alternat Med (2005)

Bottom Line: This review focuses on the potential application in antitumor therapy of naturally-occurring steroids that target tumor-associated angiogenesis.Squalamine, a 7,24 dihydroxylated 24-sulfated cholestane steroid conjugated to a spermidine at position C-3, is known to have strong antiangiogenic activity in vitro, and it significantly disrupts tumor proliferation and progression in laboratory studies.Preclinical studies with squalamine have shown additive benefits in tumor growth delay when squalamine is combined with cisplatin, paclitaxel, cyclophosphamide, genistein or radiation therapy.

View Article: PubMed Central - PubMed

ABSTRACT
Despite advances in the early detection of tumors and in the use of chemotherapy, radiotherapy and surgery for disease management, the worldwide mortality from human cancer remains unacceptably high. The treatment of cancer may benefit from the introduction of novel therapies derived from natural products. Natural products have served to provide a basis for many of the pharmaceutical agents in current use in cancer therapy. Emerging research indicates that progressive growth and spread of many solid tumors depends, in part, on the formation of an adequate blood supply, and this process of tumor-associated angiogenesis is reported to have prognostic significance in several human cancers. This review focuses on the potential application in antitumor therapy of naturally-occurring steroids that target tumor-associated angiogenesis. Squalamine, a 7,24 dihydroxylated 24-sulfated cholestane steroid conjugated to a spermidine at position C-3, is known to have strong antiangiogenic activity in vitro, and it significantly disrupts tumor proliferation and progression in laboratory studies. Work on the interactions of squalamine with vascular endothelial cells indicate that it binds with cell membranes, inhibits the membrane Na(+)/H(+) exchanger and may further function as a calmodulin chaperone. These primary actions appear to promote inhibition of several vital steps in angiogenesis, such as blockade of mitogen-induced actin polymerization, cell-cell adhesion and cell migration, leading to suppression of endothelial cell proliferation. Preclinical studies with squalamine have shown additive benefits in tumor growth delay when squalamine is combined with cisplatin, paclitaxel, cyclophosphamide, genistein or radiation therapy. This compound has also been assessed in early phase clinical trials in cancer; squalamine was found to exhibit little systemic toxicity and was generally well tolerated by treated patients with various solid tumor malignancies, including ovarian, non-small cell lung and breast cancers. Clinical trials with squalamine alone or combined with standard chemotherapies or other biologic therapies, including antiangiogenic agents, should be considered for selected cancer patients, and further study of the mechanism of action and bioactivity of squalamine is warranted.

No MeSH data available.


Related in: MedlinePlus

Squalamine, a 7,24 dihydroxylated 24-sulfated cholestane steroid conjugated to a spermidine at position C-3. This steroidal compound was initially found in tissues of dogfish shark, Squalus acanthias, primarily in sites of bile synthesis such as liver and gallbladder. However, squalamine also occurs in spleen, testes, stomach, gills and intestine. See text for additional details.
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fig1: Squalamine, a 7,24 dihydroxylated 24-sulfated cholestane steroid conjugated to a spermidine at position C-3. This steroidal compound was initially found in tissues of dogfish shark, Squalus acanthias, primarily in sites of bile synthesis such as liver and gallbladder. However, squalamine also occurs in spleen, testes, stomach, gills and intestine. See text for additional details.

Mentions: Squalamine, a natural steroidal compound initially found in several tissues of the dogfish shark, Squalus acanthias, causes changes in vascular endothelial cell shape and has been reported to possess significant antiangiogenic activity in models of lung, breast, brain and ovarian cancer (22,27,28). In the shark, squalamine is found primarily in sites of bile synthesis such as liver and gallbladder, but the aminosterol compound also occurs in smaller amounts in the spleen, testes, stomach, gills and intestine (29). In the laboratory, squalamine was originally found to have bactericidal activity against gram-negative and gram-positive bacteria, as well as some fungicidal qualities (29). More importantly, squalamine at relatively low doses was later shown to selectively inhibit the formation of new blood vessels. However, unlike previously described steroids, squalamine has significant structural differences and does not interact with glucocorticoid or minealocorticoid receptors (30). It is a 7,24 dihydroxylated 24-sulfated cholestane steroid conjugated to a spermidine at position C-3 (see Fig. 1). Squalamine has been demonstrated to be an angiostatic steroid by virtue of its inhibition of growth of vascular endothelial cells in culture, activity in the chick embryo chorioallantoic membrane assay and a rabbit corneal micropocket assay, as well as growth inhibition of gliomas and lung cancers in vivo (22,28,31). Squalamine is somewhat unique among most current anti-angiogenic agents in development because it inhibits endothelial cell proliferation and migration induced by a wide variety of growth factors, including Basic Fibroblast Growth Factor (bFGF) and VEGF (27,31; Fig. 2). This broad antiangiogenic activity of squalamine may result from its inhibition of surface sodium–proton exchangers (thus altering intracellular pH and thereby impeding intracellular signaling by several growth factors) and other downstream signaling pathways in endothelial cells (27,29). There are different theories about the mechanism of action of squalamine that remain to be investigated.


Antiangiogenic Steroids in Human Cancer Therapy.

Pietras RJ, Weinberg OK - Evid Based Complement Alternat Med (2005)

Squalamine, a 7,24 dihydroxylated 24-sulfated cholestane steroid conjugated to a spermidine at position C-3. This steroidal compound was initially found in tissues of dogfish shark, Squalus acanthias, primarily in sites of bile synthesis such as liver and gallbladder. However, squalamine also occurs in spleen, testes, stomach, gills and intestine. See text for additional details.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1062159&req=5

fig1: Squalamine, a 7,24 dihydroxylated 24-sulfated cholestane steroid conjugated to a spermidine at position C-3. This steroidal compound was initially found in tissues of dogfish shark, Squalus acanthias, primarily in sites of bile synthesis such as liver and gallbladder. However, squalamine also occurs in spleen, testes, stomach, gills and intestine. See text for additional details.
Mentions: Squalamine, a natural steroidal compound initially found in several tissues of the dogfish shark, Squalus acanthias, causes changes in vascular endothelial cell shape and has been reported to possess significant antiangiogenic activity in models of lung, breast, brain and ovarian cancer (22,27,28). In the shark, squalamine is found primarily in sites of bile synthesis such as liver and gallbladder, but the aminosterol compound also occurs in smaller amounts in the spleen, testes, stomach, gills and intestine (29). In the laboratory, squalamine was originally found to have bactericidal activity against gram-negative and gram-positive bacteria, as well as some fungicidal qualities (29). More importantly, squalamine at relatively low doses was later shown to selectively inhibit the formation of new blood vessels. However, unlike previously described steroids, squalamine has significant structural differences and does not interact with glucocorticoid or minealocorticoid receptors (30). It is a 7,24 dihydroxylated 24-sulfated cholestane steroid conjugated to a spermidine at position C-3 (see Fig. 1). Squalamine has been demonstrated to be an angiostatic steroid by virtue of its inhibition of growth of vascular endothelial cells in culture, activity in the chick embryo chorioallantoic membrane assay and a rabbit corneal micropocket assay, as well as growth inhibition of gliomas and lung cancers in vivo (22,28,31). Squalamine is somewhat unique among most current anti-angiogenic agents in development because it inhibits endothelial cell proliferation and migration induced by a wide variety of growth factors, including Basic Fibroblast Growth Factor (bFGF) and VEGF (27,31; Fig. 2). This broad antiangiogenic activity of squalamine may result from its inhibition of surface sodium–proton exchangers (thus altering intracellular pH and thereby impeding intracellular signaling by several growth factors) and other downstream signaling pathways in endothelial cells (27,29). There are different theories about the mechanism of action of squalamine that remain to be investigated.

Bottom Line: This review focuses on the potential application in antitumor therapy of naturally-occurring steroids that target tumor-associated angiogenesis.Squalamine, a 7,24 dihydroxylated 24-sulfated cholestane steroid conjugated to a spermidine at position C-3, is known to have strong antiangiogenic activity in vitro, and it significantly disrupts tumor proliferation and progression in laboratory studies.Preclinical studies with squalamine have shown additive benefits in tumor growth delay when squalamine is combined with cisplatin, paclitaxel, cyclophosphamide, genistein or radiation therapy.

View Article: PubMed Central - PubMed

ABSTRACT
Despite advances in the early detection of tumors and in the use of chemotherapy, radiotherapy and surgery for disease management, the worldwide mortality from human cancer remains unacceptably high. The treatment of cancer may benefit from the introduction of novel therapies derived from natural products. Natural products have served to provide a basis for many of the pharmaceutical agents in current use in cancer therapy. Emerging research indicates that progressive growth and spread of many solid tumors depends, in part, on the formation of an adequate blood supply, and this process of tumor-associated angiogenesis is reported to have prognostic significance in several human cancers. This review focuses on the potential application in antitumor therapy of naturally-occurring steroids that target tumor-associated angiogenesis. Squalamine, a 7,24 dihydroxylated 24-sulfated cholestane steroid conjugated to a spermidine at position C-3, is known to have strong antiangiogenic activity in vitro, and it significantly disrupts tumor proliferation and progression in laboratory studies. Work on the interactions of squalamine with vascular endothelial cells indicate that it binds with cell membranes, inhibits the membrane Na(+)/H(+) exchanger and may further function as a calmodulin chaperone. These primary actions appear to promote inhibition of several vital steps in angiogenesis, such as blockade of mitogen-induced actin polymerization, cell-cell adhesion and cell migration, leading to suppression of endothelial cell proliferation. Preclinical studies with squalamine have shown additive benefits in tumor growth delay when squalamine is combined with cisplatin, paclitaxel, cyclophosphamide, genistein or radiation therapy. This compound has also been assessed in early phase clinical trials in cancer; squalamine was found to exhibit little systemic toxicity and was generally well tolerated by treated patients with various solid tumor malignancies, including ovarian, non-small cell lung and breast cancers. Clinical trials with squalamine alone or combined with standard chemotherapies or other biologic therapies, including antiangiogenic agents, should be considered for selected cancer patients, and further study of the mechanism of action and bioactivity of squalamine is warranted.

No MeSH data available.


Related in: MedlinePlus