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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 inhibits growth of human non-small cell lung tumor cells and enhances the antitumor effects of radiation therapy and genistein. Lung cancers with estrogen receptor-α and estrogen receptor-β expression (NCI-H23) were grown as subcutaneous xenografts to 50–100 mm3 in size in ovariectomized, nude mice primed with estrogen (1.7 mg/pellet). Mice were then treated as outlined here. (A) Genistein, a phytoestrogen, and squalamine inhibit growth of human lung tumor xenografts NCI-H23 in nude mice. Mice with established tumors were treated with control solution, genistein alone (0.2 mg/kg s.c. on alternate days) (18), squalamine alone (2 mg/kg s.c.) on days 1–10, or genistein with squalamine. By 28 days, tumors showed little tumor regression after treatment with genistein alone and modest regression after squalamine alone compared to control (P < 0.05). More profound tumor growth inhibition was elicited by treatment with squalamine plus genistein (P < 0.001). Mean tumor volumes of control (CON), genistein (G), squalamine (SQ) and combined squalamine/genistein (SQ/G) treatment are shown. (B) Radiation therapy (RT) and squalamine inhibit growth of lung tumor xenografts NCI-H23 in nude mice. Mean tumor volumes of control (CON), RT (4 Gy on days 1, 4 and 7), squalamine (SQ; 2 mg/kg s.c. on days 1–10) and combined squalamine/RT (SQ/RT) treatment are shown. See Pietras et al. (54,55) and text for details.
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fig3: Squalamine inhibits growth of human non-small cell lung tumor cells and enhances the antitumor effects of radiation therapy and genistein. Lung cancers with estrogen receptor-α and estrogen receptor-β expression (NCI-H23) were grown as subcutaneous xenografts to 50–100 mm3 in size in ovariectomized, nude mice primed with estrogen (1.7 mg/pellet). Mice were then treated as outlined here. (A) Genistein, a phytoestrogen, and squalamine inhibit growth of human lung tumor xenografts NCI-H23 in nude mice. Mice with established tumors were treated with control solution, genistein alone (0.2 mg/kg s.c. on alternate days) (18), squalamine alone (2 mg/kg s.c.) on days 1–10, or genistein with squalamine. By 28 days, tumors showed little tumor regression after treatment with genistein alone and modest regression after squalamine alone compared to control (P < 0.05). More profound tumor growth inhibition was elicited by treatment with squalamine plus genistein (P < 0.001). Mean tumor volumes of control (CON), genistein (G), squalamine (SQ) and combined squalamine/genistein (SQ/G) treatment are shown. (B) Radiation therapy (RT) and squalamine inhibit growth of lung tumor xenografts NCI-H23 in nude mice. Mean tumor volumes of control (CON), RT (4 Gy on days 1, 4 and 7), squalamine (SQ; 2 mg/kg s.c. on days 1–10) and combined squalamine/RT (SQ/RT) treatment are shown. See Pietras et al. (54,55) and text for details.

Mentions: In studies of human non-small cell lung tumors grown as xenografts in nude mice, our laboratory has further assessed the effects of squalamine treatment alone and combined with either the phytoestrogen, genistein, or radiation therapy (see Fig. 3). The non-small cell lung tumor, NCI-H23, as many human lung tumors, is enriched with estrogen receptor-β and this receptor signaling pathway may also promote angiogenesis (39). Treatment with squalamine alone elicits a modest inhibition of the growth of human non-small cell lung tumor cells NCI-H23 (P < 0.05). Moreover, combination of squalamine with genistein (Fig. 3A), a potential inhibitor of estrogen receptor-β activity, appears to elicit additive antitumor effects that exceed the responses to single agent treatments (P < 0.001). In addition, squalamine was combined with radiation therapy, a common treatment intervention for non-small cell lung cancer, and this combination was highly effective in suppressing tumor growth (P < 0.001) (Fig. 3B). This latter finding supports independent data suggesting that the combination of ionizing radiation with antiangiogenic agents can improve tumor eradication, possibly without increasing deleterious effects (40).


Antiangiogenic Steroids in Human Cancer Therapy.

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

Squalamine inhibits growth of human non-small cell lung tumor cells and enhances the antitumor effects of radiation therapy and genistein. Lung cancers with estrogen receptor-α and estrogen receptor-β expression (NCI-H23) were grown as subcutaneous xenografts to 50–100 mm3 in size in ovariectomized, nude mice primed with estrogen (1.7 mg/pellet). Mice were then treated as outlined here. (A) Genistein, a phytoestrogen, and squalamine inhibit growth of human lung tumor xenografts NCI-H23 in nude mice. Mice with established tumors were treated with control solution, genistein alone (0.2 mg/kg s.c. on alternate days) (18), squalamine alone (2 mg/kg s.c.) on days 1–10, or genistein with squalamine. By 28 days, tumors showed little tumor regression after treatment with genistein alone and modest regression after squalamine alone compared to control (P < 0.05). More profound tumor growth inhibition was elicited by treatment with squalamine plus genistein (P < 0.001). Mean tumor volumes of control (CON), genistein (G), squalamine (SQ) and combined squalamine/genistein (SQ/G) treatment are shown. (B) Radiation therapy (RT) and squalamine inhibit growth of lung tumor xenografts NCI-H23 in nude mice. Mean tumor volumes of control (CON), RT (4 Gy on days 1, 4 and 7), squalamine (SQ; 2 mg/kg s.c. on days 1–10) and combined squalamine/RT (SQ/RT) treatment are shown. See Pietras et al. (54,55) and text for details.
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Related In: Results  -  Collection

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

fig3: Squalamine inhibits growth of human non-small cell lung tumor cells and enhances the antitumor effects of radiation therapy and genistein. Lung cancers with estrogen receptor-α and estrogen receptor-β expression (NCI-H23) were grown as subcutaneous xenografts to 50–100 mm3 in size in ovariectomized, nude mice primed with estrogen (1.7 mg/pellet). Mice were then treated as outlined here. (A) Genistein, a phytoestrogen, and squalamine inhibit growth of human lung tumor xenografts NCI-H23 in nude mice. Mice with established tumors were treated with control solution, genistein alone (0.2 mg/kg s.c. on alternate days) (18), squalamine alone (2 mg/kg s.c.) on days 1–10, or genistein with squalamine. By 28 days, tumors showed little tumor regression after treatment with genistein alone and modest regression after squalamine alone compared to control (P < 0.05). More profound tumor growth inhibition was elicited by treatment with squalamine plus genistein (P < 0.001). Mean tumor volumes of control (CON), genistein (G), squalamine (SQ) and combined squalamine/genistein (SQ/G) treatment are shown. (B) Radiation therapy (RT) and squalamine inhibit growth of lung tumor xenografts NCI-H23 in nude mice. Mean tumor volumes of control (CON), RT (4 Gy on days 1, 4 and 7), squalamine (SQ; 2 mg/kg s.c. on days 1–10) and combined squalamine/RT (SQ/RT) treatment are shown. See Pietras et al. (54,55) and text for details.
Mentions: In studies of human non-small cell lung tumors grown as xenografts in nude mice, our laboratory has further assessed the effects of squalamine treatment alone and combined with either the phytoestrogen, genistein, or radiation therapy (see Fig. 3). The non-small cell lung tumor, NCI-H23, as many human lung tumors, is enriched with estrogen receptor-β and this receptor signaling pathway may also promote angiogenesis (39). Treatment with squalamine alone elicits a modest inhibition of the growth of human non-small cell lung tumor cells NCI-H23 (P < 0.05). Moreover, combination of squalamine with genistein (Fig. 3A), a potential inhibitor of estrogen receptor-β activity, appears to elicit additive antitumor effects that exceed the responses to single agent treatments (P < 0.001). In addition, squalamine was combined with radiation therapy, a common treatment intervention for non-small cell lung cancer, and this combination was highly effective in suppressing tumor growth (P < 0.001) (Fig. 3B). This latter finding supports independent data suggesting that the combination of ionizing radiation with antiangiogenic agents can improve tumor eradication, possibly without increasing deleterious effects (40).

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