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Anti-cancer activity of an osthole derivative, NBM-T-BMX-OS01: targeting vascular endothelial growth factor receptor signaling and angiogenesis.

Yang HY, Hsu YF, Chiu PT, Ho SJ, Wang CH, Chi CC, Huang YH, Lee CF, Li YS, Ou G, Hsu MJ - PLoS ONE (2013)

Bottom Line: BMX also attenuated VEGF-induced microvessel sprouting from aortic rings ex vivo and reduced HCT116 colorectal cancer cells-induced angiogenesis in vivo.Taken together, this study provides evidence that BMX modulates vascular endothelial cell remodeling and leads to the inhibition of tumor angiogenesis.These results also support the role of BMX as a potential drug candidate and warrant the clinical development in the treatment of cancer.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiology, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan.

ABSTRACT
Angiogenesis occurs during tissue growth, development and wound healing. It is also required for tumor progression and represents a rational target for therapeutic intervention. NBM-T-BMX-OS01 (BMX), derived from the semisynthesis of osthole, an active ingredient isolated from Chinese herb Cnidium monnieri (L.) Cuss., was recently shown to enhance learning and memory in rats. In this study, we characterized the anti-angiogenic activities of NBM-T-BMX-OS01 (BMX) in an effort to develop novel inhibitors to suppress angiogenesis and tumor growth. BMX inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration and endothelial tube formation in human umbilical endothelial cells (HUVECs). BMX also attenuated VEGF-induced microvessel sprouting from aortic rings ex vivo and reduced HCT116 colorectal cancer cells-induced angiogenesis in vivo. Moreover, BMX inhibited the phosphorylation of VEGFR2, FAK, Akt and ERK in HUVECs exposed to VEGF. BMX was also shown to inhibit HCT116 cell proliferation and to suppress the growth of subcutaneous xenografts of HCT116 cells in vivo. Taken together, this study provides evidence that BMX modulates vascular endothelial cell remodeling and leads to the inhibition of tumor angiogenesis. These results also support the role of BMX as a potential drug candidate and warrant the clinical development in the treatment of cancer.

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Chemical structure of BMX.
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pone-0081592-g001: Chemical structure of BMX.

Mentions: Cnidium monnieri (L.) Cuss. has long been widely used in oriental medicine to improve immunity and to alleviate hepatitis. Osthole, a bioactive component extracted from the seeds of Cnidium monnieri (L.) Cuss., is thus expected to have immunomodulatory activities. Recent studies also demonstrated that osthole possesses neuroprotective [24], hepatoprotective [25], anti-diabetic [26], and anti-cancer activities [27], [28]. Given osthole's broad spectrum of biological activities, it appears to be a promising lead compound for drug discovery. Recently, NBM-T-BMX-OS01 (BMX) (Fig. 1), a derivative semisynthesized from osthole, was identified as a potent histone deacetylase inhibitor and was shown to enhance learning and memory in rats [29]. In an effort to discover tumor angiogenesis inhibitors, we thus evaluated the anti-angiogenic properties of BMX. In this study, we demonstrated that BMX inhibited VEGF-induced cell proliferation, migration, and tube formation in human umbilical endothelial cells (HUVECs). VEGF-induced phosphorylation of VEGFR2, Src, ERK, Akt and FAK were also suppressed in HUVECs exposed to BMX. By use of HCT116 colorectal cancer cells xenograft angiogenesis model, BMX was further shown to suppress tumor-associated angiogenesis. Furthermore, BMX significantly inhibited HCT116 colorectal cancer cell proliferation and suppressed tumor growth in a xenograft tumor model. Taken together, these results suggest the potential of BMX as a therapeutic agent with dual activity against both tumor proliferation and angiogenesis.


Anti-cancer activity of an osthole derivative, NBM-T-BMX-OS01: targeting vascular endothelial growth factor receptor signaling and angiogenesis.

Yang HY, Hsu YF, Chiu PT, Ho SJ, Wang CH, Chi CC, Huang YH, Lee CF, Li YS, Ou G, Hsu MJ - PLoS ONE (2013)

Chemical structure of BMX.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3842266&req=5

pone-0081592-g001: Chemical structure of BMX.
Mentions: Cnidium monnieri (L.) Cuss. has long been widely used in oriental medicine to improve immunity and to alleviate hepatitis. Osthole, a bioactive component extracted from the seeds of Cnidium monnieri (L.) Cuss., is thus expected to have immunomodulatory activities. Recent studies also demonstrated that osthole possesses neuroprotective [24], hepatoprotective [25], anti-diabetic [26], and anti-cancer activities [27], [28]. Given osthole's broad spectrum of biological activities, it appears to be a promising lead compound for drug discovery. Recently, NBM-T-BMX-OS01 (BMX) (Fig. 1), a derivative semisynthesized from osthole, was identified as a potent histone deacetylase inhibitor and was shown to enhance learning and memory in rats [29]. In an effort to discover tumor angiogenesis inhibitors, we thus evaluated the anti-angiogenic properties of BMX. In this study, we demonstrated that BMX inhibited VEGF-induced cell proliferation, migration, and tube formation in human umbilical endothelial cells (HUVECs). VEGF-induced phosphorylation of VEGFR2, Src, ERK, Akt and FAK were also suppressed in HUVECs exposed to BMX. By use of HCT116 colorectal cancer cells xenograft angiogenesis model, BMX was further shown to suppress tumor-associated angiogenesis. Furthermore, BMX significantly inhibited HCT116 colorectal cancer cell proliferation and suppressed tumor growth in a xenograft tumor model. Taken together, these results suggest the potential of BMX as a therapeutic agent with dual activity against both tumor proliferation and angiogenesis.

Bottom Line: BMX also attenuated VEGF-induced microvessel sprouting from aortic rings ex vivo and reduced HCT116 colorectal cancer cells-induced angiogenesis in vivo.Taken together, this study provides evidence that BMX modulates vascular endothelial cell remodeling and leads to the inhibition of tumor angiogenesis.These results also support the role of BMX as a potential drug candidate and warrant the clinical development in the treatment of cancer.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiology, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan.

ABSTRACT
Angiogenesis occurs during tissue growth, development and wound healing. It is also required for tumor progression and represents a rational target for therapeutic intervention. NBM-T-BMX-OS01 (BMX), derived from the semisynthesis of osthole, an active ingredient isolated from Chinese herb Cnidium monnieri (L.) Cuss., was recently shown to enhance learning and memory in rats. In this study, we characterized the anti-angiogenic activities of NBM-T-BMX-OS01 (BMX) in an effort to develop novel inhibitors to suppress angiogenesis and tumor growth. BMX inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration and endothelial tube formation in human umbilical endothelial cells (HUVECs). BMX also attenuated VEGF-induced microvessel sprouting from aortic rings ex vivo and reduced HCT116 colorectal cancer cells-induced angiogenesis in vivo. Moreover, BMX inhibited the phosphorylation of VEGFR2, FAK, Akt and ERK in HUVECs exposed to VEGF. BMX was also shown to inhibit HCT116 cell proliferation and to suppress the growth of subcutaneous xenografts of HCT116 cells in vivo. Taken together, this study provides evidence that BMX modulates vascular endothelial cell remodeling and leads to the inhibition of tumor angiogenesis. These results also support the role of BMX as a potential drug candidate and warrant the clinical development in the treatment of cancer.

Show MeSH
Related in: MedlinePlus