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학술연구/단체지원/교육 등 연구자 활동을 지속하도록 DBpia가 지원하고 있어요.
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논문 기본 정보
- 자료유형
- 학술저널
- 저자정보
- 발행연도
- 2019.1
- 수록면
- 117 - 125 (9page)
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Mebendazole (MBZ), a microtubule depolymerizing drug commonly used for the treatment of helminthic infections, has recently been noted as a repositioning candidate for angiogenesis inhibition and cancer therapy. However, the definite anti-angiogenic mechanism of MBZ remains unclear. In this study, we explored the inhibitory mechanism of MBZ in endothelial cells (ECs) and developed a novel strategy to improve its anti-angiogenic therapy. Treatment of ECs with MBZ led to inhibition of EC proliferation in a dose-dependent manner in several culture conditions in the presence of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) or FBS, without selectivity of growth factors, although MBZ is known to inhibit VEGF receptor 2 kinase. Furthermore, MBZ inhibited EC migration and tube formation induced by either VEGF or bFGF. However, unexpectedly, treatment of MBZ did not affect FAK and ERK1/2 phosphorylation induced by these factors. Treatment with MBZ induced shrinking of ECs and caused G2-M arrest and apoptosis with an increased Sub-G1 fraction. In addition, increased levels of nuclear fragmentation, p53 expression, and active form of caspase 3 were observed. The marked induction of autophagy by MBZ was also noted. Interestingly, inhibition of autophagy through knocking down of Beclin1 or ATG5/7, or treatment with autophagy inhibitors such as 3-methyladenine and chloroquine resulted in marked enhancement of anti-proliferative and pro-apoptotic effects of MBZ in ECs. Consequently, we suggest that MBZ induces autophagy in ECs and that protective autophagy can be a novel target for enhancing the anti-angiogenic efficacy of MBZ in cancer treatment.
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참고문헌 (43)
참고문헌 신청
Adelusi SA / 1982 / Tissue and blood concentrations of chloroquine following chronic administration in the rat / J. Pharm. Pharmacol 34:733~735
Bai RY / 2011 / Antiparasitic mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme / Neuro. Oncol 13:974~982
Bai RY / 2015 / Effective treatment of diverse medulloblastoma models with mebendazole and its impact on tumor angiogenesis / Neuro. Oncol 17:545~554
Bai RY / 2015 / Brain penetration and efficacy of different mebendazole polymorphs in a mouse brain tumor model / Clin. Cancer Res 21:3462~3470
Belloni D / 2010 / Bortezomib induces autophagic death in proliferating human endothelial cells / Exp. Cell Res 316:1010~1018
Bai RY / 2011 / Antiparasitic mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme / Neuro. Oncol 13:974~982
Bai RY / 2015 / Effective treatment of diverse medulloblastoma models with mebendazole and its impact on tumor angiogenesis / Neuro. Oncol 17:545~554
Bai RY / 2015 / Brain penetration and efficacy of different mebendazole polymorphs in a mouse brain tumor model / Clin. Cancer Res 21:3462~3470
Belloni D / 2010 / Bortezomib induces autophagic death in proliferating human endothelial cells / Exp. Cell Res 316:1010~1018
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