Biomol Ther.  2019 Jan;27(1):117-125. 10.4062/biomolther.2018.222.

Autophagy Is a Potential Target for Enhancing the Anti-Angiogenic Effect of Mebendazole in Endothelial Cells

• Sung SJ
• Kim HK
• Hong YK
• Joe YA

• KMID: 2432075
• DOI: http://doi.org/10.4062/biomolther.2018.222

Abstract

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.

Keyword

Mebendazole; Angiogenesis inhibitor; Autophagy; Apoptosis; Endothelial cells

MeSH Terms

Apoptosis
Autophagy*
Caspase 3
Chloroquine
Endothelial Cells*
Fibroblast Growth Factor 2
Helminths
Intercellular Signaling Peptides and Proteins
Mebendazole*
Microtubules
Phosphorylation
Phosphotransferases
Receptors, Vascular Endothelial Growth Factor
Vascular Endothelial Growth Factor A
Caspase 3
Chloroquine
Fibroblast Growth Factor 2
Intercellular Signaling Peptides and Proteins
Mebendazole
Phosphotransferases
Receptors, Vascular Endothelial Growth Factor
Vascular Endothelial Growth Factor A