A vascular disrupting agent overcomes tumor multidrug resistance by skewing macrophage polarity toward the M1 phenotype. (1st April 2018)

• Record Type: Journal Article
• Authors: Lei, Xueping; Chen, Minfeng; Li, Xiaobo; Huang, Maohua; Nie, Qiulin; Ma, Nan; Chen, Heru; Xu, Nanhui; Ye, Wencai; Zhang, Dongmei
• Is Part Of: Cancer letters. Volume 418(2018)
• Page Start: 239
• Page End: 249
• Publication Date: 2018-04-01
• Subjects: Multidrug resistance -- Vascular disrupting agent -- Tumor-associated macrophages -- Granulocyte-macrophage colony-stimulating factor; MDR multidrug resistance -- ABCB-1 ATP-binding cassette transporter B1 -- TAMs tumor-associated macrophages -- DOX doxorubicin -- VDA vascular disrupting agent -- iNOS inducible nitric oxide synthase -- Arg-1 arginase 1 -- Ly6G lymphocyte antigen 6 complex locus G6D -- IFN-β interferon-β -- CA4-P combretastatin A4 phosphate -- GM-CSF granulocyte-macrophage colony-stimulating factor -- M-CSF macrophage colony-stimulating factor -- IL-6 interleukin-6 -- IL-10 interleukin-10 -- LPS lipopolysaccharide -- INF-γ interferon gamma -- TNF-α tumor necrosis factor alpha -- HIF-1α hypoxia-inducible factor -- CSF-1R colony stimulating factor 1 recptor; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.01.016
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Multidrug resistance (MDR) mediated by ATP-binding cassette (ABC) transporters is the major obstacle for chemotherapeutic success. Although attempts have been made to circumvent ABC transporter-mediated MDR in past decades, there is still no effective agent in clinic. Here, we identified a vascular disrupting agent, Z-GP-DAVLBH, that significantly inhibited the growth of multidrug-resistant human hepatoma HepG2/ADM and human breast cancer MCF-7/ADR tumor xenografts, although these cells were insensitive to Z-GP-DAVLBH in vitro . Z-GP-DAVLBH increased the secretion of granulocyte-macrophage colony-stimulating factor in tumor tissues and serum of tumor-bearing mice to skew tumor-associated macrophages from the pro-tumor M2 phenotype to the antitumor M1 phenotype, thereby contributing to the induction of HepG2/ADM and MCF-7/ADR cell apoptosis. Our findings shed new light on the underlying mechanisms of VDAs in the treatment of drug-resistant tumors and provide strong evidence that Z-GP-DAVLBH should be a promising agent for overcoming MDR. Highlights: Z-GP-DAVLBH inhibits the growth of multidrug-resistant HepG2/ADM and MCF-7/ADR tumor xenografts. Z-GP-DAVLBH induces the repolarization of tumor-associated macrophages to the M1 phenotype in vivo. M1 macrophages contribute to the anti-cancer effect of Z-GP-DAVLBH both in vitro and in vivo. Granulocyte-macrophage colony-stimulating factor plays a key role in Z-GP-DAVLBH-induced M1 macrophage repolarization.