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