EGF-induced P-gp expression in tumor vasculature contributes to therapeutic resistance to doxorubicin-PEG-liposomes in mice bearing doxorubicin-resistant B16-BL6 tumors

We previously indicated that doxorubicin (DOX)-loaded polyethylene glycol (PEG)-modified liposomes (DOX-PEG-liposomes) were therapeutically effective in mice bearing DOX-resistant colon-26 (C26/DOX) tumors, and the efficacy was comparable in mice bearing DOX-sensitive C26 tumors. However, in the current study, DOX-PEG-liposomes exerted no therapeutic activity in DOX-resistant B16-BL6 melanoma (B16/DOX)-bearing mice, although they significantly suppressed DOX-sensitive B16 tumor growth in mice. Although we previously reported that the anti-tumor effects in C26/DOX-bearing mice were derived from the cytotoxic effects of DOX on vascular endothelial cells (VECs) in tumors, the B16/DOX tumor vasculature was not substantially damaged after administration of DOX-PEG-liposomes. In B16/DOX tumors, P-gp expression was significantly induced in the VECs, but not in the C26/DOX tumors, indicating that the high expression of P-gp in the tumor vasculature would be responsible for the lack of therapeutic effect of DOX-PEG-liposomes in B16/DOX-bearing mice. Epidermal growth factor (EGF), a possible induction factor for P-gp expression, was highly expressed in B16/DOX cells and tumor tissues, and significantly induced P-gp expression in human umbilical vein endothelial cells (HUVEC). The EGF receptor (EGFR) was also highly expressed in B16/DOX tumor VECs, suggesting that the activation of EGF/EGFR signaling may induce P-gp expression in VECs in B16/DOX tumors.