Albumin-binding and tumor vasculature determine the antitumor effect of 15-Deoxy-Δ12,14-prostaglandin-J2 in vivo

15-Deoxy-Δ^12,14-prostaglandin-J₂ (15d-PGJ ₂), a peroxisome proliferator-activated receptor y (PPARy) agonist, induces cell death in tumor cells in vitro; however, no study showed its in vivo effect on tumors. Here, we report that 15d-PGJ₂ shows antitumor effects in vivo in mice. However, its effects correlate with tumor uptake of albumin, to which it reversibly binds. 15d-PGJ₂ induces cell death in B16F10 melanoma and C26 colon carcinoma cells in vitro. These effects were not elicited through PPARy-dependent pathways because an irreversible PPARy antagonist GW9662 did not inhibit these effects. Caspase- and nuclear factor κB- (NF-κB) dependent pathways were found to be involved as determined with caspase-3/7 fluorescent assay and NF-κB containing plasmid transfection assay, respectively. Noticeably, 15d-PGJ₂ had significantly stronger effects in C26 cells compared with B16 cells in all assays. However, in vivo, there was no effect on C26 tumors, yet it significantly inhibited the B16 tumor growth in mice by 75%. We found that 15d-PGJ₂ rapidly bound to albumin and in vivo albumin greatly distributed to B16 tumors compared with C26 tumors, shown with y-camera imaging and immunohistochemical staining. Albumin accumulation can be attributed to the large blood vessel diameter in B16 tumors and an enhanced permeability and retention effect. These findings suggest that 15d-PGJ₂ can be an effective therapeutic agent for cancer, although its effects seem to be limited to the tumors allowing albumin penetration.