Albumin-binding and tumor vasculature determine the antitumor effect of 15-deoxy-Delta-(12,14)-prostaglandin-J(2) in vivo.
15-Deoxy-Delta(12,14)-prostaglandin-J(2) (15d-PGJ(2)), a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, induces cell death in tumor cells in vitro; however, no study showed its in vivo effect on tumors. Here, we report that 15d-PGJ(2) shows antitumor effects in vivo in mice. However, its effects correlate with tumor uptake of albumin, to which it reversibly binds. 15d-PGJ(2) induces cell death in B16F10 melanoma and C26 colon carcinoma cells in vitro. These effects were not elicited through PPARgamma-dependent pathways because an irreversible PPARgamma antagonist GW9662 did not inhibit these effects. Caspase- and nuclear factor kappaB- (NF-kappaB) dependent pathways were found to be involved as determined with caspase-3/7 fluorescent assay and NF-kappaB containing plasmid transfection assay, respectively. Noticeably, 15d-PGJ(2) 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-PGJ(2) rapidly bound to albumin and in vivo albumin greatly distributed to B16 tumors compared with C26 tumors, shown with gamma-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-PGJ(2) can be an effective therapeutic agent for cancer, although its effects seem to be limited to the tumors allowing albumin penetration.
Prakash
Jai
J
Department of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands. J.Prakash@rug.nl
Bansal
Ruchi
R
Post
Eduard
E
de Jager-Krikken
Alie
A
Lub-de Hooge
Marjolijn N
MN
Poelstra
Klaas
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007150:Immunohistochemistry; D007155:Immunologic Factors / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000473:pathology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D007155:Immunologic Factors; D016328:NF-kappa B; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012709:Serum Albumin; D053148:Caspase 3; D053179:Caspase 7; D015230:Prostaglandin D2