UNBS5162, a novel naphthalimide that decreases CXCL chemokine expression in experimental prostate cancers.
Several naphthalimides have been evaluated clinically as potential anticancer agents. UNBS3157, a naphthalimide that belongs to the same class as amonafide, was designed to avoid the specific activating metabolism that induces amonafide's hematotoxicity. The current study shows that UNBS3157 rapidly and irreversibly hydrolyzes to UNBS5162 without generating amonafide. In vivo UNBS5162 after repeat administration significantly increased survival in orthotopic human prostate cancer models. Results obtained by the National Cancer Institute (NCI) using UNBS3157 and UNBS5162 against the NCI 60 cell line panel did not show a correlation with any other compound present in the NCI database, including amonafide, thereby suggesting a unique mechanism of action for these two novel naphthalimides. Affymetrix genome-wide microarray analysis and enzyme-linked immunosorbent assay revealed that in vitro exposure of PC-3 cells to UNBS5162 (1 microM for 5 successive days) dramatically decreased the expression of the proangiogenic CXCL chemokines. Histopathology additionally revealed antiangiogenic properties in vivo for UNBS5162 in the orthotopic PC-3 model. In conclusion, the present study reveals UNBS5162 to be a pan-antagonist of CXCL chemokine expression, with the compound displaying antitumor effects in experimental models of human refractory prostate cancer when administered alone and found to enhance the activity of taxol when coadministered with the taxoid.
Mijatovic
Tatjana
T
Unibioscreen SA, 40 Avenue Joseph Wybran, 1070 Brussels, Belgium.
Mahieu
Tina
T
Bruyère
Céline
C
De Nève
Nancy
N
Dewelle
Janique
J
Simon
Gentiane
G
Dehoux
Mischaël J M
MJ
van der Aar
Ellen
E
Haibe-Kains
Benjamin
B
Bontempi
Gianluca
G
Decaestecker
Christine
C
Van Quaquebeke
Eric
E
Darro
Francis
F
Kiss
Robert
R
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D019743:Chemokines, CXC / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D053644:Naphthalimides / Q000494:pharmacology*; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D019743:Chemokines, CXC; D053644:Naphthalimides; C531082:UNBS 5162; D014508:Urea