UNBS5162, a Novel Naphthalimide That Decreases CXCL Chemokine Expression in Experimental Prostate Cancers.
Mijatovic
T, Mahieu T, Bruyère C, De Nève N, Dewelle J, Simon G, Dehoux MJM, van
der Aar E, Haibe-Kains B, Bontempi G, Decaestecker C, Van Quaquebeke E,
Darro F and Kiss R
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 μM 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.