Neutral Porphyrin Derivative Exerts Anticancer Activity by Targeting Cellular Topoisomerase I (Top1) and Promotes Apoptotic Cell Death without Stabilizing Top1-DNA Cleavage Complexes

Camptothecin (CPT) selectively traps
topoisomerase 1-DNA cleavable
complexes (Top1cc) to promote anticancer activity. Here, we report
the design and synthesis of a new class of neutral porphyrin derivative
5,10-bis­(4-carboxyphenyl)-15, 20-bis­(4-dimethyl­aminophenyl)­porphyrin
(compound 8) as a potent catalytic inhibitor of human
Top1. In contrast to CPT, compound 8 reversibly binds
with the free enzyme and inhibits the formation of Top1cc and promotes
reversal of the preformed Top1cc with CPT. Compound 8 induced inhibition of Top1cc formation in live cells was substantiated
by fluorescence recovery after photobleaching (FRAP) assays. We established
that MCF7 cells treated with compound 8 trigger proteasome-mediated
Top1 degradation, accumulate higher levels of reactive oxygen species
(ROS), PARP1 cleavage, oxidative DNA fragmentation, and stimulate
apoptotic cell death without stabilizing apoptotic Top1-DNA cleavage
complexes. Finally, compound 8 shows anticancer activity
by targeting cellular Top1 and preventing the enzyme from directly
participating in the apoptotic process.