3 years ago

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

Neutral Porphyrin
Derivative Exerts Anticancer Activity
by Targeting Cellular Topoisomerase I (Top1) and Promotes Apoptotic
Cell Death without Stabilizing Top1-DNA Cleavage Complexes
Nyancy Halder, Srijita Paul Chowdhuri, Harapriya Rath, Arijit Ghosh, Benu Brata Das, Subhendu K. Das, Souvik Sengupta, Krushna Chandra Sahoo, Ishita Rehman
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.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b01297

DOI: 10.1021/acs.jmedchem.7b01297

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