Novel and potent compound selectively kills cancer cells by disrupting their DNA repair machinery


27 Jan 2018

Novel and potent compound selectively kills cancer cells by disrupting their DNA repair machinery

 

By Dr. Benu Brata Das, Intermediate Fellow

Indian Association for the Cultivation of Science (IACS), Kolkata

Our recent work published in Journal of Medicinal Chemistry reports the identification of a novel and potent compound that was shown to be effective in killing cancer cells by disrupting their DNA repair machinery.

Cancer is marked by uncontrolled cellular division and growth. Topoisomerase 1 (Top1) enzyme plays a pivotal role by releasing the DNA supercoiling generated during replication and transcription and facilitates cell division. Top1 is a validated target for cancer chemotherapy. Top1 inhibitors, like camptothecin (CPT) and its derivatives, trap Top1 on the DNA to exert its cytotoxicity and are now used for the treatment of metastatic colorectal, pediatric tumors and ovarian cancer. However, these drugs suffer from several limitations including chemoresistance.

In the present work, we discovered a novel class of neutral porphyrin compounds that inhibit Top1 without trapping Top1-DNA cleavage complexes, a mechanism which is unique in comparison to the existing Top1 inhibitors like CPT.  We provide evidence that in contrast to CPT, the selected porphyrin derivative (we call it, compound 8)  binds reversibly to the free enzyme and effectively inhibits the formation of Top1-DNA cleavage complex both in vitro and in live cells to exert its anticancer activity.

We further validated that compound 8 directly targets cellular Top1 using Top1- knocked down breast cancer cells. We show that compound 8 was effective in killing cancer cells by triggering proteasome-mediated Top1 degradation, accumulation of reactive oxygen species (ROS), PARP1 cleavage, DNA fragmentation and apoptotic cell death. Future challenge include animal studies to establish its therapeutic potential.

Abstract Image

Neutral Porphyrin Derivative Exerts Anticancer Activity by Targeting Cellular Topoisomerase I (Top1) and Promotes Apoptotic Cell Death without Stabilizing Top1-DNA Cleavage Complexes. Subhendu K. Das, Arijit Ghosh, Srijita Paul Chowdhuri, Nyancy Halder, Ishita Rehman, Souvik Sengupta, Krushna Chandra Sahoo, Harapriya Rath* , and Benu Brata Das*. Journal of Medicinal Chemistry. January 2018.

Media report - IACS researchers use a novel compound to kill cancer cells. The Hindu

Banner image credit: Kevin Mackenzie, University of AberdeenDescription: Light micrograph of HeLa cells. Actin fibres (pink) and alpha tubulin fibres (blue) in the cell cytoskeleton are visible here. HeLa cells are an immortal human epithelial cell line derived from a cancerous tumour of the cervix (adenocarcinoma).