Abstract
Camptothecin (CPT), a topoisomerase I (TOP1) inhibitor, exhibits anti-tumor activity against a wide range of tumors. Redundancy of TOP1-mediated repair mechanisms is a major challenge facing the efficiency of TOP1-targetting therapies. This study aims to uncover new TOP1 targeting approaches utilising a selection of natural compounds in the presence or absence of tyrosyl DNA phosphodiesterase I (TDP1); a key TOP1-mediated protein-linked DNA break (PDB) repair enzyme. We identify, isoeugenol, a phenolic ether found in plant essential oils, as a potentiator of CPT cytotoxicity in Tdp1 deficient but not proficient cells. Consistent with our cellular data, isoeugenol did not inhibit Tdp1 enzymatic activity in vitro nor it sensitized cells to the PARP1 inhibitor olaparib. However, biochemical analyses suggest that isoeugenol inhibits TDP2 catalytic activity; a pathway that can compensate for the absence of TDP1. Consistent with this, isoeugenol exacerbated etoposide-induced cytotoxicity, which generates TOP2-mediated PDBs for which TDP2 is required for processing. Together, these findings identify isoeugenol as a potential lead compound for developing TDP2 inhibitors and encourage structure-activity relationship studies to shed more light on its utility in drug discovery programs.
Highlights
Camptothecin (CPT), a quinoline alkaloid isolated from the wood and bark of the Chinese tree Camptotheca acuminata, is a well-known topoisomerase I (TOP1) inhibitor[1] that was first isolated and identified as an anti-cancer agent in 19662
A selection of 41 diverse natural products most of which occur in foods or dietary supplements were subjected to a series of cellular and biochemical experiments to identify potential hits to improve TOP1 targeting therapy (Fig. 1A)
The library is comprised of molecules belonging to different natural products classes viz. alkaloids, flavonoids, saponins, terpenes, and phenylpropanoids
Summary
Camptothecin (CPT), a quinoline alkaloid isolated from the wood and bark of the Chinese tree Camptotheca acuminata, is a well-known topoisomerase I (TOP1) inhibitor[1] that was first isolated and identified as an anti-cancer agent in 19662. TOP1 functions to relax supercoils by creating a nick in the DNA strand and forming a covalent bond between its tyrosyl residue and a 3′DNA phosphate. An intermediate structure known as TOP1 cleavage complex (TOP1cc) is formed through cleavage, followed by religation of the DNA strand. Tyrosyl DNA phosphodiesterase I (TDP1) catalyzes the hydrolysis of the tyrosyl-3′phosphate linkage formed between TOP1 and DNA, allowing the rejoining of the DNA strand break and help cells to overcome CPT-induced cytotoxicity. Cell lines derived from patients with SCAN-1 accumulate TOP1-mediated protein-linked DNA breaks (PDBs) and were found to be hypersensitive to CPT5. Natural compounds in combination with CPT in the presence or absence of TDP1, with the goal of unraveling novel approaches to target TOP1. Our screen yielded a hit compound that appears to be a promising lead as a tyrosyl DNA phosphodiesterase II (TDP2) inhibitor. It is known that both enzymes while structurally different, can serve as back up for each other in circumstances where one is lacking, but with much less efficiency than with their preferred substrate[12]
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