UPM Institutional Repository

Metallointercalator [Ru(dppz)2(PIP)]2+ renders BRCA wild-type triple-negative breast cancer cells hypersensitive to PARP inhibition


Yusoh, Nur Aininie and Leong, Sze Wei and Chia, Suet Lin and Harun, Siti Norain and Abdul Rahman, Mohd Basyaruddin and Vallis, Katherine A. and Gill, Martin R. and Ahmad, Haslina (2020) Metallointercalator [Ru(dppz)2(PIP)]2+ renders BRCA wild-type triple-negative breast cancer cells hypersensitive to PARP inhibition. ACS Chemical Biology, 15 (2). 378 - 387. ISSN 1554-8929; ESSN:1554-8937


There is a need to improve and extend the use of clinically approved poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi), including for BRCA wild-type triple-negative breast cancer (TNBC). The demonstration that ruthenium(II) polypyridyl complex (RPC) metallointercalators can rapidly stall DNA replication fork progression provides the rationale for their combination alongside DNA damage response (DDR) inhibitors to achieve synergism in cancer cells. The aim of the present study was to evaluate use of the multi-intercalator [Ru(dppz)2(PIP)]2+ (dppz = dipyrido[3,2-a:2',3'-c]phenazine, PIP = (2-(phenyl)imidazo[4,5-f][1,10]phenanthroline, Ru-PIP) alongside the PARPi olaparib and NU1025. Cell proliferation and clonogenic survival assays indicated a synergistic relationship between Ru-PIP and olaparib in MDA-MB-231 TNBC and MCF7 human breast cancer cells. Strikingly, low dose Ru-PIP renders both cell lines hypersensitive to olaparib, with a >300-fold increase in olaparib potency in TNBC, the largest nongenetic PARPi enhancement effect described to date. A negligible impact on the viability of normal human fibroblasts was observed for any combination tested. Increased levels of DNA double-strand break (DSB) damage and olaparib abrogation of Ru-PIP-activated pChk1 signaling are consistent with PARPi-facilitated collapse of Ru-PIP-associated stalled replication forks. This results in enhanced G2/M cell-cycle arrest, apoptosis, and decreased cell motility for the combination treatment compared to single-agent conditions. This work establishes that an RPC metallointercalator can be combined with PARPi for potent synergy in BRCA-proficient breast cancer cells, including TNBC.

Download File

[img] Text

Download (9kB)

Additional Metadata

Item Type: Article
Divisions: Faculty of Biotechnology and Biomolecular Sciences
Faculty of Science
DOI Number: https://doi.org/10.1021/acschembio.9b00843
Publisher: American Chemical Society
Keywords: Toxicological synergy; Assays; Cells; Cancer; DNA replication
Depositing User: Mohamad Jefri Mohamed Fauzi
Date Deposited: 16 Nov 2021 02:23
Last Modified: 16 Nov 2021 02:23
Altmetrics: http://www.altmetric.com/details.php?domain=psasir.upm.edu.my&doi=10.1021/acschembio.9b00843
URI: http://psasir.upm.edu.my/id/eprint/86732
Statistic Details: View Download Statistic

Actions (login required)

View Item View Item