Synergistic drug combinations can extend the use of poly(ADP-ribose)
polymerase inhibitors (PARPi) such as Olaparib to BRCA-proficient
tumors and overcome acquired or de novo drug resistance. To identify
new synergistic combinations for PARPi, we screened a “micro-library”
comprising a mix of commercially available drugs and DNA-binding ruthenium(II)
polypyridyl complexes (RPCs) for Olaparib synergy in BRCA-proficient
triple-negative breast cancer cells. This identified three hits: the
natural product Curcumin and two ruthenium(II)-rhenium(I) polypyridyl
metallomacrocycles. All combinations identified were effective in
BRCA-proficient breast cancer cells, including an Olaparib-resistant
cell line, and spheroid models. Mechanistic studies indicated that
synergy was achieved via DNA-damage enhancement and resultant apoptosis.
Combinations showed low cytotoxicity toward non-malignant breast epithelial
cells and low acute and developmental toxicity in zebrafish embryos.
This work identifies RPC metallomacrocycles as a novel class of agents
for cancer combination therapy and provides a proof of concept for
the inclusion of metallocompounds within drug synergy screens.