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Discovery of Ruthenium(II) Metallocompound and Olaparib Synergy for Cancer Combination Therapy

Nur Aininie Yusoh1, Paul R Tiley2, Steffan D James2

  • 1UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, UPM, 43400 Serdang, Selangor, Malaysia.

Journal of Medicinal Chemistry
|May 15, 2023
PubMed

Insights

This study explored new drug combinations with Olaparib to treat BRCA-proficient cancers and resistance. Ruthenium(II) polypyridyl complexes (RPCs) showed promise, enhancing DNA damage and apoptosis with low toxicity.

Area of Science:

  • Medicinal Chemistry
  • Cancer Biology
  • Drug Discovery

Background:

  • Poly(ADP-ribose) polymerase inhibitors (PARPi) like Olaparib are crucial for treating certain cancers.
  • Expanding PARPi efficacy to BRCA-proficient tumors and overcoming drug resistance remain significant challenges.

Purpose of the Study:

  • To identify novel synergistic drug combinations with Olaparib for BRCA-proficient triple-negative breast cancer.
  • To evaluate the potential of ruthenium(II) polypyridyl complexes (RPCs) in combination cancer therapy.

Main Methods:

  • Screening of a micro-library containing commercial drugs and RPCs for Olaparib synergy.
  • Testing synergistic combinations in BRCA-proficient and resistant breast cancer cell lines and spheroid models.
  • Investigating mechanisms of synergy, including DNA damage and apoptosis induction.
  • Assessing cytotoxicity in non-malignant cells and toxicity in zebrafish embryos.

Main Results:

  • Curcumin and two novel ruthenium(II)-rhenium(I) polypyridyl metallomacrocycles demonstrated synergy with Olaparib.
  • Effective combinations were observed in BRCA-proficient, Olaparib-resistant cells, and spheroid models.
  • Synergy was attributed to enhanced DNA damage and apoptosis, with minimal toxicity to normal cells and embryos.

Conclusions:

  • Ruthenium(II) polypyridyl metallomacrocycles represent a new class of agents for cancer combination therapy.
  • This study validates the inclusion of metallo-compounds in drug synergy screening for novel cancer treatments.

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