Targeting cancer stem cell OXPHOS with tailored ruthenium complexes as a new anti-cancer strategy

Area of Science:

• Oncology
• Biochemistry
• Pharmacology

Background:

• Pancreatic cancer stem cells (CSCs) rely on oxidative phosphorylation (OXPHOS) for energy.
• Targeting OXPHOS presents a potential therapeutic strategy for highly tumorigenic CSCs.
• Current therapies targeting OXPHOS in CSCs are limited.

Purpose of the Study:

• To evaluate the safety and anti-CSC activity of a novel ruthenium complex, Ru1.
• To determine the mechanism of action of Ru1 in inhibiting CSCs.
• To explore Ru1 as a potential anti-cancer agent targeting CSC OXPHOS.

Main Methods:

• In vitro evaluation of Ru1 in primary pancreatic cancer cultures.
• In vivo assessment of Ru1 using 8 patient-derived xenografts (PDXs).
• RNAseq analysis and mitochondria-specific molecular assays to elucidate the mechanism of action.

Main Results:

• Ru1 inhibits CSC OXPHOS function in vitro.
• Ru1 demonstrates significant anti-cancer activity with low toxicity across pancreatic, colorectal, and osteosarcoma PDXs.
• Mechanistic studies reveal Ru1 binds to mitochondrial DNA, inhibiting OXPHOS transcription and reducing cellular respiration and ATP production.

Conclusions:

• The ruthenium complex Ru1 is a potent anti-cancer agent and a valuable tool for studying CSC OXPHOS.
• Ru1 is safe, non-toxic, and highly effective in vivo.
• Targeting CSC OXPHOS with Ru1 offers new therapeutic avenues for various cancer types.