Mitochondria-targeting iridium(III) complex enhances anticancer activity via PDK inhibition and energy metabolism...

Area of Science:

• Biochemistry
• Oncology
• Medicinal Chemistry

Background:

• Cancer cells exhibit altered energy metabolism, often shifting from oxidative phosphorylation (OXPHOS) to glycolysis.
• This metabolic adaptation can reduce the effectiveness of cancer treatments.
• Targeting cancer cell metabolism presents a promising therapeutic avenue.

Purpose of the Study:

• To develop a novel compound, Ir-DCA, that concurrently inhibits both mitochondrial glycolysis and OXPHOS.
• To evaluate the efficacy and mechanism of action of Ir-DCA in human cervical cancer cells.

Main Methods:

• Conjugation of dichloroacetate (DCA), a pyruvate dehydrogenase kinases (PDK) inhibitor, to an iridium(III) scaffold to create Ir-DCA.
• Assessment of Ir-DCA's accumulation in mitochondria, cytotoxicity, PDK inhibitory activity, and effects on mitochondrial membrane potential and reactive oxygen species (ROS) production.
• Analysis of cellular adenosine triphosphate (ATP) and lactate production, and induction of apoptosis.

Main Results:

• Ir-DCA effectively accumulates in mitochondria and exhibits high cytotoxicity against human cervical cancer cells.
• Ir-DCA potently inhibits PDK activity, depolarizes mitochondrial membrane potential, and increases intracellular ROS.
• The compound suppresses both glycolysis and glucose oxidation, blocks ATP and lactate production, and triggers caspase-dependent apoptosis.

Conclusions:

• Ir-DCA demonstrates efficacy in simultaneously inhibiting dual energy metabolic pathways in cancer cells.
• DCA-functionalized metal complexes represent a viable strategy for dual energy pathway inhibition.
• This approach holds significant translational potential for advancing cancer therapy through metabolism reprogramming.