Small structural changes on a hydroquinone scaffold determine the complex I inhibition or uncoupling of tumoral...

Area of Science:

• Biochemistry
• Cancer Biology
• Mitochondrial Metabolism

Background:

• Mitochondria are crucial in cancer cell function and represent a promising target for anti-cancer drug development.
• Ortho-carbonyl hydroquinone scaffold 14 was previously shown to inhibit complex I respiration and selectively inhibit proliferation in TA3/Ha cancer cells.
• The detailed structural requirements for hydroquinone scaffolds affecting cancer cell oxidative phosphorylation (OXPHO) remain underexplored.

Purpose of the Study:

• To characterize the mitochondrial metabolism of TA3/Ha cancer cells.
• To evaluate the impact of structural modifications on the ortho-carbonyl hydroquinone scaffold 14 concerning OXPHO in TA3/Ha cells.
• To explore the potential for designing targeted anti-cancer compounds by modulating OXPHO.

Main Methods:

• Characterization of TA3/Ha cancer cell mitochondrial metabolism.
• Synthesis and evaluation of structurally modified ortho-carbonyl hydroquinone compounds.
• Assessment of effects on isolated mitochondria respiration (states 3ADP and 4o), respiratory control ratios, and protonophoric activity.
• Analysis of effects in intact TA3/Ha cells, including mitochondrial membrane potential, ATP, NAD(P)H levels, GSH/GSSG ratio, ROS production, and anti-proliferative activity.

Main Results:

• Structural modifications of the hydroquinone scaffold yielded compounds with distinct effects on OXPHO: complex I inhibitors, OXPHO uncouplers, or dual-action agents.
• Bicyclic hydroquinone 9 acted as a protonophoric uncoupler in isolated mitochondria, increasing state 4o respiration and decreasing respiratory control ratios.
• In intact TA3/Ha cells, hydroquinone 9 induced mitochondrial depolarization, reduced ATP and NAD(P)H, altered redox balance (GSH/GSSG), slightly increased ROS, and showed selective anti-proliferative effects dependent on NAD(P)H availability.

Conclusions:

• The ortho-carbonyl hydroquinone scaffold can be chemically modified to yield compounds with specific modulatory effects on cancer cell OXPHO.
• These findings provide a basis for designing novel anti-cancer agents targeting mitochondrial respiration and energy metabolism.
• The selective anti-proliferative activity observed highlights the therapeutic potential of targeting mitochondrial pathways in cancer treatment.