Mechanistic Investigation of Adociaquinone and Xestoquinone Derivatives in Breast Cancer Cells
Yu-Dong Zhou1, Fakhri Mahdi2, Nicholas M Nagle3
1National Center for Natural Products Research, School of Pharmacy, University of Mississippi, Oxford, MS 38677-1848, USA.
Abstract:
Xestoquinone derivatives isolated from marine sponges exhibit a range of bioactivities, including the inhibition of HIF signaling, mitochondrial function, and tumor cell proliferation. Mechanistic investigation suggested that 14-hydroxymethylxestoquinone (1) acts as a protonophore. Although adociaquinones A (5) and B (6) each stimulated cellular oxygen consumption, neither affected mitochondrial membrane potential. Cell-based respiration studies revealed that adociaquinones restored sodium azide-stalled oxygen consumption and ascorbate enhanced this response, suggesting ascorbate-supported redox cycling as a possible mechanism by which adociaquinones suppress HIF and tumor cell proliferation. These xestoquinone derivatives activated cellular stress response pathways that inhibit protein translation by phosphorylating key regulatory proteins (i.e., eIF2α, eIF4E, and eEF2). Further, thiol-reducing agents NAC and DTT attenuated the monosubstituted xestoquinone derivatives' efficacy to inhibit HIF signaling, suggesting a potential mechanism of action that involves sulfhydryl modification.
Insights
Marine sponge compounds called xestoquinones inhibit tumor growth by disrupting cellular respiration and protein synthesis. Some derivatives act as protonophores, while others utilize redox cycling, offering potential anti-cancer therapeutic strategies.
Area of Science:
- Marine Natural Products Chemistry
- Cancer Biology
- Mitochondrial Physiology
Background:
- Xestoquinone derivatives from marine sponges show diverse bioactivities.
- These compounds target critical cellular processes like HIF signaling and mitochondrial function.
- Understanding their mechanisms is key for therapeutic development.
Purpose of the Study:
- To investigate the bioactivities and mechanisms of action of xestoquinone derivatives.
- To elucidate how these compounds inhibit HIF signaling and tumor cell proliferation.
- To explore their effects on mitochondrial respiration and protein translation.
Main Methods:
- Isolation and characterization of xestoquinone derivatives from marine sponges.
- Measurement of cellular oxygen consumption and mitochondrial membrane potential.
- Analysis of protein translation inhibition and activation of stress response pathways.
Main Results:
- 14-hydroxymethylxestoquinone acts as a protonophore.
- Adociaquinones stimulate oxygen consumption via ascorbate-supported redox cycling, suppressing HIF and tumor cell proliferation.
- Xestoquinones activate stress pathways, inhibiting protein translation by phosphorylating eIF2α, eIF4E, and eEF2.
- Sulfhydryl modification is implicated in the mechanism of action.
Conclusions:
- Xestoquinone derivatives possess potent anti-cancer properties by interfering with mitochondrial function and protein synthesis.
- Mechanisms involve protonophore activity, redox cycling, and modulation of stress response pathways.
- Potential therapeutic applications against cancer warrant further investigation.
Related Concept Videos
02:53Adaptive Mechanisms in Cancer Cells
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
02:53Adaptive Mechanisms in Cancer Cells
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
01:11Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase