Mechanistic Investigation of Adociaquinone and Xestoquinone Derivatives in Breast Cancer Cells

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 (<b>1</b>) acts as a protonophore. Although adociaquinones A (<b>5</b>) and B (<b>6</b>) 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.