Songs From the Wood: α- and β-Lapachones as Dual-Function Agents Acting as Aromatase Inhibitors and Estrogen Receptor Antagonists

This research explores the aromatase-inhibitory and estrogen-agonistic/antagonistic properties of two natural naphthoquinones, α- and β-lapachone, which are known for their anticancer effects. Initial tests showed that both lapachones inhibit aromatase in the sub-micromolar range, with IC₅₀(β) = 0.78 ± 0.06 μM and IC₅₀(α) = 10.6 ± 2.4μM, similar to the steroidal aromatase inhibitor Exemestane (IC₅₀: 0.02-0.2 μM). A molecular docking study comparing these compounds with androstenedione, one of the native aromatase substrates, identified their binding sites and specific interactions with the enzyme. The Yeast Estrogen Screening assay indicated that both compounds lacked hERα-agonistic activity but exhibited antagonistic effects, similar to 4-Hydroxytamoxifen (Afimoxifene; IC₅₀ = 0.81 ± 0.65 μM). The IC₅₀ values were 0.33 ± 0.24 μM for β-lapachone and 48.3 ± 18.9 μM for α-lapachone. Overall, the study propose unexplored mechanism of action and highlights the dual role of α- and β-lapachones: inhibiting estrogen synthesis and serving as potent, selective estrogen receptor modulators, emphasizing their potential in cancer treatment, especially for hormone-dependent cancers.