Pharmacological Exploitation of the α1-Adrenoreceptor Antagonist Doxazosin to Develop a Novel Class of Antitumor Agents That Block Intracellular Protein Kinase B/Akt Activation
The alpha1-adrenoreceptor antagonist doxazosin induces apoptosis in malignant cells with moderate potency via an alpha1-adrenoreceptor-independent mechanism. Here, we demonstrate that the ability of doxazosin to induce apoptosis in PC-3 prostate cancer cells was, in part, attributable to the inhibition of protein kinase B (PKB)/Akt activation. The separation of the effect of doxazosin on apoptosis from its original pharmacological activity provides molecular underpinnings to develop novel antitumor agents. Replacement of the (2,3-dihydro-benzo[1,4]dioxane)-carbonyl moiety of doxazosin with aryl-sulfonyl functions dramatically improves the potency in facilitating Akt deactivation and inducing apoptosis. The optimal compounds, 33 and 44, were effective in apoptosis induction at low micromolar concentrations irrespective of androgen dependency and p53 functional status. Both agents were active in suppressing the growth of a panel of 60 cancer-cell lines with IC50 values of 2.2 and 1.5 microM, respectively. Together, these in vitro efficacy data suggest the translational potential of these agents in prostate cancer treatment.