Pharmacological exploitation of the alpha1-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.
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, USA.
Yeng-Jeng
YJ
Shaw
Ya-Ting
YT
Yang
Jason B
JB
Garrison
Natasha
N
Kyprianou
Ching-Shih
CS
Chen
D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D017292:Doxazosin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D013329:Structure-Activity Relationship
C525921:2-(4-(biphenyl-4-sulfonyl)-piperazin-1-yl)-6,7-dipropoxyquinazolin-4-yl-amine; D000317:Adrenergic alpha-Antagonists; D000970:Antineoplastic Agents; D011518:Proto-Oncogene Proteins; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017292:Doxazosin