The alpha1-adrenergic receptor antagonist doxazosin inhibits EGFR and NF-kappaB signalling to induce breast cancer cell apoptosis.
The selective alpha(1)-adrenergic receptor antagonist doxazosin (dox) has been reported to inhibit prostate cancer proliferation. We now demonstrate that dox-treatment inhibits proliferation and induces apoptosis in breast cancer cells in vitro by mechanisms that do not wholly involve the alpha1-adrenergic receptor. Intriguingly, dox-treatment reduced phosphorylated EGFR expression, decreased pERK1/2 levels and decreased NF-kappaB, AP-1, SRE, E2F and CRE-mediated transcriptional activity. EGF- and TNFalpha treatment alone failed to block dox-mediated breast cancer apoptotic effects, but combination of EGF and TNFalpha treatments completely abrogated dox-induced breast cancer cell apoptosis, indicating doxazosin inhibits both EGFR and NF-kappaB signalling pathways to induce breast cancer cell apoptosis. Doxazosin is proposed as a possible novel medical therapy for breast cancer.
Division of Endocrinology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90024, USA.
Hongxiang
H
Hui
Manory A
MA
Fernando
Anthony P
AP
Heaney
D018674:Adrenergic Antagonists / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002450:Cell Communication / Q000187:drug effects; D017292:Doxazosin / Q000627:therapeutic use*; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D018674:Adrenergic Antagonists; D000970:Antineoplastic Agents; D016328:NF-kappa B; D066246:ErbB Receptors; D017292:Doxazosin