title: Sensitizing estrogen receptor-negative breast cancer cells to tamoxifen with OSU-03012, a novel celecoxib-derived phosphoinositide-dependent protein kinase-1/Akt signaling inhibitor.
abstract: Tamoxifen is a mainstay in the treatment of estrogen receptor (ER)-positive breast cancer patients. Although the efficacy of tamoxifen has been attributed to induction of tumor cell growth arrest and apoptosis by inhibition of ER signaling, recent evidence indicates that tamoxifen possesses ER-independent antitumor activities. Here, we use OSU-03012, a small-molecule inhibitor of phosphoinositide-dependent protein kinase-1 (PDK-1) to address the hypothesis that PDK-1/Akt signaling represents a therapeutically relevant target to sensitize ER-negative breast cancer to tamoxifen. OSU-03012 sensitized both ER-positive MCF-7 and ER-negative MDA-MB-231 cells to the antiproliferative effects of tamoxifen in an ER-independent manner. Flow cytometric analysis of phosphatidylserine externalization revealed that this augmented suppression of cell viability was attributable to a marked enhancement of tamoxifen-induced apoptosis by OSU-03012. Mechanistically, this OSU-03012-mediated sensitization was associated with suppression of a transient tamoxifen-induced elevation of Akt phosphorylation and enhanced modulation of the functional status of multiple Akt downstream effectors, including FOXO3a, GSK3alpha/beta, and p27. The growth of established MDA-MB-231 tumor xenografts was suppressed by 50% after oral treatment with the combination of tamoxifen (60 mg/kg) and OSU-03012 (100 mg/kg), whereas OSU-03012 and tamoxifen alone suppressed growth by 30% and 0%, respectively. These findings indicate that the inhibition of PDK-1/Akt signaling to sensitize ER-negative breast cancer cells to the ER-independent antitumor activities of tamoxifen represents a feasible approach to extending the use of tamoxifen to a broader population of breast cancer patients. Considering the urgent need for novel therapeutic strategies for ER-negative breast cancer patients, this combinatorial approach is worthy of continued investigation.
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 336 L.M. Parks Hall, 500 West 12th Avenue, Columbus, OH 43210, USA.
authors.forename: Shu-Chuan
authors.initials: SC
authors.lastname: Weng
authors.forename: Yoko
authors.initials: Y
authors.lastname: Kashida
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Kulp
authors.forename: Dasheng
authors.initials: D
authors.lastname: Wang
authors.forename: Robert W
authors.initials: RW
authors.lastname: Brueggemeier
authors.forename: Charles L
authors.initials: CL
authors.lastname: Shapiro
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008819:Mice, Nude; D010052:Ovariectomy; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000627:therapeutic use*; D015398:Signal Transduction; D013449:Sulfonamides / Q000627:therapeutic use*; D013629:Tamoxifen / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
chemical_list: D018931:Antineoplastic Agents, Hormonal; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C500894:OSU 03012; D011720:Pyrazoles; D013449:Sulfonamides; D013629:Tamoxifen; D064413:3-Phosphoinositide-Dependent Protein Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt