Overcoming trastuzumab resistance in HER2-overexpressing breast cancer cells by using a novel celecoxib-derived phosphoinositide-dependent kinase-1 inhibitor
Journal
Molecular Pharmacology
Journal Volume
70
Journal Issue
5
Pages
1534-1541
Date Issued
2006
Author(s)
Abstract
Although trastuzumab has been successfully used in patients with HER2-overexpressing metastatic breast cancer, resistance is a common problem that ultimately culminates in treatment failure. In light of the importance of Akt signaling in trastuzumab's antitumor action, we hypothesized that concurrent inhibition of Akt could enhance trastuzumab sensitivity and moreover reverse the resistant phenotype in HER2-positive breast cancer cells. Based on our finding that celecoxib mediates antitumor effects through the inhibition of phosphoinositide-dependent kinase-1 (PDK-1)/Akt signaling independently of cyclooxygenase-2 (COX-2), we used celecoxib as a scaffold to develop a COX-2-inactive PDK-1 inhibitor, 2-amino-N-[4-[5-(2-phenanthrenyl)-3- (trifluoromethyl)-1Hpyrazol-1-yl]phenyl]-acetamide (OSU-03012). Here, we investigated the effect of OSU-03012 on trastuzumab-mediated apoptosis in four breast cancer cell lines with different HER2 expression and trastuzumab- resistance status, including MDA-MB-231, BT474, SKBR3, and insulin-like growth factor-I receptor-overexpressing SKBR3 (SKBR3/IGF-IR). Effects of trastuzumab and OSU-03012, individually or in combination, on cell viability and changes in pertinent biomarkers including HER2 expression, phosphorylation of Akt, p27 kip1, and the PDK-1 substrate p70S6K were assessed. OSU-03012 alone was able to trigger apoptosis in all cell lines with equal potency (IC50 = 3-4 μM), suggesting no cross-resistance with trastuzumab. Medium dose-effect analysis indicates that OSU-03012 potentiated trastuzumab's antiproliferative effect in HER2-positive cells, especially in SKBR3/IGF-IR cells, through the down-regulation of PDK-1/Akt signaling. This synergy, however, was not observed in HER2-negative MDA-MB-231 cells. This combination treatment represents a novel strategy to increase the efficacy of trastuzumab and to overcome trastuzumab resistance in the treatment of HER2-positive breast cancer. Copyright ? 2006 The American Society for Pharmacology and Experimental Therapeutics.
SDGs
Other Subjects
2 amino n [4 [5 (2 phenanthrenyl) 3 trifluoromethyl 1h pyrazol 1 yl]phenyl]acetamide; biological marker; celecoxib; cyclooxygenase 2; epidermal growth factor receptor 2; osu 03012; phosphotransferase inhibitor; protein kinase B; protein p27; protein p70; trastuzumab; unclassified drug; antineoplastic activity; apoptosis; article; breast cancer; cancer cell culture; cell viability; controlled study; cross resistance; drug effect; drug potency; drug potentiation; enzyme inhibition; human; human cell; IC 50; phenotype; priority journal; protein expression; Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p27; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Gene Expression; Humans; Phenotype; Phosphorylation; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Pyrazoles; Receptor, erbB-2; Receptor, IGF Type 1; Sulfonamides; Up-Regulation
Type
journal article