title: Gamma secretase inhibitor enhances sensitivity to doxorubicin in MDA-MB-231 cells.
abstract: Deregulated expression of molecular of the Notch signaling pathway is observed in malignant tumor. Notch signaling pathway is activated by a series of catalytic cleavage of the Notch receptor by gamma secretase. Gamma secretase inhibitor (GSI) have demonstrated clinical activity in patients with solid tumor. Triple negative breast cancer (TNBC) is related to poor prognosis and a high probability of lung and brain metastases. As first line therapy for TNBC, doxorubicin is partially effective in TNBC control. An understanding of the mechanisms for enhancing sensitivity to doxorubicin would be significant for future drug development. We hypothesized that a combination of cytotoxic chemotherapy doxorubicin to inhibit cell proliferation, together with GSI, would result in more effective outcome than either monotherapy alone. We treated MDA-MB-231 cell lines with doxorubicin and evaluated the monotherapy efficacy and in combination with GSI in both vitro and vivo. GSI-induced proliferation inhibition and apoptosis was achieved with an induction of PTEN and pro-apoptotic protein Bax expression and suppression of Notch-1, HES-1, CyclinD1 and anti-apoptotic protein Bcl-2. These results indicate that MDA-MB-231 cells are susceptible to a GSI, whether alone or in combination with doxorubicin, are correlated with changing of some surrogate marker. This study demonstrates practicability of combined use of GSI and doxorubicin, and together these results encourage new therapeutic method in triple negative breast cancer.
authors.affiliation: Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University Chongqing, China.
authors.forename: Zhi-Lu
authors.initials: ZL
authors.lastname: Li
authors.affiliation: Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University Chongqing, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Cardiovascular Medicine, The First Affiliated Hospital of Chongqing Medical University Chongqing, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University Chongqing, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University Chongqing, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University Chongqing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University Chongqing, China.
authors.forename: Sheng-Chun
authors.initials: SC
authors.lastname: Liu
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D051881:Receptor, Notch1 / Q000096:biosynthesis; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D004317:Doxorubicin; D053829:Amyloid Precursor Protein Secretases
keywords: Notch-1; doxorubicin; triple negative breast cancer