title: Combination therapy of RY10-4 with the γ-secretase inhibitor DAPT shows promise in treating HER2-amplified breast cancer.
abstract: RY10-4, a novel protoapigenone analog, shows potent cytotoxicity against human breast cancer cells. However, breast cancer cell lines overexpressing human epidermal growth factor receptor 2 (HER2), SKBR3 and BT474, showed less sensitivity to RY10-4 when compared to breast cancer cells lines expressing lower levels of HER2, such as MDA-MB-231 and MCF-7 cells. This was associated with aberrant hyperactivity in Notch signaling in cells treated with RY10-4, since treatment with RY10-4 causes an increase in Notch activity by 2-to3.5-fold in SKBR3 and BT474 cell lines. The increase in activity was abrogated with a γ-secretase inhibitor, DAPT, or with Notch1 small-interfering RNA (si-Notch1). Cell proliferation was inhibited more effectively by RY10-4 plus DAPT or si-Notch1 than either agent alone. RY10-4 plus DAPT increases apoptosis in both HER2-overexpressing cell lines by two-fold compared to RY10-4 alone, while DAPT alone has no significant effects on apoptosis. In addition, we previously found RY10-4 could inhibit tumor growth through the PI3K/AKT pathway. Here we report that the combination of RY10-4 and DAPT exhibit additive suppression on AKT phosphorylation, contributing to the anti-cancer effects. In an animal model, this combination therapy inhibits the growth of SKBR3 tumor xenografts in nude mice to a greater extent than treatment with either reagent alone. These results indicate that the aberrant activation of Notch signaling impedes the inhibitory effect of RY10-4 on HER2-amplified cell proliferation. Furthermore, these adverse effects can be prevented by treatment combining RY10-4 with a Notch pathway inhibitor.
authors.affiliation: Department of Emergency, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Su
authors.affiliation: The Second Affiliated Hospital, Hunan University of Chinese Medicine, Changsha, China.
authors.forename: Shilin
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jinlan
authors.initials: J
authors.lastname: Ruan
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Yagmur
authors.initials: Y
authors.lastname: Muftuoglu
authors.affiliation: Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Longbo
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Huazhong University of Science and Technology, Wuhan, China.|Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Qianying
authors.initials: Q
authors.lastname: Yuan
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011753:Pyrones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D053829:Amyloid Precursor Protein Secretases; D004151:Dipeptides; D011753:Pyrones; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; C574037:2-(1-hydroxy-4-oxocyclohexa-2,5-dienyl)pyran-4-one; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; C508053:ERBB2 protein, human
keywords: Notch; RY10-4; breast cancer; resistance