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Combination therapy of RY10-4 with the ?-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 ?-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.

SUBMITTER: Su F

PROVIDER: S-EPMC4826195 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Combination therapy of RY10-4 with the γ-secretase inhibitor DAPT shows promise in treating HER2-amplified breast cancer.

Su Feng F Zhu Shilin S Ruan Jinlan J Muftuoglu Yagmur Y Zhang Longbo L Yuan Qianying Q

Oncotarget 20160101 4

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 incr ...[more]

PMID: 26716652

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Project description:Confocal Raman microspectral imaging was adopted to elucidate the cellular drug responses of osteosarcoma cells (OC) to N-[N-(3, 5-difluorophenyl acetyl)-L-alanyl]-sphenylglycine butyl ester (DAPT), a ?-secretase inhibitor, by identifying the drug induced subcellular compositional and structural changes. Methods: Spectral information were acquired from cultured osteosarcoma cells treated with 0 (Untreated Group, UT), 10 (10 ?M DAPT treated, 10T), 20 ?M (20 ?M DAPT treated, 20T) DAPT for 24 hours. A one-way ANOVA and Tukey's honest significant difference (HSD) post hoc multiple test were sequentially applied to address spectral features among three groups. Multivariate algorithms such as K-means clustering analysis (KCA) and Principal component analysis (PCA) were used to highlight the structural and compositional differences, while, univariate imaging was applied to illustrate the distribution pattern of certain cellular components after drug treatment. Results: Major biochemical changes in DAPT-induced apoptosis came from changes in the content and structure of proteins, lipids, and nucleic acids. By adopted multivariate algorithms, the drug induced cellular changes was identified by the morphology and spectral characteristics between untreated cells and treated cells, testified that DAPT mainly acted in the nuclear region. With the increase of the drug concentration, the content of main subcellular compositions, such nucleic acid, protein, and lipid decreased. In an addition, DAPT-induced nuclear fragmentation and apoptosis was depicted by the univariate Raman image of major cellular components (nucleic acids, proteins and lipids). Conclusions: The achieved Raman spectral and imaging results illustrated detailed DAPT-induced subcellular compositional and structural variations as a function of drug dose. Such observations can not only explain drug therapeutic mechanisms of OC DAPT treatment, and also provide new insights for accessing the medicine curative efficacy and predicting prognosis.

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Combination therapy of RY10-4 with the ?-secretase inhibitor DAPT shows promise in treating HER2-amplified breast cancer.

Publications

Combination therapy of RY10-4 with the γ-secretase inhibitor DAPT shows promise in treating HER2-amplified breast cancer.

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