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Dosing time dependent in vitro pharmacodynamics of Everolimus despite a defective circadian clock
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Zhang, Yuan, Giacchetti, Sylvie, Parouchev, Alexandre, Hadadi, Eva, Li, Xiaomei, Dallmann, Robert, Xandri-Monje, Helena, Portier, Lucie, Adam, René, Lévi, Francis A., Dulong, Sandrine and Chang, Yunhua (2018) Dosing time dependent in vitro pharmacodynamics of Everolimus despite a defective circadian clock. Cell Cycle, 17 (1). pp. 33-42. doi:10.1080/15384101.2017.1387695 ISSN 1538-4101.
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WRAP-dosing-time-dependent-vitro pharmacodynamics-defective-circadian-Dallman-2017.pdf - Accepted Version - Requires a PDF viewer. Download (3137Kb) | Preview |
Official URL: https://doi.org/10.1080/15384101.2017.1387695
Abstract
Everolimus (EV), a rapamycin analogue mTOR inhibitor, is used in the clinic to treat Estrogen positive (ER+) breast cancer in order to avoid the resistance to hormonotherapy. Here, we investigated whether EV efficacy varied according to administration timing by using the ER+ breast cancer cell line MCF-7 as model system. Our results showed that instead of apoptosis, EV induced a G0/G1 phase blockage of MCF-7 cells. Following serum shock, MCF-7 cells displayed a statistically significant 24h rhythm of mammalian target of Rapamycin (mTOR) activity, but perturbed circadian clock genes oscillations. Interestingly, the different delivery schedule of EV presented different efficacy in G0/G1 phase blockage in serum shocked MCF-7 cells. Moreover, serum shock induced also a circadian-like oscillation in expression or activity of several important G1 phase progression proteins, such as Cyclin D1 and phosphorylated Retinoblastoma protein (RB). Inhibition mTOR activity by EV reduced Cyclin D1 and Cyclin D3 protein level as well as RB phosphorylation level. Taken together, the results indicated that serum shock synchronization induced a circadian oscillation in mTOR activity in MCF-7 cells, which rhythmically regulated the synthesis or phosphorylation of key G1 progression proteins, such as Cyclin D1 and phosphorylated RB, ultimately resulting in different G0/G1 blockage efficiency according to different EV administration timing.
Item Type: | Journal Article | |||||||||||||||
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Subjects: | R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) | |||||||||||||||
Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School | |||||||||||||||
Library of Congress Subject Headings (LCSH): | Breast cancer, Cancer -- Treatment., Circadian rhythms. | |||||||||||||||
Journal or Publication Title: | Cell Cycle | |||||||||||||||
Publisher: | Landes Bioscience | |||||||||||||||
ISSN: | 1538-4101 | |||||||||||||||
Official Date: | 2 January 2018 | |||||||||||||||
Dates: |
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Volume: | 17 | |||||||||||||||
Number: | 1 | |||||||||||||||
Page Range: | pp. 33-42 | |||||||||||||||
DOI: | 10.1080/15384101.2017.1387695 | |||||||||||||||
Status: | Peer Reviewed | |||||||||||||||
Publication Status: | Published | |||||||||||||||
Access rights to Published version: | Open Access (Creative Commons) | |||||||||||||||
Date of first compliant deposit: | 2 October 2017 | |||||||||||||||
Date of first compliant Open Access: | 3 November 2018 | |||||||||||||||
RIOXX Funder/Project Grant: |
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