Palbociclib and fulvestrant act in synergy to modulate central carbon metabolism in breast cancer cells

Benedikt Warth; Amelia Palermo; Nicholas J.W. Rattray; Nathan V. Lee; Zhou Zhu; Linh T. Hoang; Yuping Cai; Anthony Mazurek; Stephen Dann; Todd VanArsdale; Valeria R. Fantin; David Shields; Gary Siuzdak; Caroline H. Johnson

doi:10.3390/metabo9010007

Palbociclib and fulvestrant act in synergy to modulate central carbon metabolism in breast cancer cells

Benedikt Warth, Amelia Palermo, Nicholas J.W. Rattray, Nathan V. Lee, Zhou Zhu, Linh T. Hoang, Yuping Cai, Anthony Mazurek, Stephen Dann, Todd VanArsdale, Valeria R. Fantin, David Shields, Gary Siuzdak, Caroline H. Johnson^*

^*Corresponding author for this work

Strathclyde Institute Of Pharmacy And Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

9 Citations (Scopus)

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Abstract

The aims of this study were to determine whether combination chemotherapeutics exhibit a synergistic effect on breast cancer cell metabolism. Palbociclib, is a selective inhibitor of cyclin-dependent kinases 4 and 6, and when patients are treated in combination with fulvestrant, an estrogen receptor antagonist, they have improved progression-free survival. The mechanisms for this survival advantage are not known. Therefore, we analyzed metabolic and transcriptomic changes in MCF-7 cells following single and combination chemotherapy to determine whether selective metabolic pathways are targeted during these different modes of treatment. Individually, the drugs caused metabolic disruption to the same metabolic pathways, however fulvestrant additionally attenuated the pentose phosphate pathway and the production of important coenzymes. A comprehensive effect was observed when the drugs were applied together, confirming the combinatory therapy’s synergism in the cell model. This study also highlights the power of merging high-dimensional datasets to unravel mechanisms involved in cancer metabolism and therapy.

Original language	English
Article number	7
Number of pages	15
Journal	Metabolites
Volume	9
Issue number	1
DOIs	https://doi.org/10.3390/metabo9010007
Publication status	Published - 2 Jan 2019

Funding

The Scripps Research Institute, Scripps Center for Metabolomics and Mass Spectrometry, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA; [email protected] (B.W.); [email protected] (A.P.), [email protected] (L.T.H.), [email protected] (G.S.) Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, Währingerstraße 38, 1090 Vienna, Austria Vienna Metabolomics Center (VIME), University of Vienna, 1090 Vienna, Austria Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT 06511, USA; [email protected] (N.J.W.R.), [email protected] (Y.C.) Oncology Research, Pfizer Worldwide Research and Development, San Diego, CA 92121, USA; [email protected] (N.V.L.); [email protected] (Z.Z.); [email protected] (A.M.); [email protected] (S.D.); [email protected] (T.V.); [email protected] (V.R.F.); [email protected] (D.S.) Correspondence: [email protected]; Tel.: +1-203-785-2882 Funding: The authors further thank the Austrian Science Fund (FWF; Erwin Schrödinger Fellowship J-3808 awarded to B.W.) for its financial support.

Keywords

breast cancer
combination drug therapy
metabolomics
multi-omics
RNA-seq
XCMS online

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10.3390/metabo9010007Licence: CC BY 4.0

Warth-etal-Metabolites-2019-Palbociclib-and-fulvestrant-act-in-synergy-to-modulate-central-carbonFinal published version, 2.58 MBLicence: CC BY 4.0

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title = "Palbociclib and fulvestrant act in synergy to modulate central carbon metabolism in breast cancer cells",

abstract = "The aims of this study were to determine whether combination chemotherapeutics exhibit a synergistic effect on breast cancer cell metabolism. Palbociclib, is a selective inhibitor of cyclin-dependent kinases 4 and 6, and when patients are treated in combination with fulvestrant, an estrogen receptor antagonist, they have improved progression-free survival. The mechanisms for this survival advantage are not known. Therefore, we analyzed metabolic and transcriptomic changes in MCF-7 cells following single and combination chemotherapy to determine whether selective metabolic pathways are targeted during these different modes of treatment. Individually, the drugs caused metabolic disruption to the same metabolic pathways, however fulvestrant additionally attenuated the pentose phosphate pathway and the production of important coenzymes. A comprehensive effect was observed when the drugs were applied together, confirming the combinatory therapy{\textquoteright}s synergism in the cell model. This study also highlights the power of merging high-dimensional datasets to unravel mechanisms involved in cancer metabolism and therapy.",

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AU - Rattray, Nicholas J.W.

AU - Lee, Nathan V.

AU - Zhu, Zhou

AU - Hoang, Linh T.

AU - Cai, Yuping

AU - Mazurek, Anthony

AU - Dann, Stephen

AU - VanArsdale, Todd

AU - Fantin, Valeria R.

AU - Shields, David

AU - Siuzdak, Gary

AU - Johnson, Caroline H.

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N2 - The aims of this study were to determine whether combination chemotherapeutics exhibit a synergistic effect on breast cancer cell metabolism. Palbociclib, is a selective inhibitor of cyclin-dependent kinases 4 and 6, and when patients are treated in combination with fulvestrant, an estrogen receptor antagonist, they have improved progression-free survival. The mechanisms for this survival advantage are not known. Therefore, we analyzed metabolic and transcriptomic changes in MCF-7 cells following single and combination chemotherapy to determine whether selective metabolic pathways are targeted during these different modes of treatment. Individually, the drugs caused metabolic disruption to the same metabolic pathways, however fulvestrant additionally attenuated the pentose phosphate pathway and the production of important coenzymes. A comprehensive effect was observed when the drugs were applied together, confirming the combinatory therapy’s synergism in the cell model. This study also highlights the power of merging high-dimensional datasets to unravel mechanisms involved in cancer metabolism and therapy.

AB - The aims of this study were to determine whether combination chemotherapeutics exhibit a synergistic effect on breast cancer cell metabolism. Palbociclib, is a selective inhibitor of cyclin-dependent kinases 4 and 6, and when patients are treated in combination with fulvestrant, an estrogen receptor antagonist, they have improved progression-free survival. The mechanisms for this survival advantage are not known. Therefore, we analyzed metabolic and transcriptomic changes in MCF-7 cells following single and combination chemotherapy to determine whether selective metabolic pathways are targeted during these different modes of treatment. Individually, the drugs caused metabolic disruption to the same metabolic pathways, however fulvestrant additionally attenuated the pentose phosphate pathway and the production of important coenzymes. A comprehensive effect was observed when the drugs were applied together, confirming the combinatory therapy’s synergism in the cell model. This study also highlights the power of merging high-dimensional datasets to unravel mechanisms involved in cancer metabolism and therapy.

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Palbociclib and fulvestrant act in synergy to modulate central carbon metabolism in breast cancer cells

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