TY - JOUR
T1 - Palbociclib and fulvestrant act in synergy to modulate central carbon metabolism in breast cancer cells
AU - Warth, Benedikt
AU - Palermo, Amelia
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.
PY - 2019/1/2
Y1 - 2019/1/2
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.
KW - breast cancer
KW - combination drug therapy
KW - metabolomics
KW - multi-omics
KW - RNA-seq
KW - XCMS online
UR - http://www.scopus.com/inward/record.url?scp=85060004315&partnerID=8YFLogxK
U2 - 10.3390/metabo9010007
DO - 10.3390/metabo9010007
M3 - Article
AN - SCOPUS:85060004315
SN - 2218-1989
VL - 9
JO - Metabolites
JF - Metabolites
IS - 1
M1 - 7
ER -