![]() ![]() This induces cell cycle arrest in the G 1-phase. The development of CDK4/6 inhibitors such as palbociclib (Ibrance ®, PD0332991) target the adenosine triphosphate (ATP) binding site of CDK4-cyclin D and CDK6-cyclin D complexes. In recent years, agents have been developed which selectively target CDK4/6. Thus, the re-establishment of normal cell cycle control through the inhibition of CDKs is an interesting option for the development of targeted cancer therapy. Both are correlated with estrogen receptor positive (ER+) breast cancers. Mutations to the CDK-RB1-E2F pathway typically result in the amplification of CCND1 which encodes cyclin D1. CDKs 4 and 6 phosphorylate the retinoblastoma (RB) protein enabling the release of E2F transcription factors (E2Fs) which mediates transition into the S-phase. ![]() Cyclin-dependent kinases (CDKs) control this regulation enabling quiescent cells to enter the G 1-phase and transition to the S phase. This study also highlights the power of merging high-dimensional datasets to unravel mechanisms involved in cancer metabolism and therapy.Ĭell cycle regulation is frequently disrupted in breast cancer. A comprehensive effect was observed when the drugs were applied together, confirming the combinatory therapy’s synergism in the cell model. 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. 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. The mechanisms for this survival advantage are not known. 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 aims of this study were to determine whether combination chemotherapeutics exhibit a synergistic effect on breast cancer cell metabolism.
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