title: The Novel Cyclin-Dependent Kinase 4/6 Inhibitor Ribociclib (LEE011) Alone and in Dual-Targeting Approaches Demonstrates Antitumoral Efficacy in Neuroendocrine Tumors in vitro.
abstract: Cyclin-dependent kinases (CDKs) are crucial for cell cycle regulation, and alterations in the cell cycle are often observed in human cancer. CDK4/6 in particular orchestrates G1 phase progression and the G1/S transition. Here, we investigated the in vitro effects of the CDK4/6 inhibitor LEE011 in human neuroendocrine tumor cells.
  
  
  
  The human neuroendocrine tumor cell lines BON1, QGP1, NCI-H727 and GOT1 were treated with different concentrations of LEE011 alone and in combination with 5-fluorouracil and everolimus.
  
  
  
  Cell viability decreased in a time- and dose-dependent manner in BON1, QGP1, and NCI-H727 cells upon LEE011 treatment, whereas GOT1 cells were treatment resistant. Treatment sensitivity towards LEE011 was associated with the high expression of cyclin D1 and Rb. LEE011 caused the dephosphorylation of Rb and a subsequent G1 phase cell cycle arrest. Combined treatment with LEE011 and 5-fluorouracil or everolimus showed a significant enhancement in the inhibition of cell viability when compared to single-substance treatments due to PI3K-Akt-mTOR and Ras-Raf-MEK-ERK pathway downregulation and cooperative downregulation of cell cycle components. However, LEE011 also exhibited antagonizing effects with 5-fluorouracil, protecting NET cells from DNA-damaging chemotherapy by blocking PARP cleavage and caspase-3/7 activity.
  
  
  
  Our data demonstrate that the CDK 4/6 inhibitor LEE011 exhibits promising anti-tumoral properties alone and in combination treatment approaches with 5-fluorouracil or everolimus in human neuroendocrine tumor cell lines.
authors.affiliation: Department of Internal Medicine II, Campus Grosshadern, University Hospital, Ludwig-Maximilians University of Munich, Munich, Germany.
authors.forename: Elke Tatjana
authors.initials: ET
authors.lastname: Aristizabal Prada
authors.forename: Svenja
authors.initials: S
authors.lastname: Nölting
authors.forename: Gerald
authors.initials: G
authors.lastname: Spoettl
authors.forename: Julian
authors.initials: J
authors.lastname: Maurer
authors.forename: Christoph Josef
authors.initials: CJ
authors.lastname: Auernhammer
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D004359:Drug Therapy, Combination; D000068338:Everolimus / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011687:Purines; D000068338:Everolimus; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C000589651:ribociclib; D005472:Fluorouracil
keywords: CDK4/6 inhibitor; Dual targeting; LEE011; Neuroendocrine tumor; Ribociclib