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

Background/Aim: 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. Methods: 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. Results: 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. Conclusions: 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.

Targeted therapy of gastroenteropancreatic neuroendocrine tumours: preclinical strategies and future targets

“…( 225 ) LEE011 Aristizabal Prada et al . ( 227 ) ZK 304709 Scholz et al . ( 226 ) Palbociclib Tang et al .…”

“…The CDK4/6 inhibitor Palbociclib (PD0332991) reactivated Rb1, induced G1 cell cycle arrest and inhibited tumour cell growth in BON1 and QGP1 cells in vitro and also showed anti-tumoural activity in a QGP1 xenograft model in vivo ( 225 ). The CDK4/6 inhibitor ribociclib (LEE011) decreased tumour cell proliferation in BON1, QGP1 and H727 cells, through dephosphorylation of Rb and a subsequent G1 phase cell cycle arrest in vitro ( 227 ). LEE011 was ineffective in GOT1 cells, and treatment sensitivity towards LEE011 was associated with high expression of cyclin D1 and Rb ( 227 ).…”

“…The CDK4/6 inhibitor ribociclib (LEE011) decreased tumour cell proliferation in BON1, QGP1 and H727 cells, through dephosphorylation of Rb and a subsequent G1 phase cell cycle arrest in vitro ( 227 ). LEE011 was ineffective in GOT1 cells, and treatment sensitivity towards LEE011 was associated with high expression of cyclin D1 and Rb ( 227 ). Combination treatment of LEE011 and 5-fluorouracil or everolimus showed a significant enhancement in the inhibition of cell viability when compared to single-substance treatments because of PI3K–Akt–mTOR and Ras–Raf–MEK–ERK pathway downregulation and cooperative downregulation of cell cycle components ( 227 ).…”

“…LEE011 was ineffective in GOT1 cells, and treatment sensitivity towards LEE011 was associated with high expression of cyclin D1 and Rb ( 227 ). Combination treatment of LEE011 and 5-fluorouracil or everolimus showed a significant enhancement in the inhibition of cell viability when compared to single-substance treatments because of PI3K–Akt–mTOR and Ras–Raf–MEK–ERK pathway downregulation and cooperative downregulation of cell cycle components ( 227 ). However, LEE011 also exhibited antagonising effects with 5-fluorouracil, protecting NET cells from the DNA-damaging effects of chemotherapy ( 227 ).…”

“…Combination treatment of LEE011 and 5-fluorouracil or everolimus showed a significant enhancement in the inhibition of cell viability when compared to single-substance treatments because of PI3K–Akt–mTOR and Ras–Raf–MEK–ERK pathway downregulation and cooperative downregulation of cell cycle components ( 227 ). However, LEE011 also exhibited antagonising effects with 5-fluorouracil, protecting NET cells from the DNA-damaging effects of chemotherapy ( 227 ). Hence, the efficiency of a dual targeting approach with LEE011 and chemotherapeutic agents in NETs remains to be assessed in the clinic ( 227 ).…”