Simultaneous inhibition of MEK and CDK4 leads to potent apoptosis in human melanoma cells.
ABSTRACT Deregulation of RAS-RAF-MEK-ERK and p16INK4A-cycylin D:CDK4/6-RB pathways is important for melanoma development. Chemotherapeutic agents targeting both pathways were developed but results of clinical studies with monotherapies were disappointing. We examined the effect of co-targeting both pathways with MEK inhibitor PD98059 and CDK4 inhibitor 219476 on human melanoma cells lines, and found that combinatorial treatment dramatically increased apoptosis compared to the single agent treatment. The apoptosis was associated with downregulation of BCL2, BCL2L1, BIRC5, and upregulation of BIM. Our results indicate that simultaneously targeting ERK and RB pathways is a promising strategy for melanoma treatment and should encourage further in-depth investigations.
Li
Jing
J
Department of Pathology and Sealy Center for Cancer Cell Biology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0743, USA.
Xu
Meixiang
M
Yang
Zhen
Z
Li
Albert
A
Dong
Jianli
J
D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D005419:Flavonoids; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D051358:Cyclin-Dependent Kinase 4; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one