To determine a molecular profile/phenotype that will predict CDK4/6 inhibitor activity, researchers will have to take into account simultaneously occurring events in the cyclin-D/CDK4/CDK6/retinoblastoma and associated pathways.
PD0332991 also inhibited CDK6‑specific phosphorylation of retinoblastoma on Ser780, reduced the expression of cyclin D1, and induced expression of p53 and p27.
To explore the possible anti-lung cancer effects of PL, A549 cells were treated with PL (0-40 μM) for 24 h. Alterations in the expression of cell cycle-associated proteins (cyclin D1, cyclin-dependent kinase 4 (CDK4), CDK6 and retinoblastoma (Rb)) and intracellular signaling molecules (extracellular signal receptor-activated kinase 1/2 (ERK1/2), Akt, p38 and nuclear factor-κB (NF-κB)) were examined in cells following treatment of PL using Western blot analysis.
Compound 50 (FN-1501), which possesses potent inhibitory activities against FLT3, CDK2, CDK4, and CDK6 with IC<sub>50</sub> values in the nanomolar range, shows antiproliferative activities against MV4-11 cells (IC<sub>50</sub>: 0.008 μM), which correlates with the suppression of retinoblastoma phosphorylation, FLT3, ERK, AKT, and STAT5 and the onset of apoptosis.
Over-expression of miR-495 in T98 cells downregulated the expression of CDK6 and inhibited retinoblastoma phosphorylation, and knockdown of CDK6 in U87-MG and T98 cells by siRNAs resulted in cell cycle arrest at the G1/S transition and inhibition of cell proliferation.
PD 0332991 is an orally active, highly selective inhibitor of the cyclin D kinases (CDK)4 and CDK6 with ability to block retinoblastoma (Rb) phosphorylation in the low nanomolar range.
These results provide the grounds for new therapeutic strategies in ALL either targeting the epigenetic regulation of microRNAs and/or directly targeting the CDK6-Rb pathway.
HDHS also decreased the protein expression of cyclins (D1 and E), cyclin-dependent kinases (CDK2, CDK4, and CDK6), and retinoblastoma phosphorylation in PCa cells, which suggest cell cycle arrest in the G(1) phase.
We also demonstrate that miR-34a targets the 3'-untranslated mRNA region of CCND1 as well as CDK6, which in turn interferes with phosphorylation of retinoblastoma.
In an attempt to model oral cancer in a human cell-based system, we analyzed normal oral epithelial keratinocytes with the pRB pathway dysregulated by loss of expression of the cyclin-dependent kinase (cdk) 4/cdk6 inhibitor p16(INK4A) and/or ectopic expression of cdk4 or expression of the human papillomavirus (HPV) type 16 E7 oncoprotein.
Genes examined included the retinoblastoma susceptibility gene (Rb-1); cyclins D1, D2, A, and E; the CDK inhibitors p18, p19, and p27; CDK2 and CDK6; transcription factors E2F-4, E2F-5, and DP-1; and the neurofibromatosis type 2 gene.
In this line, cdk6 activity was decreased after 5-aza-2'deoxycytidine treatment, and the hypophosphorylated, growth suppressive form of the retinoblastoma tumor suppressor protein pRB was detected.
The growth suppressing activity of the retinoblastoma suspectibility gene product, pRb, is down regulated by cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) whose kinase activity is negatively regulated by CDK inhibitors of the p16 family.
The p16INK4 family of CDK inhibitors specifically prevent the phosphorylation of the retinoblastoma susceptibility gene product, pRb, by inhibiting the kinase activity of CDK4 and CDK6, thereby keeping pRb in its active form as a growth suppressor.
p16INK4A, a specific inhibitor of cyclin-dependent kinase (cdk)4 and cdk6, is a candidate tumor suppressor in malignancies with wild-type retinoblastoma (Rb).
Since most hematological malignancies-except ALL-are infrequently associated with p16INK4A and retinoblastoma (Rb) gene alteration it seems worthwhile to explore cdk4 and cdk6 expression to determine whether or not the disruption of the p16INK4A/Rb/cdk4/cdk6 regulatory loop might play a role in their pathogenesis.