scholarly journals Insight into the mechanisms of action of estrogen receptor β in the breast, prostate, colon, and CNS

2013 ◽  
Vol 51 (3) ◽  
pp. T61-T74 ◽  
Author(s):  
Prasenjit Dey ◽  
Rodrigo P A Barros ◽  
Margaret Warner ◽  
Anders Ström ◽  
Jan-Åke Gustafsson
Keyword(s):  
Small Molecules ◽  
Kinase Inhibitor ◽  
Anxiety And Depression ◽  
Pharmaceutical Companies ◽  
Biological Processes ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinases ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Key Pathways ◽  
Insight Into

Estrogen and its receptors (ERs) influence many biological processes in physiology and pathology in men and women. ERs are involved in the etiology and/or progression of cancers of the prostate, breast, uterus, ovary, colon, lung, stomach, and malignancies of the immune system. In estrogen-sensitive malignancies, ERβ usually is a tumor suppressor and ERα is an oncogene. ERβ regulates genes in several key pathways including tumor suppression (p53, PTEN); metabolism (PI3K); survival (Akt); proliferation pathways (p45Skp2, cMyc, and cyclin E); cell-cycle arresting factors (p21WAF1, cyclin-dependent kinase inhibitor 1 (CDKN1A)), p27Kip1, and cyclin-dependent kinases (CDKs); protection from reactive oxygen species, glutathione peroxidase. Because they are activated by small molecules, ERs are excellent targets for pharmaceuticals. ERα antagonists have been used for many years in the treatment of breast cancer and more recently pharmaceutical companies have produced agonists which are very selective for ERα or ERβ. ERβ agonists are being considered for preventing progression of cancer, treatment of anxiety and depression, as anti-inflammatory agents and as agents, which prevent or reduce the severity of neurodegenerative diseases.

Phase I Clinical and Pharmacokinetic Study of Flavopiridol Administered as a Daily 1-Hour Infusion in Patients With Advanced Neoplasms

2002 ◽  
Vol 20 (19) ◽  
pp. 4074-4082 ◽  
Author(s):  
Antoinette R. Tan ◽  
Donna Headlee ◽  
Richard Messmann ◽  
Edward A. Sausville ◽  
Susan G. Arbuck ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Single Agent ◽  
Optimal Schedule ◽  
Maximum Tolerated Dose ◽  
Chemotherapeutic Agents ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinases ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Tumor Pain ◽  
Micromolar Range

PURPOSE: To define the maximum-tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of the cyclin-dependent kinase inhibitor flavopiridol administered as a daily 1-hour infusion every 3 weeks. PATIENTS AND METHODS: Fifty-five patients with advanced neoplasms were treated with flavopiridol at doses of 12, 17, 24, 30, 37.5, and 52.5 mg/m2/d for 5 days; doses of 50 and 62.5 mg/m2/d for 3 days; and doses of 62.5 and 78 mg/m2/d for 1 day. Plasma sampling was performed to characterize the pharmacokinetics of flavopiridol with these schedules. RESULTS: Dose-limiting neutropenia developed at doses ≥ 52.5 mg/m2/d. Nonhematologic toxicities included nausea, vomiting, diarrhea, hypotension, and a proinflammatory syndrome characterized by anorexia, fatigue, fever, and tumor pain. The median peak concentrations of flavopiridol achieved at the MTDs on the 5-day, 3-day, and 1-day schedule were 1.7 μmol/L (range, 1.3 to 4.2 μmol/L), 3.2 μmol/L (range, 1.7 to 4.8 μmol/L), and 3.9 μmol/L (1.8 to 5.1 μmol/L), respectively. Twelve patients had stable disease for ≥ 3 months, with a median duration of 6 months (range, 3 to 11 months). CONCLUSION: The recommended phase II doses of flavopiridol as a 1-hour infusion are 37.5 mg/m2/d for 5 days, 50 mg/m2/d for 3 days, and 62.5 mg/m2/d for 1 day. Flavopiridol as a daily 1-hour infusion can be safely administered and can achieve concentrations in the micromolar range, sufficient to inhibit cyclin-dependent kinases in preclinical models. Further studies to determine the optimal schedule of flavopiridol as a single agent and in combination with chemotherapeutic agents are underway.

scholarly journals The cyclin-dependent kinase inhibitor p21 (WAF1) is required for survival of differentiating neuroblastoma cells.

1996 ◽  
Vol 16 (4) ◽  
pp. 1335-1341 ◽  
Author(s):  
W Poluha ◽  
D K Poluha ◽  
B Chang ◽  
N E Crosbie ◽  
C M Schonhoff ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Neuronal Differentiation ◽  
Kinase Inhibitor ◽  
Cyclin E ◽  
Neuroblastoma Cells ◽  
Protein Kinase Activity ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinases ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Differentiated Cells

We are employing recent advances in the understanding of the cell cycle to study the inverse relationship between proliferation and neuronal differentiation. Nerve growth factor and aphidicolin, an inhibitor of DNA polymerases, synergistically induce neuronal differentiation of SH-SY5Y neuroblastoma cells and the expression of p21WAF1, an inhibitor of cyclin-dependent kinases. The differentiated cells continue to express p21WAF1, even after removal of aphidicolin from the culture medium. The p21WAF1 protein coimmunoprecipitates with cyclin E and inhibits cyclin E-associated protein kinase activity. Each of three antisense oligonucleotides complementary to p21WAF1 mRNA partially blocks expression of p21WAF1 and promotes programmed cell death. These data indicate that p21WAF1 expression is required for survival of these differentiating neuroblastoma cells. Thus, the problem of neuronal differentiation can now be understood in the context of negative regulators of the cell cycle.

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