Beta-Adrenergic Receptors Regulating Growth and Replication of Breast Cancer cells: Basic and Therapeutic Implications
Abstract
This study explores beta-adrenoceptors on breast cancer cells as a therapeutic target. MDA-MB-231 human breast cancer cells express high beta2-adrenoceptor levels that are linked to inhibition of mitosis through the production of cyclic AMP. Receptor stimulation by beta-agonists, or administration of the phosphodiesterase inhibitor, theophylline, led to mitotic arrest and a consequent reduction in cell number, accompanied by altered cellular morphology. We showed that the effects were mediated by the cellular intermediate, cyclic AMP; the responses did not desensitize even with prolonged drug exposure and could be enhanced by the coadministration of glucocorticoids, such as dexamethasone, that enhance beta-adrenoceptor-mediated cyclic AMP production. The largest effects were seen for theophylline, which exerted additional actions mediated through adenosine receptors and the production of reactive oxygen species. Theophylline evoked specific changes in the expression/function of membrane-bound adenylyl cyclase activity, effects that are likely to contribute to sustained reactivity of these cells to other cyclic AMP-related inhibitors of cell proliferation, such as beta-adrenergic agonists. Strategies focusing on cell surface receptors, such as beta-adrenoceptors, may combat cancers that are unresponsive to hormonal agents, or that have developed multidrug resistance, since the drugs do not need to penetrate the cell membrane to work.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2001
- Accession Number
- ADA392558
Entities
People
- Theodore Slotkin
Organizations
- Duke University Hospital