Table of Contents

May 2003; 3 (3)

Speaking of Pharmacology



  • In some cases, treatment of ovarian cancer cells with tumor necrosis factor-α can induce an apoptotic signal leading to the death of these cells; however, many ovarian malignancies are resistant to the effects of TNF-α. A new publication describes how these ovarian tumors may evade death receptor-mediated apoptosis. Apparently, the extracellular signals transduced by death receptors (e.g., TNF receptors) are extinguished before the cascade of caspases, which proteolytically cleave other proteins, can be activated. Overexpression of FLIP, a protein that blocks the caspase activity of FLICE, mediates the observed resistance. Thus, FLIP, which normally prevents inappropriate apoptosis, may become a tumor progression factor. Strategies to overcome this FLIP-mediated blockade of programmed cell death in tumors might become useful for positive prognoses.

  • The amplification of AURORA-A is frequently observed in specific epithelial cell malignancies. The overexpression of aurora-A, a Ser-Thr kinase known to localize to centrosomes during mitosis, appears to imbue cancerous cells with resistance to spindle-checkpoint-targeting drugs such as paclitaxel (Taxol). Indeed, a recent publication by Anand et al. indicates that overexpression of AURORA-A may interefere with spindle-microtubule attachment and disrupt the regulation of the spindle checkpoint by allowing cells with abnormal chromosomal separation to enter anaphase. Thus, the design of new drugs that specifically target aurora-A rather than other checkpoint proteins might alleviate the resistance to Taxol-like clinical therapeutics observed in some tumors.

  • Mutations in ion channels have been implicated in the formation of long QT syndrome (LQTS). However, Mohler et al. have recently uncovered a role for ankyrin-B, a non-ion channel protein, in type IV LQTS. Calcium signalling is altered, and the functions of several channels and pumps that normally interact with wild-type ankyrin-B are impaired in the presence of mutant ankyrin-B. The authors suggest that by disrupting the functions of these channels, a new mechanism has been uncovered that can lead to cardiac myopathy.


  • What is galanin, a neuropeptide, doing in the brains of Alzheimer patients? In normal brains, galanin is relatively prominent in certain cholinergic neurons in the basal forebrain, and these cells are both dependent on the peptide for their survival in early development and likely regulated by the peptide into adulthood. Moreover, the supply of galanin to these cholinergic neurons, which are involved in cognitive functions, is increased in Alzheimer disease, raising the suspicion that increased expression of the neuropeptide serves a protective role. On the other hand, the experimental overexpression of galanin in animals has been associated with neuronal loss and cognitive impairment. The development of therapies that might exploit the role(s) of galanin in Alzheimer disease will necessitate a better understanding of the neuroscience of both the neuropeptide and the disease.

  • Many people consider the age of modern pharmacology to have begun with Withering’s use of Digitalis to inhibit, albeit unknowingly to him, Na+-K+-ATPase activity in the heart and thereby increase myocardial contractility. But only recently has recognition of the ion-pumping properties of the ubiquitous membrane-bound ATPase been complemented by a regard for the protein’s function as a signaling molecule in a wider context of signal transduction. The Na+-K+-ATPase has been implicated in a number of protein-protein interactions that ultimately regulate cell function, and the intracellular reaction cascades that are dependent on the protein that is often thought of exclusively as a "sodium pump" are proving to be extensive and varied.

Beyond the Bench

Net Results