Anti-cancer therapy: targeting the mevalonate pathway.

The mevalonate pathway has become an important target for anti-cancer therapy. Manipulation of this pathway results in alteration of malignant cell growth and survival in cell culture and animal models, with promising potential for application in human cancers. Mevalonate is synthesized from 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA). Mevalonate is further metabolized to farnesyl pyrophosphate (FPP), which is the precursor for sterols. In addition, the farnesyl moiety from FPP is utilized for post-translational modification of proteins including small GTPases, such as Ras and Ras related proteins, which play a role in malignant transformation of cells. FPP is a precursor for geranylgeranyl pyrophosphate (GGPP), which is similarly involved in post-translational modification of proteins. There has been intense interest in manipulating the pathway through HMG-CoA reductase inhibition. More recently, the focus has been on manipulating the pathway by post-translational modification of key regulatory proteins through farnesyl prenyl transferase (FPTase) or geranylgeranyl prenyl transferase (GGPTase) inhibition. This review focuses on the mevalonate pathway and the application of rational drug therapies to manipulate this pathway. Included in the review are a summary of agents demonstrating success in preclinical investigations such as; farnesyl transferase inhibitors, geranylgeranyl transferase inhibitors, dual inhibitors, statins, bisphosphonates, histone deacetylase inhibitors and other compounds. While these agents have shown preclinical success, translation to success in clinical trials has been more difficult. These clinical trials are reviewed along with evaluation of some of the potential problems with these agents in their clinical application.

Preclinical evidence for the effect of bisphosphonates and cytotoxic drugs on tumor cell invasion.

Bisphosphonates (BPs) are stable pyrophosphate analogs currently used in the treatment of patients with metastatic bone disease, known to affect bone resorption by reducing osteoclast activity. Use of these drugs in adjuvant therapy is currently under investigation following reports of an effect of BPs on tumor cell apoptosis in preclinical models. Recent evidence has suggested that BPs might also affect tumor cell invasion in vitro, and the component processes of adhesion, migration and degradation, through mechanisms including inhibition of prenylation of intracellular small GTPases such as Ras and Rho. The effects potentially may be enhanced through co-administration with chemotherapy agents, as both synergistic and additive effects have been described in vitro. This review discusses the preclinical evidence for the potential use of BPs and cytotoxic drugs for inhibiting tumor cell invasion, a key process in cancer progression.

Functional serotonin-2B receptors are expressed by a teratocarcinoma-derived cell line during serotoninergic differentiation.

Among immortalized teratocarcinoma-derived cells, the clone 1C11 is a committed precursor of the neuronal lineage. On day 2 of its serotoninergic differentiation, this clone expresses only one subtype of serotonin [5-hydroxytryptamine (5-HT)] receptor, which is functionally coupled to phosphatidylinositol hydrolysis. The identity of these receptors was established by comparing their properties with those of 5-HT2B receptors expressed by LMTK- fibroblasts stably transfected with the recently cloned murine cDNA NP75 (LM5 cells). In both cell types, the analysis of (+/-)-1-(2,5-dimethoxy-4-[125I]iodophenyl)- 2-aminopropane HCl ([125I]DOI) binding revealed the presence of a single class of sites, the affinity of which was 1 order of magnitude lower than that reported for 5-HT2A receptors. In 1C11 cells differentiated for 2 days, as well as in LM5 cells, DOI binding was decreased by nonhydrolyzable analogs of GTP, indicating that the 5-HT2B receptor is functionally coupled to a G protein. The DOI-induced increase of phosphoinositide hydrolysis, which was correlated with both GTPase activity and binding data, is mediated by a Gq protein. This work demonstrates that the 5-HT2B receptor is functionally expressed before complete serotoninergic differentiation of 1C11 cells. The inducible 1C11 clone thus provides an in vitro model to investigate the possible role of the 5-HT2B receptor in the expression of the serotoninergic phenotype.