Tropolone-induced effects on the unfolded protein response pathway and apoptosis in multiple myeloma cells are dependent on iron.

Tropolones are naturally occurring seven-membered non-benzenoid aromatic compounds that are of interest due to their cytotoxic properties. MO-OH-Nap is a novel α-substituted tropolone that induces caspase cleavage and upregulates markers associated with the unfolded protein response (UPR) in multiple myeloma (MM) cells. Given previous reports that tropolones may function as iron chelators, we investigated the effects of MO-OH-Nap, as well as the known iron chelator deferoxamine (DFO), in MM cells in the presence or absence of supplemental iron. The ability of MO-OH-Nap to induce apoptosis and upregulate markers of the UPR could be completely prevented by co-incubation with either ferric chloride or ammonium ferrous sulfate. Iron also completely prevented the decrease in BrdU incorporation induced by either DFO or MO-OH-Nap. Ferrozine assays demonstrated that MO-OH-Nap directly chelates iron. Furthermore, MO-OH-Nap upregulates cell surface expression and mRNA levels of transferrin receptor. In vivo studies demonstrate increased Prussian blue staining in hepatosplenic macrophages in MO-OH-Nap-treated mice. These studies demonstrate that MO-OH-Nap-induced cytotoxic effects in MM cells are dependent on the tropolone's ability to alter cellular iron availability and establish new connections between iron homeostasis and the UPR in MM.

Isoprenoid metabolism as a therapeutic target in gram-negative pathogens.

Gram-negative Enterobacteria include a variety of human pathogens, perhaps most notably E. coli, Salmonella, Shigella, Yersinia, and Proteus. While there are treatment options for the diseases caused by these organisms, multi-drug resistance is often a problem and development of novel antibiotics has lagged over recent years. In humans, the isoprenoid biosynthetic pathway has become a subject of intense research for therapeutic modulation of human enzymes in diseases including hypercholesterolemia, osteoporosis, and cancer. In bacteria, isoprenoid metabolism is arguably just as important, giving rise to components that are essential for electron transport and cell wall biosynthesis. Blocking these biosynthetic processes, either with the antibiotic fosmidomycin or by gene knockout strategies, has demonstrated the necessity of isoprenoid biosynthesis for bacterial growth. In this review, current knowledge of the biochemical pathways involved in farnesyl diphosphate metabolism in Enterobacteria, efforts to develop inhibitors of the involved enzymes, and insights from inhibitors of human isoprenoid metabolism that may be relevant for future studies of antibiotics that target these key enzymes, are described.

The intermediate enzymes of isoprenoid metabolism as anticancer targets.

Inhibitors of isoprenoid biosynthesis are widely used to treat human disease including statins and nitrogenous bisphosphonates. Due to the importance of core human isoprenoid biosynthesis for diverse cellular processes related to cancer cell growth and metastasis, inhibition of this pathway may produce beneficial anticancer consequences. For example, ras oncogenes are well known; ras proteins are overexpressed in many human cancers, and these proteins must be isoprenylated to function. The rho proteins are important for regulating cell motility, and also must be isoprenylated. This has drawn significant attention to inhibitors of protein prenyl transferases. In addition to the reactions that are targeted in current clinical applications, there are other enzymes that have not been studied as extensively. Inhibition of these enzymes, from mevalonate kinase to geranylgeranyl diphosphate synthase, could be attractive as a single agent therapy or in combination with current agents for treatment of cancers in which isoprenylated proteins have been implicated. While detailed in vivo data for many of these putative targets is lacking, there have been several breakthroughs in recent years that could facilitate further studies. In particular, compounds that specifically inhibit some of the downstream isoprenoid biosynthesis enzymes have been developed and their effects in cancer models are emerging. This review will discuss current knowledge of these lesser known isoprenoid pathway enzymes, identify trends in the development of their small molecule inhibitors, and describe the applications and effects of these compounds in cancer models.