piperidines and manumycin

The shortage of geranylgeranyl-pyrophosphate (GGPP) was associated to an increased IL-1β release in the autoinflammatory syndrome mevalonate kinase deficiency (MKD), a rare inherited disease that has no specific therapy. Farnesyltransferase inhibitors (FTIs) act at the end of mevalonate pathway. Two FTIs, tipifarnib (Tip) and lonafarnib (Lon), were therefore evaluated as possible therapeutical choices for the treatment of MKD. FTIs could lead to a redirection of the limited available number of mevalonate intermediates preferentially to GGPP synthesis, eventually preventing the uncontrolled inflammatory response. The effect of Tip and Lon on intracellular cholesterol level (ICL) and on proinflammatory cytokines secretion was evaluated in a cellular model of MKD, chemically obtained treating RAW 264.7 cells with lovastatin (Lova) and alendronate (Ald). The combination of FTIs with the isoprenoid geraniol (GOH) was also tested both in this model and in monocytes isolated from MKD patients. Tip and Lon proved to revert the ICL lowering and to significantly reduce the lipopolysaccharide-induced cytokines secretion in Ald-Lova -RAW 264.7 cells. This anti-inflammatory effect was amplified combining the use of GOH with FTIs. The effect of GOH and Tip was successfully replicated in MKD patients' monocytes. Tip and Lon showed a dramatic anti-inflammatory effect in monocytes where mevalonate pathway was chemically or genetically impaired.

Topics: Acyclic Monoterpenes; Alendronate; Animals; Anti-Inflammatory Agents; Cell Line; Child; Child, Preschool; Cholesterol; Cytokines; Dose-Response Relationship, Drug; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Inflammation Mediators; Lovastatin; Male; Mevalonate Kinase Deficiency; Mice; Monocytes; Phosphotransferases (Alcohol Group Acceptor); Piperidines; Polyenes; Polyisoprenyl Phosphates; Polyunsaturated Alkamides; Pyridines; Quinolones; Terpenes

The mechanisms of action of farnesyltransferase inhibitors (FTIs) involve Rheb and the phosphatidylinositide 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway. mTOR in particular plays a key role in the regulation of autophagy. Collectively, the literature suggests that FTIs very likely induce autophagy, but thus far there have been no reports that FTIs affect this process relevant to cancer cell biology. We hypothesized that FTIs can induce autophagy. In this study, we found that the FTIs manumycin A, FTI-276, and lonafarnib induced autophagy in two human cancer cell lines. We also found that neither inhibition of apoptosis with a pan-caspase inhibitor nor inhibition of autophagy increased the number of clones of lonafarnib-treated U2OS osteosarcoma cells that formed in soft agar. Although whether autophagy is a cell death or cell survival mechanism after FTI treatment remains unresolved, our data show that cancer cells apparently can shift between apoptosis and autophagy once they are committed to die after FTI treatment.

Topics: Apoptosis; Autophagy; Cell Line, Tumor; Dose-Response Relationship, Drug; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Microscopy, Electron, Transmission; Microscopy, Fluorescence; Pancreatic Neoplasms; Piperidines; Polyenes; Polyunsaturated Alkamides; Protein Kinases; Pyridines; RNA, Small Interfering; Signal Transduction; TOR Serine-Threonine Kinases