# Recent Advances in the Development of Mammalian Geranylgeranyl Diphosphate Synthase Inhibitors
## 4 Cellular Effects of GGDPS Inhibition  
Several of the GGDPS inhibitors described above have effects on cellular proliferation and cell death in vitro [34; 37; 49; 52]. The mechanism by which this occurs is not always clear, although one would reason that it is caused by a disruption of protein geranylgeranylation [53]. While Rho and Rab proteins predominately function as regulators of cytoskeletal reorganization and vesicle trafficking, respectively, some reports suggest they play a role in cellular proliferation and survival as well. RhoA has been implicated in several studies. Apoptosis induced by IBP inhibitors can be rescued by either exogenous delivery of GGPP or expression of constitutively active RhoA [54; 55; 56]. In breast cancer cell lines, expression of Rab27B promotes cell cycle progression, proliferation, and invasion and this activity is dependent on the geranylgeranylation of Rab27B [57]. In mesothelioma cells, inhibition of Rab6 geranylgeranylation activates the apoptotic pathway [58]. In addition to their role in regulating cell proliferation, GGDPS inhibitors also influence autophagy. In both breast cancer and prostate cancer cell lines, [PERSON] et al. demonstrated that inhibition of FDPS and GGDPS, but not FTase or GGTase I promotes autophagy as measured by accumulation of the autophagy marker LC3-II [59]. Studies performed in myeloma cells utilizing lovastatin, DGBP, or specific GGTase I or II inhibitors demonstrated that IBP inhibition induces a net increase in autophagy as a consequence of disruption of isoprenoid biosynthesis which is not recapitulated by direct geranylgeranyl transferase inhibition [60].  
Given the role of geranylgeranylated Rab proteins in regulating intracellular vesicle trafficking and secretion, one would predict that inhibition of Rab geranylgeranylation would affect cellular secretion. In fact, inhibitors of the IBP pathway have been shown to disrupt normal cellular secretion in numerous cell types. Lovastatin was reported to decrease secretion of cholecystin in endocrine cells [61]. Another statin, simvastatin, reduced IgM secretion in lymphoplasmacytic lymphoma cell lines [62]. Our group demonstrated that disruption of Rab geranylgeranylation, either through depletion of GGPP or by inhibition of GGTase II, inhibits the secretion of monoclonal protein in multiple myeloma cells [52]. The novel triazole-based GGDPS inhibitors potentially disrupt monoclonal protein secretion [37; 40]. The monoclonal protein subsequently accumulates within the endoplasmic reticulum, resulting in induction of the unfolded protein response (UPR) pathway and ultimately apoptosis in multiple myeloma cells [52]. During times of reversible stress, the UPR slows protein synthesis, upregulates chaperone proteins and promotes degradation of misfolded protein. However, in instances of prolonged stress, such as continuous inhibition of protein trafficking as caused by Rab inhibitors, the UPR can activate apoptotic pathways. Multiple myeloma cells express near maximal levels of UPR-associated proteins to aid in the secretion of continuously synthesized proteins. It is for this reason that they are particularly sensitive to induction of the pro-apoptotic arm of the UPR [63]. Thus, GGDPS inhibitors may be particularly relevant with respect to anti-myeloma therapy and represent a novel strategy by which to induce myeloma cell death.