A Novel Geranylgeranyl Transferase Inhibitor in Combination with Lovastatin Inhibits Proliferation and Induces Autophagy in STS-26T MPNST Cells

Abstract

Prenylation inhibitors have gained increasing attention as potential therapeutics for cancer. Initial work focused on inhibitors of farnesylation , but more recently geranylgeranyl transferase inhibitors (GGTIs) have begun to be evaluated for their potential antitumor activity in vitro and in vivo. In this study, we have developed a nonpeptidomimetic GGTI, termed GGTI-2Z [(5-nitrofuran-2-yl)methyl-(2Z,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraenyl 4-chlorobutyl(methyl)phosphoramidate], which in combination with lovastatin inhibits geranylgeranyl transferase I (GGTase I) and GGTase II/RabGGTase, without affecting farnesylation. The combination treatment results in a G 0 /G 1 arrest and synergistic inhibition of proliferation of cultured STS-26T malignant peripheral nerve sheath tumor cells. We also show that the antiproliferative activity of drugs in combination occurs in the context of autophagy. The combination treatment also induces autophagy in the MCF10.DCIS model of human breast ductal carcinoma in situ and in 1c1c7 murine hepatoma cells, where it also reduces proliferation. At the same time, there is no detectable toxicity in normal immortalized Schwann cells. These studies establish GGTI-2Z as a novel geranylgeranyl pyrophosphate derivative that may work through a new mechanism involving the induction of autophagy and, in combination with lovastatin, may serve as a valuable paradigm for developing more effective strategies in this class of antitumor therapeutics.Lipid modifications of proteins are known to facilitate their membrane association, cellular localization, and protein-protein interactions, which are related to their functions including cell survival, proliferation, differentiation, and invasion. Most GTPases, like Ras, contain a C-terminal CaaX motif that undergoes prenylation catalyzed by prenyl transferase enzymes, including farnesyl transferase (FTase) or geranylgeranyl transferase I (GGTase I), followed by serial modification via several other enzymes (Konstantinopoulos et al., 2007). The substrate specificities of FTase and GGTase I are not mutually exclusive and, therefore, cross-prenylation can

Anti-cancer characteristics of mevinolin against three different solid tumor cell lines was not solely p53-dependent

“…Defective apoptosis has been reflected in the form of cell resistance to apoptotic inducing agents and, consequently, treatment failure. MVN has been suggested to induce cell death via multiple apoptotic 13 , necrotic 24 and autophagic pathways 14 . In the current work, MCF-7 seemed to undergo apoptosis by the p53-dependent pathway; however both Bcl 2 and BAX were not significantly affected (Figure 2).…”

“…However, the exact signaling mechanism of MVNinduced cell death remain controversial. Few reports attribute the anti-cancer activity of MVN to the induction of apoptosis 13 , while others negate any role of apoptosis in MVN-induced cell death 14 . Whether the apoptosis pathway is involved in MVN-induced cytotoxicity, or not, remained an open issue by 2011.…”

Bisphosphonates Induce Autophagy by Depleting Geranylgeranyl Diphosphate

“…It remains uncertain whether this prevention is due to restoration of isoprenoid levels or protein prenylation. In addition, a novel GGTase I/II inhibitor, when combined with a statin, induced autophagy in the STS-26T malignant peripheral nerve sheath tumor cell line (Sane et al, 2010), suggesting that the impairment of prenylation can induce autophagy. However, this drug combination does not allow for the distinction of whether the impairment of GGTase I or GGTase II substrate geranylgeranylation is responsible for autophagic induction.…”

Anticancer Agents in Combination with Statins

“…Hence combination treatment is one of the better options to target the tumor at multiple points at same time. GTIs like GGTI-2Z [(5-nitrofuran-2-yl)methyl-(2Z,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraenyl-4-chlorobutyl(methyl)phosphoramidate] were developed and tested in vitro with combination of Lovastatin [3]. GGTI-2Z is a geranylgeranyl phosphate derivative.…”

“…By targeting the mevalonate pathway, statins exert growth inhibitory activity in cancer cells evident from in vitro and animal studies [2]. Protein prenylation is necessary for anchoring of proteins to cell membranes, protein-protein interactions and localization [3]. The isoprenoid intermediates of mevalonate pathway, farnesyl and geranyl-geranyl pyrophosphate are essential for post-translational modification of variety of intracellular proteins including Rho, Rac, and Ras.…”