ggti-298 and Lung-Neoplasms

Dysregulation of epidermal growth factor receptor (EGFR) signaling is responsible for the resistance to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, and is thereby associated with the progression of tumors in non‑small cell lung cancers (NSCLCs). Immunoblotting results revealed that geranylgeranyl transferase 1 inhibitor (GGTI)‑298, a geranylgeranyl transferase 1 inhibitor with potential antitumor effects, effectively inhibited the phosphorylation of EGFR and its downstream target protein kinase B (AKT). A combination of gefitinib and GGTI‑298 amplified the inhibition of the EGFR‑AKT signaling pathway. In addition, GGTI‑298 treatment produced a synergistic effect on the inhibition of proliferation as indicated by the combination index values of <1 when combined with gefitinib in the NSCLC cell lines HCC827 and A549. These synergistic effects were also observed to induce apoptosis and migration inhibition. Further mechanistic studies demonstrated that GGTI‑298 inhibited the activity of Ras homolog family member A (RhoA), and downregulation of RhoA with small interfering RNA impaired the phosphorylation of EGFR, which suggested that EGFR inhibition by GGTI‑298 may be exerted mainly through RhoA mediation. These results presented a novel, promising therapeutic strategy involving a combination of two drugs for targeting EGFR signaling in lung cancer.

Topics: Alkyl and Aryl Transferases; Antineoplastic Agents; Apoptosis; Benzamides; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cyclin D1; Drug Synergism; Enzyme Inhibitors; ErbB Receptors; Gefitinib; Humans; Lung Neoplasms; Models, Biological; Phosphorylation; Proto-Oncogene Proteins c-akt; rhoA GTP-Binding Protein; Signal Transduction

Geranylgeranyltransferase I (GGTase I) has emerged as a cancer therapeutic target. Accordingly, small molecules that inhibit GGTase I have been developed and exhibit encouraging anticancer activity in preclinical studies. However, their underlying anticancer mechanisms remain unclear. Here we have demonstrated a novel mechanism by which GGTase I inhibition modulates apoptosis.. The GGTase I inhibitor GGTI-298 induced apoptosis and augmented tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human lung cancer cells. GGTI-298 induced DR4 and DR5 expression and reduced c-FLIP levels. Enforced c-FLIP expression or DR5 knockdown attenuated apoptosis induced by GGTI-298 and TRAIL combination. Surprisingly, DR4 knockdown sensitized cancer cells to GGTI298/TRAIL-induced apoptosis. The combination of GGTI-298 and TRAIL was more effective than each single agent in decreasing the levels of IkappaBalpha and p-Akt, implying that GGTI298/TRAIL activates NF-kappaB and inhibits Akt. Interestingly, knockdown of DR5, but not DR4, prevented GGTI298/TRAIL-induced IkappaBalpha and p-Akt reduction, suggesting that DR5 mediates reduction of IkappaBalpha and p-Akt induced by GGTI298/TRAIL. In contrast, DR4 knockdown further facilitated GGTI298/TRAIL-induced p-Akt reduction.. Both DR5 induction and c-FLIP downregulation contribute to GGTI-298-mediated augmentation of TRAIL-induced apoptosis. Moreover, DR4 appears to play an opposite role to DR5 in regulation of GGTI/TRAIL-induced apoptotic signaling.

Topics: Alkyl and Aryl Transferases; Apoptosis; Benzamides; Carcinoma, Non-Small-Cell Lung; CASP8 and FADD-Like Apoptosis Regulating Protein; Cell Line, Tumor; Cell Survival; Down-Regulation; Drug Screening Assays, Antitumor; Humans; I-kappa B Proteins; Lung Neoplasms; NF-KappaB Inhibitor alpha; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyridines; Receptors, TNF-Related Apoptosis-Inducing Ligand; rhoB GTP-Binding Protein; TNF-Related Apoptosis-Inducing Ligand; Up-Regulation

The mechanism by which the geranylgeranyltransferase I inhibitor GGTI-298 and the farnesyltransferase inhibitor FTI-277 inhibit human tumor growth is not known. Herein, we demonstrate that in the human lung adenocarcinoma A549 cells, GGTI-298 induced a G1-G0 block whereas FTI-277 induced an enrichment in the G2-M phase of the cell cycle. Although FTI-277, GGTI-298, and compactin inhibited A549 cell growth, only GGTI-298 and compactin induced apoptosis as demonstrated by four criteria: 4',6-diamidine-2-phenylindoledihydrochloride staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, DNA fragmentation assay, and flow cytometry. Furthermore, the involvement of geranylgeranylated proteins in apoptotic pathways was confirmed by demonstrating that geranylgeraniol was able to block the ability of compactin to induce apoptosis. These results suggest that protein geranylgeranylation is critical for the control of programmed cell death and that, in A549 cells, farnesylated and geranylgeranylated proteins are involved in G2-M and G0-G1, respectively.

Topics: Adenocarcinoma; Alkyl and Aryl Transferases; Apoptosis; Benzamides; Cell Division; Enzyme Inhibitors; G1 Phase; G2 Phase; Humans; Lung Neoplasms; Methionine; Mitosis; Resting Phase, Cell Cycle; Transferases; Tumor Cells, Cultured