fti-277 and Lung-Neoplasms

Farnesyltransferase inhibitors (FTIs) are anticancer agents with a spectrum of activity in Ras-dependent and independent tumor cellular and xenograph models. How inhibition of protein farnesylation by FTIs results in reduced cancer cell proliferation is poorly understood due to the multiplicity of potential FTase targets. The low toxicity and oral availability of FTIs led to their introduction into clinical trials for the treatment of breast cancer, hematopoietic malignancy, advanced solid tumor and pancreatic cancer treatment, and Hutchinson-Gilford Progeria Syndrome. Although their efficacy in combinatorial therapies with conventional anticancer treatment for myeloid malignancy and solid tumors is promising, the overall results of clinical tests are far below expectations. Further exploitation of FTIs in the clinic will strongly rely on understanding how these drugs affect global cellular activity.. Using FTase inhibitor I and genome-wide chemical profiling of the yeast barcoded deletion strain collection, we identified genes whose inactivation increases the antiproliferative action of this FTI peptidomimetic. The main findings were validated in a panel of cancer cell lines using FTI-277 in proliferation and biochemical assays paralleled by multiparametric image-based analyses.. ABC transporter Pdr10 or p-21 activated kinase (PAK) gene deletion increases the antiproliferative action of FTase inhibitor I in yeast cells. Consistent with this, enhanced inhibition of cell proliferation by combining group I PAK inhibition, using IPA3, with FTI-277 was observed in melanoma (A375MM), lung (A549) and colon (HT29), but not in epithelial (HeLa) or breast (MCF7), cancer cell lines. Both HeLa and A375MM cells show changes in the nuclear localization of group 1 PAKs in response to FTI-277, but up-regulation of PAK protein levels is observed only in HeLa cells.. Our data support the view that group I PAKs are part of a pro-survival pathway activated by FTI treatment, and group I PAK inactivation potentiates the anti-proliferative action of FTIs in yeast as well as in cancer cells. These findings open new perspectives for the use of FTIs in combinatorial strategies with PAK inhibitors in melanoma, lung and colon malignancy.

Topics: Antineoplastic Agents; Cell Line, Tumor; Colonic Neoplasms; Farnesyltranstransferase; Female; Humans; Lung Neoplasms; Melanoma; Methionine; p21-Activated Kinases

The ability of Ras oncoproteins to cause malignant transformation requires their post-translational modifications by prenyl groups. Because K-Ras can be both farnesylated and geranylgeranylated it is not known whether both farnesyltransferase and geranylgeranyltransferase I inhibitors are required for suppressing human tumor growth in whole animals. In this paper we report that oncogenic Ras processing, MAP kinase activation and growth in nude mice are inhibited by the farnesyltransferase inhibitor FTI-276 in H- and N-Ras transformed NIH3T3 cells; whereas in KB-Ras transformed NIH3T3 cells both FTI-276 and the geranylgeranyltransferase I inhibitor GGTI-297 are required for inhibition. Furthermore, human lung A-549 and Calu-1 carcinoma cell lines were found to co-express H-, N- and K-Ras. In Calu-1 cells, the processing of H- and N-Ras is inhibited greatly by FTI-276 but only partially by GGTI-297 whereas K-Ras processing inhibition requires both FTI-276 and GGTI-297. In contrast, in A-549 cells the processing of H- and N-Ras is inhibited only by FTI-276 and K-Ras processing is resistant to co-treatment with FTI-276 and GGTI-297. Yet, the growth in nude mice of A-549 and Calu-1 xenografts, both of which express K-Ras mutations, is inhibited by FTI-276 (80% inhibition) and GGTI-297 (60%). Furthermore, FTI-276 inhibits tumor growth of NIH3T3 cells transformed by a form of oncogenic H-Ras that is exclusively geranylgeranylated and whose processing is resistant to this inhibitor. Taken together, the results demonstrate that both FTase and GGTase I inhibitors are required for inhibition of K-Ras processing but that each alone is sufficient to suppress human tumor growth in nude mice.

Topics: 3T3 Cells; Alkyl and Aryl Transferases; Animals; Benzamides; Cell Division; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Lung Neoplasms; Methionine; Mice; Mice, Nude; Neoplasm Transplantation; Oncogene Protein p21(ras); Protein Prenylation; Signal Transduction

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