The Potential of Farnesyltransferase Inhibitors as Cancer Chemotherapeutics

Gibbs, Jackson B.; Oliff, Allen

doi:10.1146/annurev.pharmtox.37.1.143

Cited by 302 publications

(202 citation statements)

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“…Farnesyltransferase (FTase) and geranylgeranyltransferase I (GGTase) inhibitors (FTIs and GGTIs) are novel classes of antitumor agents whose development was based upon the discovery that post-translational prenylation is required for the oncogenic properties of some GDP/GTP binding GTPases such as Ras and Rho (Cox and Der, 1997;Gibbs and Oliff, 1997;Sebti and Der, 2003). Protein prenylation involves C-terminal addition of C15 (farnesyl) by FTase or C20 (geranylgeranyl) by GGTase I (Zhang and Casey, 1996).…”

Section: Introductionmentioning

confidence: 99%

“…FTIs and GGTIs are potent inhibitors of Ras and Rho processing, respectively, and suppress the growth of murine and human tumors in various animal models (Kohl et al, 1994;Nagasu et al, 1995;Barrington et al, 1998;Liu et al, 1998;Sun et al, 1998;Hunt et al, 2000). Recent investigations into the biological mechanisms that underlie FTI anti-transforming effects have raised questions about their exact mode of action (Cox and Der, 1997;Gibbs and Oliff, 1997;Sebti and Hamilton, 2000;Sebti and Der, 2003). For example, there was no correlation between the Ras mutation status and reversal of transformation as some cancer cells that do not express oncogenic Ras were sensitive to FTI, and inversely, some cancer cells containing activated Ras were resistant to FTI (Cox and Der, 1997;Gibbs and Oliff, 1997;Sebti and Hamilton, 2000;Sebti and Der, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…Recent investigations into the biological mechanisms that underlie FTI anti-transforming effects have raised questions about their exact mode of action (Cox and Der, 1997;Gibbs and Oliff, 1997;Sebti and Hamilton, 2000;Sebti and Der, 2003). For example, there was no correlation between the Ras mutation status and reversal of transformation as some cancer cells that do not express oncogenic Ras were sensitive to FTI, and inversely, some cancer cells containing activated Ras were resistant to FTI (Cox and Der, 1997;Gibbs and Oliff, 1997;Sebti and Hamilton, 2000;Sebti and Der, 2003). In addition, in vitro and in vivo experiments have shown that K-Ras was geranylgeranylated in cells treated with FTIs (Rowell et al, 1997;Whyte et al, 1997;Sun et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

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Farnesyltransferase and geranylgeranyltransferase I inhibitors upregulate RhoB expression by HDAC1 dissociation, HAT association and histone acetylation of the RhoB promoter

Adnane

Joshi

et al. 2006

Oncogene

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Recently, we have shown that RhoB suppresses EGFR-, ErbB2-, Ras-and Akt-mediated malignant transformation and metastasis. In this paper, we demonstrate that the novel antitumor agents farnesyltransferase inhibitors (FTIs) and geranylgeranyltransferase I inhibitors (GGTIs) upregulate RhoB expression in a wide spectrum of human cancer cells including those from pancreatic, breast, lung, colon, bladder and brain cancers. RhoB induction by FTI-277 and GGTI-298 occurs at the transcriptional level and is blocked by actinomycin D. Reverse transcription-PCR experiments documented that the increase in RhoB protein levels is due to an increase in RhoB transcription. Furthermore, treatment with FTIs and GGTIs of cancer cells results in HDAC1 dissociation, HAT association and histone acetylation of the RhoB promoter. Thus, promoter acetylation is a novel mechanism by which RhoB expression levels are regulated following treatment with the anticancer agents FTIs and GGTIs.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Farnesyltransferase and geranylgeranyltransferase I inhibitors upregulate RhoB expression by HDAC1 dissociation, HAT association and histone acetylation of the RhoB promoter

Adnane

Joshi

et al. 2006

Oncogene

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“…3,4 When ®rst evaluated, it was felt that these agents might be best suited for tumors harboring mutant Ras genes. In an earlier study, we showed, however, that these compounds inhibited the growth of human cancer lines, including prostate, in which Ras mutations are rarely found.…”

Section: Introductionmentioning

confidence: 99%

Farnesyl:protein transferase inhibitors as potential agents for the management of human prostate cancer

Sepp‐Lorenzino

Tjaden

Moasser

et al. 2001

Prostate Cancer Prostatic Dis

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The effects of farnesyl:protein transferase inhibitors (FTIs) were evaluated against hormone-dependent and hormone-independent prostate cancer cell lines harboring mutant and wild type Ras. The combinations of the FTI with hormones and chemotherapy were explored. The effect of FTI on the growth of human prostate cancer lines was examined under anchorage-dependent and -independent conditions. Changes in Ras processing and cellular localization were examined by immunoblotting and immunocytochemistry. Hormonedependent (LNCaP) and -independent (TSU-Pr1, PC3 and DU145) human prostate cancer cell lines were growth-inhibited by the FTI L-744,832 at concentrations ranging from 100 nM to 20 mM. The inhibition was accompanied by loss of protein farnesylation and with the accumulation of Ha-Ras as its unprocessed, cytosolic form. No effect on N-and Ki-Ras processing was observed. The transformed phenotype of TSU-Pr1 cells, which possess a Ha-Ras Gly-12-Val activating mutation, reverted following FTI treatment. Enhanced antitumor effects were observed when the FTI was combined with gamma-radiation, etoposide, doxorubicin, cisplatin, estramustine and the antihormone bicalutamide. In particular, the combination of taxol and FTI was synergistic for DU145 cells, a cell line that is only marginally sensitive to the FTI alone. The sensitivity of human prostate cancer cell lines to the FTI is independent of the presence of mutations of tumor suppressors, cell cycle regulators and of the activation of a variety of oncogenes, including Ras. A cell line expressing mutated Ha-Ras is particularly sensitive. Enhanced antitumor effects were observed with an antiandrogen, g-irradiation, and several chemotherapeutic agents. These ®ndings support the clinical evaluation of FTIs alone or in combination as treatment for this disease. Prostate Cancer and Prostatic Diseases (2001) 4, 33±43.

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“…3,4 In cultured human tumor cells, SCH-66336 effectively inhibits the isoprenylation of H-Ras but not of K-or N-Ras as these proteins can be alternatively lipidated by GGTase I. 5 Furthermore, SCH-66336 reduces activated, GTP-bound Ras levels, 6 suggesting that pathways downstream of Ras are perturbed by the FTI.…”

mentioning

confidence: 99%

Farnesyltransferase inhibitor SCH‐66336 downregulates secretion of matrix proteinases and inhibits carcinoma cell migration

Desrosiers

Cusson

Turcotte

et al. 2005

Intl Journal of Cancer

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The ras oncogenes are among those most frequently found in human cancers. Blocking Ras farnesylation is a promising strategy for arresting cancer growth. Ras activates several signaling pathways with key roles in cellular proliferation, invasion, metastasis and angiogenesis. Furthermore, proteolytic activities of matrix proteinases such as urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs) are regulated by Ras isoforms. Thus, we investigated the effects of SCH-66336, a farnesyltransferase inhibitor, on secretion of components of the plasminogen activation system as well as on the gelatinases MMP-2 and MMP-9, which play pivotal roles in matrix remodeling. SCH-66336 up to 5 M did not significantly alter the viability of prostate (PC-3) and renal (Caki-1) cancer cells incubated in serum-depleted medium. SCH-66336 partly inhibited the processing of H-Ras, while levels of mature N-Ras and K-Ras remained unaffected. Under these noncytotoxic conditions, uPA and tPA levels were lowered in culture medium but raised in cell lysates, suggesting inhibition of trafficking pathways. In contrast, SCH-66336 had no effect on uPAR expression or on secreted PAI-1 levels. As expected, the reduction of uPA and tPA activities by SCH-66336 inhibited the conversion of plasminogen to plasmin by about 25% in PC-3 cells. SCH-66336 also inhibited the levels of secreted pro-MMP-2 and pro-MMP-9 as well as the release of their inhibitors TIMP-1 and TIMP-2. SCH-66336 decreased both the adhesion and even more so the migration of PC-3 cells on gelatin. Thus, SCH-66336 inhibited farnesylation in both cancer cell types, and H-Ras functions should be reduced by the drug. In addition, the lower levels of secreted proteinases in the presence of SCH-66336 suggest that reduced matrix remodeling and cell migration should occur in treated tumors.

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The Potential of Farnesyltransferase Inhibitors as Cancer Chemotherapeutics

Cited by 302 publications

References 108 publications

Farnesyltransferase and geranylgeranyltransferase I inhibitors upregulate RhoB expression by HDAC1 dissociation, HAT association and histone acetylation of the RhoB promoter

Farnesyltransferase and geranylgeranyltransferase I inhibitors upregulate RhoB expression by HDAC1 dissociation, HAT association and histone acetylation of the RhoB promoter

Farnesyl:protein transferase inhibitors as potential agents for the management of human prostate cancer

Farnesyltransferase inhibitor SCH‐66336 downregulates secretion of matrix proteinases and inhibits carcinoma cell migration

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