J-104,871, a Novel Farnesyltransferase Inhibitor, Blocks Ras Farnesylation In Vivo in a Farnesyl Pyrophosphate-Competitive Manner

1998 ◽  
Vol 54 (1) ◽  
pp. 1-7 ◽  
Author(s):  
Mari Yonemoto ◽  
Toshihiko Satoh ◽  
Hiroharu Arakawa ◽  
Ikuko Suzuki-Takahashi ◽  
Yoshiaki Monden ◽  
...  
Keyword(s):  
Farnesyl Pyrophosphate ◽  
Farnesyltransferase Inhibitor

Anti-Inflammatory Activity in Vitro and in Vivo of the Protein Farnesyltransferase Inhibitor Tipifarnib

2005 ◽  
Vol 317 (1) ◽  
pp. 53-60 ◽  
Author(s):  
Xiaohua Xue ◽  
Kuei-Tai A. Lai ◽  
Jing-Feng Huang ◽  
Yin Gu ◽  
Lars Karlsson ◽  
...  
Keyword(s):  
Inflammatory Activity ◽  
Farnesyltransferase Inhibitor ◽  
Protein Farnesyltransferase ◽  
Anti Inflammatory

Nitrogen-containing bisphosphonates can inhibit angiogenesis in vivo without the involvement of farnesyl pyrophosphate synthase

Bone ◽  
2011 ◽  
Vol 48 (2) ◽  
pp. 259-266 ◽  
Author(s):  
Verena Stresing ◽  
Pierrick G. Fournier ◽  
Akeila Bellahcène ◽  
Ismahène Benzaïd ◽  
Hannu Mönkkönen ◽  
...  
Keyword(s):  
Farnesyl Pyrophosphate ◽  
Farnesyl Pyrophosphate Synthase

scholarly journals Activation of autophagy during farnesyl pyrophosphate synthase inhibition is mediated through PI3K/AKT/mTOR signaling

2019 ◽  
Vol 48 (4) ◽  
pp. 030006051987537
Author(s):  
Jie Han ◽  
Chaoyang Huang ◽  
Jiukun Jiang ◽  
Dongmei Jiang
Keyword(s):  
Molecular Mechanisms ◽  
Cellular Proliferation ◽  
Umbilical Vein ◽  
Mtor Signaling ◽  
Farnesyl Pyrophosphate ◽  
Farnesyl Pyrophosphate Synthase ◽  
Acridine Orange Staining ◽  
Autophagy Induction

Objectives Autophagy is divided into three phases: autophagosome engulfment of intracellular organelles and proteins, autophagosome fusion with lysosomes, and autolysosome degradation. The farnesyl pyrophosphate synthase inhibitor ibandronate (IBAN) has in vivo cardioprotective properties, potentially via anti-oxidant effects. Whether autophagy is involved in the cardioprotective effect of IBAN remains unexplored. Methods Human umbilical vein endothelial cells (HUVECs) were treated in vitro with IBAN to assess autophagy induction. Lysosomal activation and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling were assessed using a LysoTracker assay, acridine orange staining and western blotting. An MTS assay was used to assess cellular proliferation. Autophagy was inhibited using chloroquine or RNA silencing of autophagy-related 7 (Atg7) expression. Results IBAN induced autophagy in HUVECs. Moreover, IBAN activated lysosomal function, which is pivotal to autophagy induction. PI3K/AKT/mTOR activity was inhibited in IBAN-treated HUVECs, indicating the involvement of this pathway in IBAN-induced autophagy. Inhibition of autophagy using either chloroquine or Atg7 siRNA potentiated inhibition of HUVEC growth by IBAN, suggesting the involvement of non-autophagy pathways in the antiproliferative effects of IBAN. Conclusions These findings provide insights into the role of autophagy in the cardioprotective effects of IBAN and the molecular mechanisms underlying autophagy induction by IBAN.

scholarly journals Sesquiterpene α-Farnesene Synthase: Partial Purification, Characterization, and Activity in Relation to Superficial Scald Development in Apples

2000 ◽  
Vol 125 (1) ◽  
pp. 111-119 ◽  
Author(s):  
H.P. Vasantha Rupasinghe ◽  
Gopinadhan Paliyath ◽  
Dennis P. Murr
Keyword(s):  
Metal Ion ◽  
Maximal Activity ◽  
Exchange Chromatography ◽  
Cytosolic Fraction ◽  
Skin Tissue ◽  
Hill Coefficient ◽  
Partial Purification ◽  
Farnesyl Pyrophosphate ◽  
Superficial Scald

To decipher the relation between α-farnesene metabolism and the development of superficial scald in apples, trans,trans-α-farnesene synthase, the enzyme that catalyzes the conversion of farnesyl pyrophosphate to α-farnesene, was partially purified from skin tissue of `Delicious' apples (Malus ×domestica Borkh.) and characterized. Total and specific activities of the enzyme were higher in the cytosolic fraction than in membrane fractions. α-Farnesene synthase was purified 70-fold from the cytosolic fraction by ion exchange chromatography and gel permeation, and the native molecular weight was estimated to be 108,000. The enzyme had optimal activity at a pH of 5.6 and absolutely required a divalent metal ion such as Mg2+ or Mn2+ for activity. It exhibited allosteric kinetics, S(0.5) for farnesyl pyrophosphate being 84±18 μmol·L-1, and a Hill coefficient (nH) of 2.9, indicating the number of subunits to be two or three. Enzyme activity was highest between 10 and 20 °C, while 50% of the maximal activity was retained at 0 °C. In vivo α-farnesene synthase activity was minimal at harvest, then increased rapidly during 16 weeks storage in air at 0 °C, and decreased during further storage. Activity of α-farnesene synthase, α-farnesene content, and conjugated triene alcohol (the putative scald-causing oxidation product of α-farnesene) content in skin tissue were not correlated to the inherent nature of scald susceptibility or resistance in 11 apple cultivars tested.

scholarly journals Active oral regimen for elderly adults with newly diagnosed acute myelogenous leukemia: a preclinical and phase 1 trial of the farnesyltransferase inhibitor tipifarnib (R115777, Zarnestra) combined with etoposide

Blood ◽  
2009 ◽  
Vol 113 (20) ◽  
pp. 4841-4852 ◽  
Author(s):  
Judith E. Karp ◽  
Karen Flatten ◽  
Eric J. Feldman ◽  
Jacqueline M. Greer ◽  
David A. Loegering ◽  
...  
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Phase 1 ◽  
Myelogenous Leukemia ◽  
Elderly Adults ◽  
Farnesyltransferase Inhibitor ◽  
Phase 1 Trial ◽  
Histone H2ax ◽  
Acute Myelogenous ◽  
Orally Bioavailable

AbstractThe farnesyltransferase inhibitor tipifarnib exhibits modest activity against acute myelogenous leukemia. To build on these results, we examined the effect of combining tipifarnib with other agents. Tipifarnib inhibited signaling downstream of the farnesylated small G protein Rheb and synergistically enhanced etoposide-induced antiproliferative effects in lymphohematopoietic cell lines and acute myelogenous leukemia isolates. We subsequently conducted a phase 1 trial of tipifarnib plus etoposide in adults over 70 years of age who were not candidates for conventional therapy. A total of 84 patients (median age, 77 years) received 224 cycles of oral tipifarnib (300-600 mg twice daily for 14 or 21 days) plus oral etoposide (100-200 mg daily on days 1-3 and 8-10). Dose-limiting toxicities occurred with 21-day tipifarnib. Complete remissions were achieved in 16 of 54 (30%) receiving 14-day tipifarnib versus 5 of 30 (17%) receiving 21-day tipifarnib. Complete remissions occurred in 50% of two 14-day tipifarnib cohorts: 3A (tipifarnib 600, etoposide 100) and 8A (tipifarnib 400, etoposide 200). In vivo, tipifarnib plus etoposide decreased ribosomal S6 protein phosphorylation and increased histone H2AX phosphorylation and apoptosis. Tipifarnib plus etoposide is a promising orally bioavailable regimen that warrants further evaluation in elderly adults who are not candidates for conventional induction chemotherapy. These clinical studies are registered at www.clinicaltrials.gov as #NCT00112853.

scholarly journals The activity and kinetic properties of mevalonate kinase in superovulated rat ovary

1970 ◽  
Vol 120 (1) ◽  
pp. 145-150 ◽  
Author(s):  
A. P. F. Flint
Keyword(s):  
Luteinizing Hormone ◽  
Total Activity ◽  
Partial Purification ◽  
Kinetic Properties ◽  
Mevalonate Kinase ◽  
Farnesyl Pyrophosphate ◽  
Rat Ovary ◽  
High Concentrations ◽  
Geranyl Pyrophosphate

Methods are described for the assay and partial purification of mevalonate kinase from superovulated rat ovary. The total activity of mevalonate kinase in superovulated rat ovary was 1.6±0.14units/g wet wt.; it was unchanged by the administration of luteinizing hormone in vivo. The Km of a partially purified preparation of mevalonate kinase for dl-Mevalonate was 3.6±0.5μm; its Km for MgATP2− was 120±7.7μm. The enzyme was inhibited by geranyl pyrophosphate and farnesyl pyrophosphate, but not by isopentenyl pyrophosphate or 3,3′-dimethylallyl pyrophosphate. dl-mevalonate 5-phosphate inhibited at high concentrations. With both geranyl pyrophosphate and farnesyl pyrophosphate the inhibition was competitive with respect to MgATP2−. The Ki for inhibition by geranyl pyrophosphate was 1.3±0.2μm; the Ki for inhibition by farnesyl pyrophosphate was 1.0±0.3μm. These findings are discussed with reference to the control by luteinizing hormone of steroidogenesis from acetate.

scholarly journals In Vivo Activities of Farnesyl Pyrophosphate Synthase Inhibitors against Leishmania donovani and Toxoplasma gondii

2002 ◽  
Vol 46 (3) ◽  
pp. 929-931 ◽  
Author(s):  
Vanessa Yardley ◽  
Anis A. Khan ◽  
Michael B. Martin ◽  
Teri R. Slifer ◽  
Fausto G. Araujo ◽  
...  
Keyword(s):  
Body Weight ◽  
Toxoplasma Gondii ◽  
Intravenous Administration ◽  
Leishmania Donovani ◽  
Effective Dosage ◽  
Farnesyl Pyrophosphate ◽  
Farnesyl Pyrophosphate Synthase

ABSTRACT The in vivo activities of three bisphosphonates were determined against Leishmania donovani and Toxoplasma gondii. Alendronate was essentially inactive against both parasites. Pamidronate was active against L. donovani by intravenous administration. Risedronate had a 50% effective dosage of five 2.6-mg/kg of body weight intraperitoneal doses against L. donovani-infected mice but was less effective against T. gondii-infected mice.

In Vitro and In Vivo Effects of a Farnesyltransferase Inhibitor onNf1-Deficient Hematopoietic Cells

Blood ◽  
1999 ◽  
Vol 94 (7) ◽  
pp. 2469-2476 ◽  
Author(s):  
Nidal Mahgoub ◽  
Brigit R. Taylor ◽  
Mary Gratiot ◽  
Nancy E. Kohl ◽  
Jackson B. Gibbs ◽  
...  
Keyword(s):  
Map Kinase ◽  
Bone Marrow Cells ◽  
Hematopoietic Cells ◽  
Cancer Therapeutics ◽  
Detectable Effect ◽  
Ras Signaling ◽  
Farnesyltransferase Inhibitor ◽  
Gm Csf

Oncogenic RAS alleles encode proteins that accumulate in the guanosine triphosphate (GTP)-bound state. Because post-translational processing of Ras by farnesyltransferase is essential for biologic function, inhibitors of this enzyme have been developed as rational cancer therapeutics. We have investigated farnesyltransferase inhibitor (FTI) L-744,832 in an in vivo murine model of myeloid leukemia that is associated with inactivation of the Nf1 tumor suppressor gene.Nf1 encodes a GTPase activating protein for Ras, andNf1-deficient (Nf1−/−) hematopoietic cells show hyperactive Ras signaling through the mitogen-activated protein (MAP) kinase pathway. L-744,832 inhibited H-Ras prenylation in cell lines and in primary hematopoietic cells and abrogated the in vitro growth of myeloid progenitor colonies in response to granulocyte-macrophage colony-stimulating factor (GM-CSF). This FTI also partially blocked GM-CSF–induced MAP kinase activation, but did not reduce constitutively elevated levels of MAP kinase activity in primaryNf1−/− cells. Injection of a single dose of 40 or 80 mg/kg of L-744,832 increased the amount of unprocessed H-Ras in bone marrow cells, but had no detectable effect on N-Ras. Adoptive transfer ofNf1−/− hematopoietic cells into irradiated mice induces a myeloproliferative disorder that did not respond to L-744,832 treatment. We speculate that the lack of efficacy in this model is due to the resistance of N-Ras and K-Ras processing to inhibition by this FTI.

In vivo apoptosis detection with radioiodinated Annexin V in LoVo tumour-bearing mice following Tipifarnib (Zarnestra, R115777) farnesyltransferase inhibitor therapy

2005 ◽  
Vol 32 (3) ◽  
pp. 233-239 ◽  
Author(s):  
Bart Cornelissen ◽  
Christophe Lahorte ◽  
Veerle Kersemans ◽  
Gabriela Capriotti ◽  
Elena Bonanno ◽  
...  
Keyword(s):  
Annexin V ◽  
Inhibitor Therapy ◽  
Farnesyltransferase Inhibitor ◽  
Tumour Bearing ◽  
Apoptosis Detection
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