Disease relevance of NSC622141

• The combination of manumycin and paclitaxel is also effective in vivo with no significant toxicity observed [1].
• To identify the molecular mechanisms of manumycin A action, cultured human HepG2 hepatoma cells were transiently transfected with various IKKalpha and IKKbeta constructs, and a striking difference in manumycin A sensitivity was observed [2].
• Epidermal growth factor (EGF)-induced activation of the enzyme in the same cell system was more rapid (peaking at 1 min), sustainable for at least 60 min, and could be suppressed by prior treatment with either pertussis toxin or a noncompetitive inhibitor of Ras acceptor protein, manumycin A [3].
• We evaluated the FTI manumycin A (manumycin) in two myeloid leukemia cell lines (U937 and HL-60) [4].
• Apoptosis of medulloblastoma cells in vitro follows inhibition of farnesylation using manumycin A [5].

High impact information on NSC622141

• Moreover, manumycin, a specific inhibitor of FTase, was effective in inhibiting mitosis and growth in these cells [6].
• Using synchronized BY-2 cells, manumycin completely blocked mitosis when added at the early S phase but not when added at the G2 phase [6].
• We show here that two farnesyltransferase inhibitors, manumycin and gliotoxin, suppress the Multivulva phenotype resulting from an activated let-60 ras mutation, but not the Multivulva phenotype resulting from mutations in the lin-1 gene or the lin-15 gene, which act downstream and upstream of let-60 ras, respectively, in the signaling pathway [7].
• Similarly, treatment of cells with a Ras farnesyltransferase inhibitor, manumycin A, strongly inhibited the HA-dependent MMP-2 secretion [8].
• Similarly, a Ras farnesyltransferase inhibitor, manumycin A, and a MEK1 inhibitor, U0126, suppressed MMP secretion in a dose-dependent manner, whereas a PI3 kinase inhibitor, wortmannin, could not [9].

Chemical compound and disease context of NSC622141

• Enhancement of manumycin A-induced apoptosis by methoxyamine in myeloid leukemia cells [4].
• Ang II-stimulated Raf-1 activity was unaffected by down-regulation of protein kinase C and intracellular Ca2+ chelation (using BAPTA) but was partially inhibited by pertussis toxin, and was abolished by manumycin A [10].
• We have tested the effect of the FPTase inhibitors manumycin, an analogue of farnesyl diphosphate, and KT7595, a gliotoxin derivative, on Ras farnesylation, DNA synthesis and the anchorage-dependent and -independent growth of human colon carcinoma (LoVo), hepatoma (Mahlavu and PLC/PRF/5) and gastric carcinoma (KATO III) [11].
• Nisamycin, a new manumycin group antibiotic, was isolated from the culture broth of Streptomyces sp. K106 [12].
• Chromic acid oxidation of manumycin (1), an antibiotic produced by Streptomyces parvulus (strain Tü 64), led to the isolation of 2-(2-methyl-4-oxo-2-pentenoylamino)-5,6-epoxy-1,4-benzoquinone (3) and (-)-(R)-2-methylhexanoic acid (4) [13].

Biological context of NSC622141

• Manumycin plus paclitaxel has enhanced cytotoxic effects and increased apoptotic cell death in ATC cells in vitro compared with either drug by itself [1].
• EBS contribution to hormone induction was prevented by manumycin A, an inhibitor of Ras farnesylation [14].
• Raf-1 phosphorylation at Ser338 by BK was inhibited by manumycin A and GW 5074 [15].
• Furthermore, cells expressing wild-type IKKbeta and IKKbeta mutated in the activation loop at Cys-179 exhibited covalent homotypic dimerization of IKKbeta in response to manumycin A, whereas substitution of Cys-662 and -716 conferred protection against dimer formation [2].
• However, the mechanism of the manumycin-induced apoptosis is not fully understood [16].

Anatomical context of NSC622141

• In combination, manumycin enhanced the effect of paclitaxel in all six of the cell lines [1].
• Manumycin enhances the cytotoxic effect of paclitaxel on anaplastic thyroid carcinoma cells [1].
• Our laboratory has investigated the anticancer effects of combined manumycin (a farnesyltransferase inhibitor) and paclitaxel (a microtubule inhibitor) against anaplastic thyroid carcinoma (ATC) [17].
• We also found that manumycin induced translocation of Bcl-2-associated X protein (Bax), another possible mediator of cytochrome c release, from the cytosol to the mitochondria [16].
• Histologically, the manumycin- and gliotoxin-treated corneas showed minimum edema and good epithelialization [18].

Associations of NSC622141 with other chemical compounds

• BK-induced ERK activation was inhibited by HOE140, manumycin A, GW 5074, and PD 098059 [15].
• Similarly, treatment of v-Src-transfomed cells with a Ras farnesyltransferase inhibitor, manumycin A, restored GJIC, whereas tyrosine phosphorylation of Cx43 remained unchanged [19].
• A Ras inhibitor (manumycin A), a PI3K inhibitor (wortmannin), an Akt inhibitor (1l-6-Hydroxymethyl-chiro-inositol2-[(R)-2-O-methyl-3-O-octadecylcarbonate]), and an NF-kappaB inhibitor [pyrrolidine dithiocarbamate (PDTC)] all reduced YC-1-induced COX-2 expression [20].
• Bongkrekic acid and cyclosporin A, which are known inhibitors of the voltage-dependent anion channel, failed to inhibit cytochrome c release induced by manumycin or manumycin plus paclitaxel, suggesting that mitochondrial permeability transition pores were not involved [16].
• In a cell-free reconstitution assay, DNA fragmentation occurred after incubating nuclei purified from untreated KAT-4 cells with deoxy-ATP, exogenous cytochrome c and S-100 extracts from control KAT-4 cells, and also after incubation of purified KAT-4 nuclei with S-100 extracts from KAT-4 cells treated with manumycin-plus-paclitaxel [21].

Gene context of NSC622141

• Binding of manumycin A inhibits IkappaB kinase beta activity [2].
• Other effective inhibitors of ODC induction proved to be genistein, manumycin A, herbimycin A, LY294002, wortmannin and KT5823, suggesting the involvement of other key proteins of signal-transduction pathways, i.e. Ras, Src, phosphatidylinositol 3-kinase and cGMP-dependent protein kinase, which may have a positive impact on MAPK [22].
• Effects of the farnesyltransferase inhibitor UCF-1C/manumycin on growth and p21-ras post-translational processing in NIH3T3 cells [23].
• Immunoblot analysis of isolated cell membranes and total cellular lysates of COLO320-DM cells demonstrated that manumycin dose-dependently reduced p21 ras farnesylation with a 50% inhibitory concentration (IC50) of 2.51 +/- 0.11 microM and 2.68 +/- 0.20 microM, respectively, while the geranylgeranylation of p21 rhoA and p21rap1 was not affected [24].
• The present findings indicate that the inhibition of p21ras processing and signal transduction by manumycin is associated with marked inhibition of cell proliferation and apoptosis in colon cancer cells and the effect on cell growth does not require the presence of a mutated ras gene for maximal expression of chemotherapeutic activity [24].

Analytical, diagnostic and therapeutic context of NSC622141

• The in vivo effect and toxicity of combined manumycin and paclitaxel treatments were evaluated in a nude mouse xenograft model using ARO and KAT-4 cells [1].
• In this study, we discovered that mitochondrial ultrastructure condensation occurred after treatment with manumycin or manumycin plus paclitaxel [16].
• Western blotting experiments demonstrated that this effect was related to inhibition of the post-translational Ras processing.Further analysis showed that manumycin-induced apoptosis involved caspase-3 [25].
• Tumor-bearing mice received intraperitoneal injection of 1 or 5mg/kg manumycin daily for 5 days, or 2 mg/kg manumycin daily for 2 weeks [26].
• The expression of HSP70 increased with the length of exposure to, and the dose of manumycin as demonstrated by ELISA [27].

References