Disease relevance of NSC330507

• Administration of 17-AAG markedly ameliorated motor impairments in the SBMA transgenic mouse model without detectable toxicity, by reducing amounts of monomeric and aggregated mutant AR [1].
• 17-AAG would thus provide a new therapeutic approach to SBMA and probably to other related neurodegenerative diseases [1].
• In addition, neoplastic mast cells isolated from patients with mastocytosis, incubated with 17-AAG ex vivo, are selectively sensitive to the drug compared to the mononuclear fraction [2].
• Here, we demonstrate that treatment of the human acute myeloid leukemia HL-60 cells with 17-AAG attenuates the intracellular levels of a number of Hsp-90 client proteins, including Akt, c-Raf-1, and c-Src [3].
• These data provide compelling evidence that 17-AAG may be effective in the treatment of c-kit-related diseases including mastocytosis, GISTs, mast cell leukemia, subtypes of acute myelogenous leukemia, and testicular cancer [2].

High impact information on NSC330507

• We examined the therapeutic effects of 17-allylamino-17-demethoxygeldanamycin (17-AAG), a potent Hsp90 inhibitor, and its ability to degrade polyglutamine-expanded mutant AR [1].
• 17-AAG also mildly induced Hsp70 and Hsp40 [1].
• The first-in-class HSP90 inhibitor in clinical trials is the geldanamycin analog, 17-allylamino, 17-demethoxygeldanamycin (17-AAG) [4].
• The toxicity of 17-AAG has been mild [4].
• Furthermore, the metabolic profile of IPI-504 was compared with that of 17-AAG, a geldanamycin analog currently in clinical trials [5].

Chemical compound and disease context of NSC330507

• PURPOSE: To determine the clinical toxicities of 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) given as a 1-hour infusion daily for 5 days every 3 weeks [6].
• Interest in the use of 17-AAG in combination with cytotoxic drugs led us to study both GA and 17-AAG with cisplatin (DDP) in the human colon adenocarcinoma cell lines HT29 and HCT116 [7].
• Treatment with 17-AAG or PD180970 also induced apoptosis of CD34+ leukemic cells from three patients with chronic myeloid leukemia in blast crisis who had progressive leukemia while receiving Gleevec therapy [8].
• 17-allylamino-17-demethoxygeldanamycin (17-AAG), a less toxic and less potent derivative of GA, inhibited the clonogenicity of glioma cells with IC(50) values of 13 nM in C6 cells and 35 nM in T98G cells [9].
• We investigated the effects of oxaliplatin and 17-allylamino-17-demethoxygeldanamycin (17-AAG) in a panel of four colon adenocarcinoma cell lines [10].

Biological context of NSC330507

• Cotreatment with HA14-1, a nonpeptidic ligand that can bind and inhibit the antiapoptotic activity of Bcl-2, significantly overcame the resistance to 17-AAG-induced apoptosis in HL-60/Bcl-2 cells [3].
• 17-AAG promotes cell death of both HMC mast cell lines [2].
• Treatment with 17-AAG induced cell cycle G(1) phase accumulation and apoptosis of MV4-11 cells [11].
• 17-AAG/SAHA-treated cells also displayed down-regulation of the antiapoptotic protein Mcl-1 and evidence of Bcl-2 cleavage [12].
• 17-AAG and Taxol could be administered together at their maximally tolerated doses to tumor-bearing mice [13].

Anatomical context of NSC330507

• Treatment with 17-AAG of the mast cell line HMC-1.2, harboring the Asp816Val and Val560Gly KIT mutations, and the cell line HMC-1.1, harboring a single Val560Gly mutation, causes both the level and activity of KIT and downstream signaling molecules AKT and STAT3 to be down-regulated following drug exposure [2].
• 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is effective in down-regulating mutated, constitutively activated KIT protein in human mast cells [2].
• Cotreatment with LBH589 and 17-AAG exerted synergistic apoptosis of MV4-11 and K562 cells [14].
• Treatment with 17-AAG triggered the B-cell lymphoma-2 (Bcl-2)-associated X protein (Bax) conformational change associated with apoptosis, while Bax-deficient cells were resistant to 17-AAG-induced apoptosis [3].
• Simultaneous exposure (30 hours) of U937 monocytic leukemia cells to minimally toxic concentrations of 17-AAG (eg, 400 nM) and UCN-01 (eg, 75 nM) triggered a pronounced increase in mitochondrial injury (ie, loss of mitochondrial membrane potential [Deltapsim]; cytosolic release of cytochrome c), caspase activation, and apoptosis [15].

Associations of NSC330507 with other chemical compounds

• Treatment with Hsp90 inhibitors such as 17-AAG and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) induced ZAP-70 degradation and apoptosis in CLL cells but not in T cells, and also impaired B-cell receptor signaling in leukemia cells [16].
• Conversely, treatment with 100 to 300 nM 17-AAG for 24 hours caused Chk1 depletion that was accompanied by diminished cytarabine-induced S-phase accumulation, decreased Cdc25A degradation, and enhanced cytotoxicity as measured by inhibition of colony formation and induction of apoptosis [17].
• Cells expressing high levels of Nm23-H1 exhibited increased KSR1 degradation in the presence of either cycloheximide or an Hsp90-directed drug currently in clinical trial, 17-allylamino-17-demethoxygeldanamycin (17-AAG) [18].
• 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG) is an ansamycin antibiotic that binds to a conserved pocket in Hsp90 and induces the degradation of proteins that require this chaperone for conformational maturation [19].
• In addition to 17-AAG, other Hsp90 inhibitors, such as radicicol and herbimycin A, also enhanced osteoclastogenesis [20].

Gene context of NSC330507

• Interactions between the protein kinase C (PKC) and Chk1 inhibitor UCN-01 and the heat shock protein 90 (Hsp90) antagonist 17-AAG have been examined in human leukemia cells in relation to effects on signal transduction pathways and apoptosis [15].
• Together, these findings indicate that the Hsp90 antagonist 17-AAG potentiates UCN-01 cytotoxicity in a variety of human leukemia cell types and suggest that interference with both the Akt and Raf-1/MEK/MAP kinase cytoprotective signaling pathways contribute to this phenomenon [15].
• Synergistic antileukemic interactions between 17-AAG and UCN-01 involve interruption of RAF/MEK- and AKT-related pathways [15].
• In addition, inducible expression of both a constitutively active MEK1/2 or myristolated Akt construct, which overcame inhibition of ERK and Akt activation, respectively, significantly attenuated 17-AAG/UCN-01-mediated lethality [15].
• High-performance liquid chromatography (HPLC) analysis of the metabolism of 17-AAG by recombinant human NQO1 revealed the formation of a more polar metabolite 17-AAGH2 [21].

Analytical, diagnostic and therapeutic context of NSC330507

• Phase II clinical trials in various cancers have been initiated as well as Phase I trials of combined therapy with 17-AAG [4].
• In addition, 17-AAG significantly inhibited the growth of a glioma xenograft in nude mice [9].
• Therefore, tumors that are dependent on these kinases may be especially sensitive to 17-AAG either alone or in combination with chemotherapy [22].
• CONCLUSION: It has been possible to demonstrate that 17-AAG exhibits a tolerable toxicity profile with therapeutic plasma concentrations and target inhibition for 24 hours after treatment and some indications of clinical activity at the dose level 450 mg/m(2)/week [23].
• HPLC analysis of 17-AAG metabolism using cell sonicates and intact cells showed that 17-AAGH2 was formed by MDA468/NQ16 cells, and formation of 17-AAGH2 could be inhibited by ES936 [21].

References