| 名稱 | AG14361 |
| 描述 | AG14361 is an effective inhibitor of PARP1 (Ki<5 nM). |
| 細(xì)胞實驗 | LoVo and SW620 colorectal cancer cells and A549 non–small-cell lung carcinoma cells are maintained in RPMI-1640 medium containing 10% fetal calf serum. Cell growth inhibition is estimated in exponentially growing LoVo, A549, and SW620 cells in 96-well plates. Cells are exposed to AG14361 (0–20 μM) alone or in the presence of 400 μM temozolomide. After 5 days of culture, these cells are fixed with 10% trichloroacetic acid and stained with sulforhodamine B. The concentration of temozolomide, topotecan, and AG14361 alone or in combination that inhibits growth by 50% (GI50) is calculated from computer-generated curves. Recovery from potentially lethal damage is measured in confluent LoVo cell cultures arrested in G1 phase to mimic the radiation-resistant quiescent cell population in tumors. Such cells are exposed to 8 Gy of γ-irradiation and then harvested and plated for colony formation assay immediately or maintained as growth-arrested confluent cultures for a 4-hour or 24-hour recovery period before harvesting and plating for the colony formation assay. Where indicated, 0.4 μM AG14361 is added 30 minutes before irradiation and is present in the recovery incubation. (Only for Reference) |
| 激酶實驗 | PARP-1 Activity Assays: The activity of full-length recombinant human PARP-1 is measured in a reaction mixture containing 20 nM PARP-1, 500 μM NAD+ plus [32P]NAD+ (0.1–0.3 μCi per reaction mixture), and activated calf thymus DNA (10 μg/mL) at 25oC; the reaction is terminated after 4 minutes by adding ice-cold 10% (wt/vol) trichloroacetic acid. The reaction product [32P]ADP-ribose incorporated into acid-insoluble material is deposited onto Whatman GF/C glass fiber filters with a Bio-Dot microfiltration apparatus and quantified with a PhosphorImager. Inhibition of PARP-1 activity by AG14361 at 0–600 nM is measured, and the Ki for AG14361 is calculated by nonlinear regression analysis. |
| 體外活性 | 在無毒劑量內(nèi),AG14361可提高伊立替康、x射線照射及替莫唑胺誘導(dǎo)的LoVo移植瘤生長延遲,提高2到3倍.在SW620移植瘤中, AG14361（10 mg/kg,i.p.）處理4小時以上可抑制75%以上的PARP-1活性.在攜帶LoVo移植瘤的小鼠體內(nèi),先以AG14361處理再進(jìn)行統(tǒng)計學(xué)輻射,看顯著提高對放射療法的敏感性.在移植瘤中,AG14361可顯著提高血流,故可能促進(jìn)藥物輸送到移植瘤. |
| 體內(nèi)活性 | AG14361（0.4 μM）對癌細(xì)胞基因表達(dá)或生長無影響,但可提高替莫唑胺和拓?fù)涮婵悼乖鲋郴钚?且抑制LoVo細(xì)胞從潛在的致命γ輻射損傷中恢復(fù),抑制達(dá)73％。AG14361（0.4 μM）對基因表達(dá)無大幅影響。在A549細(xì)胞中, AG14361（0.4 μM）在17小時后對6800種基因表達(dá)均無影響。因此,盡管0.4 μM AG14361抑制85%以上細(xì)胞PARP-1 活性,但其不影響基因表達(dá)和細(xì)胞增殖。AG14361在更高濃度會影響基因表達(dá),但是這種影響與PARP-1受抑制無關(guān),因為在PARP-/-和PARP-1+/+細(xì)胞中,細(xì)胞增殖一樣受影響。AG14361可增加喜樹堿誘導(dǎo)DNA單鏈斷裂的持久性。AG14361的效果比苯甲酰胺至少高1×103倍。AG14361對透性化SW620細(xì)胞（IC50：29 nM）和完整SW620細(xì)胞（IC50：14 nM）有抑制作用。AG14361對細(xì)胞生長的抑制作用與PARP-1抑制無關(guān),因為在比GI50濃度低很多時(≤1 μM),對PARP-1也有最大抑制效果。 |
| 存儲條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year
Shipping with blue ice/Shipping at ambient temperature. |
| 溶解度 | DMSO : 15 mg/mL (46.82 mM), Sonication is recommended.
10% DMSO+40% PEG300+5% Tween 80+45% Saline : 1 mg/mL (3.12 mM), Sonication is recommended.
H2O : < 1 mg/mL (insoluble or slightly soluble)
Ethanol : < 1 mg/mL (insoluble or slightly soluble)
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| 關(guān)鍵字 | poly ADP ribose polymerase | PARP1 | PARP | Inhibitor | inhibit | AG14361 |
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