Novel small molecule XPO1/CRM1 inhibitors induce nuclear accumulation of TP53, phosphorylated MAPK and apoptosis in human melanoma cells.
Novel small molecule XPO1/CRM1 inhibitors induce nuclear accumulation of TP53, phosphorylated MAPK and apoptosis in human melanoma cells.
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新型小分子 XPO1/CRM1 抑制剂可诱导人黑色素瘤细胞中 TP53 的核积聚、磷酸化 MAPK 和细胞凋亡。
DOI：
10.1371/journal.pone.0102983
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Lesinski GB
中科院分区：
文献类型：
--
作者：
Yang J;Bill MA;Young GS;La Perle K;Landesman Y;Shacham S;Kauffman M;Senapedis W;Kashyap T;Saint-Martin JR;Kendra K;Lesinski GB
XPO1/CRM1 is a key nuclear exporter protein that mediates translocation of numerous cellular regulatory proteins. We investigated whether XPO1 is a potential therapeutic target in melanoma using novel selective inhibitors of nuclear export (SINE). In vitro effects of SINE on cell growth and apoptosis were measured by MTS assay and flow cytometry [Annexin V/propidium iodide (PI)], respectively in human metastatic melanoma cell lines. Immunoblot analysis was used to measure nuclear localization of key cellular proteins. The in vivo activity of oral SINE was evaluated in NOD/SCID mice bearing A375 or CHL-1 human melanoma xenografts. SINE compounds induced cytostatic and pro-apoptotic effects in both BRAF wild type and mutant (V600E) cell lines at nanomolar concentrations. The cytostatic and pro-apoptotic effects of XPO1 inhibition were associated with nuclear accumulation of TP53, and CDKN1A induction in the A375 cell line with wild type TP53, while pMAPK accumulated in the nucleus regardless of TP53 status. The orally bioavailable KPT-276 and KPT-330 compounds significantly inhibited growth of A375 (p<0.0001) and CHL-1 (p = 0.0087) human melanoma cell lines in vivo at well tolerated doses. Inhibition of XPO1 using SINE represents a potential therapeutic approach for melanoma across cells with diverse molecular phenotypes by promoting growth inhibition and apoptosis.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
3.8
作者：
Chen, Lixia;Shao, Changxia;Gao, Weimin
通讯作者：
Gao, Weimin
影响因子：
8.8
作者：
Newlands, ES;Rustin, GJS;Brampton, MH
通讯作者：
Brampton, MH
DOI：
10.1083/jcb.148.5.849
发表时间：
2000-03-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Adachi M;Fukuda M;Nishida E
通讯作者：
Nishida E
DOI：
10.1073/pnas.97.15.8501
发表时间：
2000-07-18
影响因子：
11.1
作者：
Hietanen, S;Lain, S;Lane, DP
通讯作者：
Lane, DP