Topically applied Hsp90 inhibitor 17AAG inhibits UVR-induced cutaneous squamous cell carcinomas.
Topically applied Hsp90 inhibitor 17AAG inhibits UVR-induced cutaneous squamous cell carcinomas.
复制标题
DOI：
10.1038/jid.2014.460
复制
发表时间：
2015-04
影响因子：
6.5
通讯作者：
Verma, Ajit K.
中科院分区：
文献类型：
--
作者：
Singh, Anupama;Singh, Ashok;Sand, Jordan M.;Bauer, Samuel J.;Bin Hafeez, Bilal;Meske, Louise;Verma, Ajit K.
我们在这里介绍热休克蛋白90（Hsp 90）抑制剂17-（烯丙基氨基）-17-去甲氧基格尔德霉素（17 AAG），当局部应用于小鼠皮肤，抑制紫外线辐射（UVR）诱导的皮肤鳞状细胞癌（SCC）的发展。在这些实验中，将17 AAG（500 nmol）的DMSO：丙酮（1：40 v/v）溶液局部施用至小鼠皮肤，同时进行每次UVR暴露（1.8 kJ/m2）。紫外线辐射源是柯达过滤的FS-40日光灯（约60%的UVB和40%的UVA）。在三个独立的小鼠品系（SKH-1无毛小鼠、野生型FVB和PKCε过表达转基因FVB小鼠）的独立实验中，17 AAG处理增加了UVR诱导的SCC的潜伏期，并降低了UVR诱导的SCC的发生率和多样性。局部17 AAG单独或与UVR治疗结合既不引起皮肤毒性，也不引起全身毒性。17-AAG抑制SCC诱导的同时，UVR诱导的以下方面的表达减少：1）增生; 2）Hsp 90 β-PKCε相互作用; 3）Hsp 90 β、Stat 3、pStat 3Ser 727、pStat 3 Tyr 705、pAktSer 473和基质金属蛋白酶（MMPs）的表达水平。本研究结果表明，局部热休克蛋白90抑制剂17 AAG可有效预防紫外线诱导的表皮增生和鳞状细胞癌。从本文提供的临床前数据可以得出结论，局部17 AAG可用于预防UVR暴露或器官移植人群中发生的UVR诱导的炎症和皮肤SCC。
We present here that Heat shock protein 90 (Hsp90) inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17AAG), when topically applied to mouse skin, inhibits ultraviolet radiation (UVR)-induced development of cutaneous squamous cell carcinoma (SCC). In these experiments, DMSO:acetone (1:40 v/v) solution of 17AAG (500nmol) was applied topically to mouse skin in conjunction with each UVR exposure (1.8 kJ/m2). The UVR source was Kodacel-filtered FS-40 sun lamps (approximately 60% UVB and 40% UVA). In independent experiments with three separate mouse lines (SKH-1 hairless mice, wild-type FVB, and PKCε overexpressing transgenic FVB mice), 17AAG treatment increased the latency and decreased both the incidence and multiplicity of UVR-induced SCC. Topical 17AAG alone or in conjunction with UVR treatments elicited neither skin nor systemic toxicity. 17AAG-caused inhibition of SCC induction was accompanied by decrease in UVR-induced: 1) hyperplasia, 2) Hsp90β-PKCε interaction, 3) expression levels of Hsp90β, Stat3, pStat3Ser727, pStat3Tyr705, pAktSer473 and matrix metalloproteinase (MMPs). The results presented here indicate that topical Hsp90 inhibitor 17AAG is effective in prevention of UVR-induced epidermal hyperplasia and SCC. One may conclude from the preclinical data presented here that topical 17AAG may be useful for prevention of UVR-induced inflammation and cutaneous SCC either developed in UVR exposed or organ transplant population.
登录
查看更多内容
影响因子：
3.8
作者：
Gartner, Elaina M.;Silverman, Paula;Simon, Michael;Flaherty, Lawrence;Abrams, Judith;Ivy, Percy;LoRusso, Patricia M.
通讯作者：
LoRusso, Patricia M.
影响因子：
11.2
作者：
Aziz, Moammir H.;Manoharan, Herbert T.;Verma, Ajit K.
通讯作者：
Verma, Ajit K.
DOI：
10.1038/jidsymp.2009.11
发表时间：
2009-08-01
影响因子：
--
作者：
Imokawa, Genji
通讯作者：
Imokawa, Genji
影响因子：
3.4
作者：
Hubbard, Joleen;Erlichman, Charles;Toft, David O.;Qin, Rui;Stensgard, Bridget A.;Felten, Sara;Ten Eyck, Cynthia;Batzel, Gretchen;Ivy, S. Percy;Haluska, Paul
通讯作者：
Haluska, Paul
影响因子：
6.5
作者：
Berton, TR;Mitchell, DL;Locniskar, MF
通讯作者：
Locniskar, MF