Thailandepsins are new small molecule class I HDAC inhibitors with potent cytotoxic activity in ovarian cancer cells: a preclinical study of epigenetic ovarian cancer therapy.
Thailandepsins are new small molecule class I HDAC inhibitors with potent cytotoxic activity in ovarian cancer cells: a preclinical study of epigenetic ovarian cancer therapy.
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DOI：
10.1186/1757-2215-5-12
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发表时间：
2012-04-24
影响因子：
4
通讯作者：
Khabele D
中科院分区：
文献类型：
--
作者：
Wilson AJ;Cheng YQ;Khabele D
新的治疗策略正在出现，以靶向卵巢癌中的DNA损伤反应途径。我们的小组先前已经表明，I类偏向HDAC抑制剂罗米地辛（FK 228）诱导DNA损伤反应，并在卵巢癌细胞中具有强效细胞毒性作用。在这里，我们研究了新发现的HDAC抑制剂，泰国地辛A（TDP-A）和泰国地辛B（TDP-B），以确定对卵巢癌细胞的细胞活力，凋亡和DNA损伤反应的影响。FK 228、TDP-A和TDP-B在5个卵巢癌细胞系中进行了测试。通过3-（4，5-二甲基噻唑-2-基）-2，5-二苯基溴化四唑（MTT）测定来测量细胞活力。免疫荧光测定用于评估活化的半胱天冬酶3。Western blot检测PARP裂解、pH 2AX、P-糖蛋白和微管蛋白乙酰化的蛋白表达。在研究的五种卵巢癌细胞系中，用TDP治疗在纳摩尔浓度下降低了四种细胞的存活率。与FK 228相似，两种TDP化合物对NCI/ADR-RES卵巢癌细胞的影响最小。在对TDP敏感的四种细胞系中，TDP-B对细胞活力的抑制作用始终大于TDP-A。与TDP-A相比，TDP-B在促进细胞凋亡和诱导pH 2AX（DNA损伤反应的标志）方面也具有相对更大的作用。TDP-B的这些抗肿瘤作用与等浓度的FK 228诱导的抗肿瘤作用具有相似的幅度。与FK 228相似，纳摩尔浓度的TDP对微管蛋白乙酰化（II类HDAC 6抑制的标志）几乎没有影响。新的小分子HDAC抑制剂TDP-A和TDP-B是FK 228类似物，在纳摩尔药物浓度下抑制细胞活力并诱导细胞凋亡。TDP-B与FK 228的生物学活性最为相似，其体外细胞毒作用强于TDP-A。我们的研究结果表明FK 228样小分子I类HDAC偏向HDAC抑制剂对卵巢癌具有治疗潜力。
New treatment strategies are emerging to target DNA damage response pathways in ovarian cancer. Our group has previously shown that the class I biased HDAC inhibitor romidepsin (FK228) induces DNA damage response and has potent cytotoxic effects in ovarian cancer cells. Here, we investigated newly discovered HDAC inhibitors, thailandepsin A (TDP-A) and thailandepsin B (TDP-B), to determine the effects on cell viability, apoptosis and DNA damage response in ovarian cancer cells. FK228, TDP-A and TDP-B were tested in five ovarian cancer cell lines. Cellular viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Immunofluorescence assays were used to assess activated caspase 3. Western blots were performed to detect protein expression of PARP cleavage, pH2AX, P-glycoprotein and tubulin acetylation. Treatment with TDPs decreased cell viability at nanonomolar concentrations in four of the five ovarian cancer cell lines studied. Similar to FK228, both TDP compounds exerted minimal effects on NCI/ADR-RES ovarian cancer cells. Across the four cell lines sensitive to the TDPs, TDP-B consistently had a greater inhibitory effect than TDP-A on cell viability. TDP-B also had relatively greater effects on promoting cell apoptosis and induction of pH2AX (a mark of DNA damage response), than TDP-A. These antitumor effects of TDP-B were of similar magnitude to those induced by an equal concentration of FK228. Similar to FK228, the nanomolar concentrations of the TDPs had little effect on tubulin acetylation (a mark of class II HDAC6 inhibition). The new small molecule HDAC inhibitors TDP-A and TDP-B are FK228 analogues that suppress cell viability and induce apoptosis at nanomolar drug concentrations. TDP-B showed the most similarity to the biological activity of FK228 with greater cytotoxic effects than TDP-A in vitro. Our results indicate that FK228-like small molecule class I HDAC-biased HDAC inhibitors have therapeutic potential for ovarian cancer.
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影响因子：
64.8
作者：
Hubbert, C;Guardiola, A;Yao, TP
通讯作者：
Yao, TP
影响因子：
3.8
作者：
Banáth JP;Klokov D;MacPhail SH;Banuelos CA;Olive PL
通讯作者：
Olive PL
影响因子：
45.3
作者：
Piekarz, Richard L.;Frye, Robin;Bates, Susan E.
通讯作者：
Bates, Susan E.
DOI：
10.1124/jpet.105.083956
发表时间：
2005-07-01
影响因子：
3.5
作者：
Xiao, JJ;Huang, Y;Chan, KK
通讯作者：
Chan, KK
影响因子：
3.6
作者：
Wilson, Andrew J.;Holson, Edward;Khabele, Dineo
通讯作者：
Khabele, Dineo