Preclinical studies of celastrol and acetyl lsogambogic acid in melanoma
Preclinical studies of celastrol and acetyl lsogambogic acid in melanoma
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DOI：
10.1158/1078-0432.ccr-07-1536
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发表时间：
2007-11-15
影响因子：
11.5
通讯作者：
Ronai, Zeev A.
中科院分区：
文献类型：
--
作者：
Abbas, Sabiha;Bhoumik, Anindita;Ronai, Zeev A.
目的：通过模拟激活转录因子 2 (ATF2) 驱动的肽的活性的化合物，使黑色素瘤对细胞凋亡敏感，并抑制其生长和转移潜力。实验设计：筛选由 3,280 种化合物组成的小分子化学库，以鉴定可引发 ATF2 肽特性的化合物，包括 (a) 黑色素瘤细胞对细胞凋亡的敏感性， (b) 抑制 ATF2 转录活性，(c) 激活 c-Jun NH(2)-末端激酶 (JNK) 和 c-Jun 转录活性，以及 (d) 抑制小鼠模型中的黑色素瘤生长和转移。结果：雷公藤红醇 (CSL) 和乙酰异藤黄酸这两种化合物可以在低微摩尔范围内有效、快速地 引起黑色素瘤细胞死亡。这两种化合物都能有效抑制 ATF2 转录活性、激活 JNK 并增加 c-Jun 转录活性。与 ATF2 pepticle 类似，这两种化合物都需要 JNK 活性才能抑制黑色素瘤细胞活力。 CSL 衍生物被鉴定为小鼠和人类黑色素瘤细胞死亡的有效诱导剂。 CSL 及其衍生物 (CA19) 还可以有效抑制人和小鼠黑色素瘤肿瘤的生长，并减少同基因和异种移植小鼠模型中肺转移的数量。结论：这些研究首次表明 CSL 和乙酰异藤黄酸对黑色素瘤的作用。这些化合物引发的活性类似于已充分表征的 ATF2 pepticle，因此可能为治疗这种肿瘤类型提供新方法。
Purpose: Sensitize melanomas to apoptosis and inhibit their growth and metastatic potential by compounds that mimic the activities of activating transcription factor 2 (ATF2) -driven pepticles.Experimental Design: Small-molecule chemical library consisting of 3,280 compounds was screened to identify compounds that elicit properties identified for ATF2 peptide, including (a) sensitization of melanoma cells to apoptosis, (b) inhibition of ATF2 transcriptional activity, (c) activation of c-Jun NH(2)-terminal kinase (JNK) and c-Jun transcriptional activity, and (d) inhibition of melanoma growth and metastasis in mouse models.Results: Two compounds, celastrol (CSL) and acetyl isogambogic acid, could, within a low micromolar range, efficiently iciently elicit cell death in melanoma cells. Both compounds efficiently inhibit ATF2 transcriptional activities, activate JNK, and increase c-Jun transcriptional activities. Similar to the ATF2 pepticle, both compounds require JNK activity for their ability to inhibit melanoma cell viability. Derivatives of CSL were identified as potent inducers of cell death in mouse and human melanomas. CSL and a derivative (CA19) could also efficiently inhibit growth of human and mouse melanoma tumors and reduce the number of lung metastases in syngeneic and xenograft mouse models.Conclusions: These studies show for the first time the effect of CSL and acetyl isogambogic acid on melanoma. These compounds elicit activities that resemble the well-characterized ATF2 pepticle and may therefore offer new approaches for the treatment of this tumor type.