Pina Paulo S S, Jang Yeejin, Emerick Carolina, Scarini João Figueira, Sousa Suzana C O M, Squarize Cristiane H, Castilho Rogerio M
Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Stomatology, School of Dentistry, University of São Paulo, Sao Paulo 05508-270, Brazil.
Int J Mol Sci. 2024 Jan 29;25(3):1646. doi: 10.3390/ijms25031646.
Adenoid cystic carcinoma (ACC) is a rare neoplasm known for its indolent clinical course, risk of perineural invasion, and late onset of distant metastasis. Due to the scarcity of samples and the tumor's rarity, progress in developing effective treatments has been historically limited. To tackle this issue, a high-throughput screening of epigenetic drugs was conducted to identify compounds capable of disrupting the invasive properties of the tumor and its cancer stem cells (CSCs). ACC cells were screened for changes in tumor viability, chromatin decondensation, Snail inhibition along tumor migration, and disruption of cancer stem cells. Seven compounds showed potential clinical interest, and further validation showed that Scriptaid emerged as a promising candidate for treating ACC invasion. Scriptaid demonstrated a favorable cellular toxicity index, effectively inhibited Snail expression, induced hyperacetylation of histone, reduced cell migration, and effectively disrupted tumorspheres. Additionally, LMK235 displayed encouraging results in four out of five validation assays, further highlighting its potential in combating tumor invasion in ACC. By targeting the invasive properties of the tumor and CSCs, Scriptaid and LMK235 hold promise as potential treatments for ACC, with the potential to improve patient outcomes and pave the way for further research in this critical area.
腺样囊性癌（ACC）是一种罕见的肿瘤，以其惰性的临床病程、神经周围侵犯风险和远处转移的迟发性而闻名。由于样本稀缺以及该肿瘤的罕见性，历史上开发有效治疗方法的进展一直有限。为了解决这个问题，进行了高通量表观遗传药物筛选，以鉴定能够破坏肿瘤及其癌症干细胞（CSC）侵袭特性的化合物。对ACC细胞进行了肿瘤活力变化、染色质解聚、沿肿瘤迁移的Snail抑制以及癌症干细胞破坏等方面的筛选。七种化合物显示出潜在的临床应用价值，进一步验证表明，司立通（Scriptaid）成为治疗ACC侵袭的有前景的候选药物。司立通表现出良好的细胞毒性指数，有效抑制Snail表达，诱导组蛋白高度乙酰化，减少细胞迁移，并有效破坏肿瘤球。此外，LMK235在五项验证试验中的四项中显示出令人鼓舞的结果，进一步突出了其在对抗ACC肿瘤侵袭方面的潜力。通过靶向肿瘤和CSC的侵袭特性，司立通和LMK235有望成为ACC的潜在治疗方法，有可能改善患者预后，并为这一关键领域的进一步研究铺平道路。
