研究动态
Articles below are published ahead of final publication in an issue. Please cite articles in the following format: authors, (year), title, journal, DOI.

苯并[a]吩恶嗪化合物促进溶酶体功能障碍的抗癌活性。

Anticancer Activity of Benzo[a]phenoxazine Compounds Promoting Lysosomal Dysfunction.

发表日期:2024 Aug 20
作者: João Carlos Canossa Ferreira, M Sameiro T Gonçalves, Ana Preto, Maria João Sousa
来源: Cell Death & Disease

摘要:

具体的癌症治疗仍然是一个有待解决的问题。乳腺癌和结直肠癌是患病率和死亡率最高的癌症之一。尽管有一些治疗选择,但针对这些癌症的有效药物仍然很少,这构成了需要进一步研究的临床问题。溶酶体在癌细胞的生存中发挥着重要作用,并且针对溶酶体的研究引起了越来越多的关注。近年来,我们的团队一直在合成和测试新型苯并[a]吩恶嗪衍生物,因为它们已被证明具有有效的药理活性。在这里,我们研究了我们文库中三种最有效的衍生物 C9、A36 和 A42 对结直肠癌和乳腺癌来源的细胞系的抗癌活性,并将其与对非肿瘤细胞系的作用进行了比较。我们观察到这三种化合物对癌细胞(即 RKO 结直肠癌细胞系和 MCF7 乳腺癌细胞系)具有选择性。在这两种模型中,这些化合物减少了细胞增殖、细胞存活和细胞迁移,在溶酶体上积累,并诱导细胞死亡并伴有溶酶体膜透化(LMP),增加细胞内 pH 值和 ROS 积累。我们的结果表明,这些化合物特异性靶向癌细胞的溶酶体,使其成为癌症治疗中 LMP 诱导剂的有希望的候选者。
Specific cancer therapy remains a problem to be solved. Breast and colorectal cancer are among the cancers with the highest prevalence and mortality rates. Although there are some therapeutic options, there are still few effective agents for those cancers, which constitutes a clinical problem that requires further research efforts. Lysosomes play an important role in cancer cells' survival, and targeting lysosomes has gained increased interest. In recent years, our team has been synthetizing and testing novel benzo[a]phenoxazine derivatives, as they have been shown to possess potent pharmacological activities. Here, we investigated the anticancer activity of three of the most potent derivatives from our library, C9, A36, and A42, on colorectal- and breast-cancer-derived cell lines, and compared this with the effect on non-neoplastic cell lines. We observed that the three compounds were selective for the cancer cells, namely the RKO colorectal cancer cell line and the MCF7 breast cancer cell line. In both models, the compounds reduced cell proliferation, cell survival, and cell migration, accumulated on the lysosome, and induced cell death accompanied by lysosomal membrane permeabilization (LMP), increasing the intracellular pH and ROS accumulation. Our results demonstrated that these compounds specifically target lysosomes from cancer cells, making them promising candidates as LMP inducers for cancer therapy.