Centre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal.
IBS-Institute of Science and Innovation for Bio-Sustainability, University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal.
Cells. 2024 Aug 20;13(16):1385. doi: 10.3390/cells13161385.
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[]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, , , and , 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.
特定的癌症治疗仍然是一个待解决的问题。乳腺癌和结直肠癌是发病率和死亡率最高的癌症之一。尽管有一些治疗选择，但对于这些癌症来说，仍然缺乏有效的药物，这构成了一个需要进一步研究努力的临床问题。溶酶体在癌细胞的存活中起着重要作用，靶向溶酶体的研究越来越受到关注。近年来，我们团队一直在合成和测试新型苯并[]吩嗪衍生物，因为它们已被证明具有很强的药理活性。在这里，我们研究了我们库中三种最有效的衍生物 、 、 对结直肠和乳腺癌衍生细胞系的抗癌活性，并将其与对非肿瘤细胞系的影响进行了比较。我们观察到这三种化合物对癌细胞具有选择性，即 RKO 结直肠癌细胞系和 MCF7 乳腺癌细胞系。在这两种模型中，化合物均能降低细胞增殖、细胞存活和细胞迁移，在溶酶体上积累，并诱导伴有溶酶体膜通透性（LMP）的细胞死亡，增加细胞内 pH 值和 ROS 积累。我们的结果表明，这些化合物特异性地靶向癌细胞的溶酶体，使它们成为溶酶体通透性诱导剂治疗癌症的有前途的候选药物。
