The problems of resistance to apoptosis-inducing drugs, recurrence, and metastases that have bedeviled cancer treatment have been attributed to the presence of cancer stem cells (CSCs) in tumors, and there is currently no clinically indicated drug for their eradication. We previously reported that glycosylated antitumor ether lipids (GAELs) display potent activity against CSCs. Here, we show that by carefully modulating the amphiphilic nature of a monoamine-based GAEL, we can generate a potent triamino scaffold that is active against a panel of hard-to-kill epithelial cancer cell lines (including triple-negative breast) and BT474 CSCs. The most active compound of this set, which acts via a nonmembranolytic, nonapoptotic caspase-independent mechanism, is more effective than cisplatin and doxorubicin against these cell lines and more potent than salinomycin against BT474 CSCs. Understanding the combination of factors crucial for the enhanced cytotoxicity of GAELs opens new avenues to develop potent compounds against drug-resistant cancer cells and CSCs.

中文翻译：

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糖基化的抗肿瘤醚脂质的两亲调节导致有效的三氨基支架抗上皮癌细胞系和BT474癌症干细胞。

对凋亡诱导药物的耐药性，复发和转移已使癌症治疗变得困难的问题已归因于肿瘤中存在癌症干细胞（CSC），并且目前尚无临床指示的药物可用于根除它们。我们先前曾报道糖基化的抗肿瘤醚脂质（GAELs）对CSCs表现出强大的活性。在这里，我们表明，通过仔细调节基于单胺的GAEL的两亲性质，我们可以产生有效的三氨基支架，该支架对一组难以杀死的上皮癌细胞系（包括三阴性乳腺癌）和BT474具有活性CSC。该组中活性最高的化合物，通过非膜分解性，非凋亡的半胱天冬酶独立机制起作用，对这些细胞系比顺铂和阿霉素更有效，对BT474 CSC比对盐霉素更有效。了解对GAELs增强细胞毒性至关重要的因素的组合，为开发针对耐药性癌细胞和CSC的有效化合物开辟了新途径。