Amphiphilic Modulation of Glycosylated Antitumor Ether Lipids Results in a Potent Triamino Scaffold against Epithelial Cancer Cell Lines and BT474 Cancer Stem Cells

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.