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 g...

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Published inJournal of medicinal chemistry Vol. 60; no. 23; pp. 9724 - 9738
Main Authors Idowu, Temilolu, Samadder, Pranati, Arthur, Gilbert, Schweizer, Frank
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 14.12.2017
Amer Chemical Soc
Subjects
Amination
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Cell Line, Tumor
Cell Survival - drug effects
Chemistry, Medicinal
Epithelial Cells - drug effects
Epithelial Cells - pathology
Glycosylation
Humans
Life Sciences & Biomedicine
Lipids - chemistry
Lipids - pharmacology
Neoplasms - drug therapy
Neoplasms - pathology
Neoplastic Stem Cells - drug effects
Neoplastic Stem Cells - pathology
Pharmacology & Pharmacy
Science & Technology
PATHWAYS
DESIGN
CYTOTOXIC PROPERTIES
GLUCOSAMINE
MEMBRANE
RESISTANCE
TUMOR-CELLS
MECHANISMS
ANTIMICROBIAL PEPTIDES
EXPRESSION
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Summary: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.
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content type line 23
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.7b01198