Abstract
BackgroundChemotherapy resistance is one of the major factors contributing to mortality from human epithelial ovarian cancer (EOC). Identifying drugs that can effectively kill chemotherapy-resistant EOC cells would be a major advance in reducing mortality. Glycosylated antitumour ether lipids (GAELs) are synthetic glycolipids that are cytotoxic to a wide range of cancer cells. They appear to induce cancer cell death in an apoptosis-independent manner.MethodsHerein, the effectiveness of two GAELs, GLN and MO-101, in killing chemotherapy-sensitive and –resistant EOC cells lines and primary cell samples was tested using monolayer, non-adherent aggregate, and non-adherent spheroid cultures.ResultsOur results show that EOC cells exhibit a differential sensitivity to the GAELs. Strikingly, both GAELs are capable of inducing EOC cell death in chemotherapy-sensitive and –resistant cells grown as monolayer or non-adherent cultures. Mechanistic studies provide evidence that apoptotic-cell death (caspase activation) contributes to, but is not completely responsible for, GAEL-induced cell killing in the A2780-cp EOC cell line, but not primary EOC cell samples.ConclusionsStudies using primary EOC cell samples supports previously published work showing a GAEL-induced caspase-independent mechanism of death. GAELs hold promise for development as novel compounds to combat EOC mortality due to chemotherapy resistance.
Highlights
Chemotherapy resistance is one of the major factors contributing to mortality from human epithelial ovarian cancer (EOC)
We have recently reported that Glycosylated antitumour ether lipids (GAELs) inhibited spheroid formation by tumour propagating cells derived from breast cancer cell lines, but they caused the disintegration of tumour propagating cell spheroids and killed the cells [28]
Cisplatin sensitivity of adherent vs. non-adherent EOC cultures While cell spheroids may be observed in malignant ascites, our laboratory more frequently observes single EOC cells and loose cell aggregates (Additional file 3: Figure S2)
Summary
Chemotherapy resistance is one of the major factors contributing to mortality from human epithelial ovarian cancer (EOC). Identifying drugs that can effectively kill chemotherapy-resistant EOC cells would be a major advance in reducing mortality. Glycosylated antitumour ether lipids (GAELs) are synthetic glycolipids that are cytotoxic to a wide range of cancer cells. Chemotherapy resistance of epithelial ovarian cancer (EOC) cells is a major contributor to reducing the survival rate among EOC patients [1,2,3]. Recurrent disease is treated with drugs such as gemcitabine, liposomal doxorubicin, or topotecan, which have been shown to increase progression-free survival by 10-30% in platinum-resistant EOC [2, 6]. Evaluating novel drug treatments using models of chemotherapy resistant disease becomes critical to improve outcome for this patient population
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