Glycosylated Antitumor Ether Lipids: Activity and Mechanism of Action

Glycosylated antitumor ether lipids (GAELs) are distinguished from the alkyllysophospholipids or alkylphosphocholines classes of antitumor ether lipids (AEL) by the presence of a sugar moiety. Non-phosphorus GAELs, the subject of this review, have a sugar moiety in place of the phosphobase found in alkyllysophospholipids. Analogues of non-phosphorus GAELs with glucose, maltose, arabinose, or disaccharide moieties have been synthesized. Non-phosphorus GAELs with monosaccharides have cytotoxic and antiproliferative effects against cancer cells derived from a wide range of tissues, including drug resistant cell lines. The most active compound of this group to date is 1-O-hexadecyl-2-O-methyl-3-O-(2'-amino-2'-deoxy-beta-D-glucopyranosyl)-sn-glycerol (11), which displays in vitro activity similar to or greater than that of ET-18-OCH3, the AEL gold standard. While the detailed molecular mechanism of action of non-phosphorus GAELs is not known, the data indicate that non-phosphorus GAELs are taken up by endocytosis and incorporated into early endosomes. The presence of non-phosphorus GAELs perturbs the maturation of the endocytic vesicles, resulting in the formation of large acidic vacuoles. Cell death appears to be the result of the release of cathepsins from the vacuoles into the cytosol and subsequent activation of a death pathway that is independent of the mitochondria and independent of apoptosis. The ability of these GAELs to kill cells via an apoptosis-independent mechanism makes them prime candidates for development of effective compounds against chemo-resistant tumors and cancer stem cells. The disaccharide-linked GAELs do not have cytotoxic activity but rather inhibit cancer cell motility due to the ability of the compounds to block specific calcium-activated potassium channels in cells. The antitumor activities displayed by these experimental compounds augurs well for their eventual development into clinically useful agents for cancer treatment.