Prior studies reported significant anticancer activities of
ceramides. However, anticancer activities of
homoserine based
ceramides have not been tested. With a view to compare the anticancer activity of
ceramides and homoceramides, in the present study, we have synthesized four
serine based and four
homoserine based
C8-ceramide analogues. Since many
cancer cells have shown resistance to
ceramides,
curcumin is now being used in combination with
ceramides because of its ability to reverse multidrug resistance. Aimed at targeting
curcumin-
ceramide combination to
tumor endothelial cells, herein we have used a
tumor vasculature targeting
liposomes of a newly synthesized pegylated RGDGWK-
lipopeptide. Importantly, the liposomal formulations of the
homoserine based
C8-ceramide analogue containing oleyl chain showed more promising
antineoplastic activities under both in vitro and systemic settings than the liposomal formulations of commercially available
C8-ceramide. Findings in the mouse
tumor growth inhibition study revealed synergistic therapeutic benefit from simultaneous delivery of
curcumin and a
homoserine based
ceramide containing oleyl chain to
tumor vasculature. Results in RT-PCR and Western blot experiments suggest that inhibition of solid
tumor growth is mediated via inhibition of PI3K-Akt signaling pathway. The present structure-activity study is the first report to demonstrate therapeutic promise of
curcumin-
homoserine based
ceramide combination in antiangiogenic
cancer therapy.