sp²-Iminosugar-type
castanospermine analogues have been shown to exhibit anti-
tumor activity. However, their effects on cell proliferation and apoptosis and the molecular mechanism at play are not fully understood. Here, we investigated the effect of two representatives, namely the pseudo-S- and C-octyl
glycoside 2-oxa-3-oxocastanospermine derivatives SO-OCS and CO-OCS, on MCF-7 and MDA-MB-231
breast cancer and MCF-10A mammary normal cell lines. We found that SO-OCS and CO-OCS inhibited
breast cancer cell viability in a concentration- and time-dependent manner. This effect is specific to
breast cancer cells as both molecules had no impact on normal MCF-10A cell proliferation. Both drugs induced a cell cycle arrest. CO-OCS arrested cell cycle at G1 and G2/M in MCF-7 and MDA-MB-231 cells respectively. In MCF-7 cells, the G1 arrest is associated with a reduction of
CDK4 (cyclin-dependent kinase 4),
cyclin D1 and
cyclin E expression, pRb phosphorylation, and an overexpression of p21(Waf1/Cip1). In MDA-MB-231 cells, CO-OCS reduced CDK1 but not
cyclin B1 expression. SO-OCS accumulated cells in G2/M in both cell lines and this blockade was accompanied by a decrease of CDK1, but not
cyclin B1 expression. Furthermore, both drugs induced apoptosis as demonstrated by the increased percentage of
annexin V positive cells and Bax/Bcl-2 ratio. Interestingly, in normal MCF-10A cells the two drugs failed to modify cell proliferation, cell cycle progression,
cyclins, or CDKs expression. These results demonstrate that the effect of CO-OCS and SO-OCS is triggered by both cell cycle arrest and apoptosis, suggesting that these
castanospermine analogues may constitute potential anti-
cancer agents against
breast cancer.