title: New castanospermine glycoside analogues inhibit breast cancer cell proliferation and induce apoptosis without affecting normal cells.
abstract: 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.
authors.affiliation: Laboratory of Cellular and Molecular Physiology (EA 4667), SFR CAP-SANTE (FED 4132), UFR of Sciences, UPJV, Amiens, France.
authors.forename: Ghada
authors.initials: G
authors.lastname: Allan
authors.forename: Halima
authors.initials: H
authors.lastname: Ouadid-Ahidouch
authors.forename: Elena M
authors.initials: EM
authors.lastname: Sanchez-Fernandez
authors.forename: Rocío
authors.initials: R
authors.lastname: Risquez-Cuadro
authors.forename: José M Garcia
authors.initials: JM
authors.lastname: Fernandez
authors.forename: Carmen
authors.initials: C
authors.lastname: Ortiz-Mellet
authors.forename: Ahmed
authors.initials: A
authors.lastname: Ahidouch
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007212:Indolizines / Q000494:pharmacology*; D054836:Indolizidines
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D007212:Indolizines; C037806:castanospermine; D054836:Indolizidines