A Lactosylated Steroid Contributes in Vivo Therapeutic Benefits in Experimental Models of Mouse Lymphoma and Human Glioblastoma

Abstract

Various mono- and disaccharides were grafted onto a steroid backbone. Whereas in vitro these glycosylated steroids had no cytotoxic effects on six different human cancer cell lines, several of the glycosylated steroids under study did significantly modify the levels of in vitro migration of the human U373 glioblastoma, the A549 non-small-cell-lung cancer (NSCLC), and the PC-3 prostate cancer cells, with more pronounced effects in the case of a monosubstituted beta-L-fucopyranosyl-steroid (19), a monosubstituted beta-D-isomaltosyl-steroid (22), and a monosubstituted beta-D-lactosyl-steroid (24). These three compounds significantly increased the survival of conventional mice grafted subcutaneously with the P388 lymphoma, a lymphoma that metastasizes toward the liver. In vivo, the monosubstituted beta-D-lactosyl-steroid (24) also increased the antitumor effectiveness of cisplatin, a cytotoxic pro-apoptotic drug, in the case of the P388 lymphoma model. This compound also increased the survival of immunodeficient mice into whose brains human U373 glioblastoma cells had been orthotopically grafted.

Galectins: matricellular glycan-binding proteins linking cell adhesion, migration, and survival

“…For example, knocking down Gal-1 expression, at least in gliomas, has been shown to impair cell migration, invasiveness, and metastasis [46,162]. Lactosylated steroids also blocked in vitro migration of human U373 glioblastoma, A549 non-small-cell lung and PC-3 prostate cancer cells [163]. Finally, anti-galectin compounds such as lectin-specific synthetic peptides and siRNA are being developed by different groups, opening a new era of non-toxic therapeutic strategies for the treatment of inflammatory and neoplastic diseases.…”

Platinated Copper(3‐Clip‐Phen) Complexes as Effective DNA‐Cleaving and Cytotoxic Agents

“…In the present study, we report on the fact that platinated Cu(3-Clip-Phen) complexes with weak cytotoxic activity in vitro (as revealed by the MTT colorimetric assay) [34][35][36] are associated with marked antimigratory effects (as revealed by computer-assisted phase-contrast microscopy), [37][38][39] and vice versa.…”

“…The micro-wells are then shaken for 5 min and read on a spectrophotometer at 2 wavelengths (570 nm: the maximum formazan absorb-ance wavelength; 630 nm: the background noise wavelength). [39] The IC 50 value of the 3-Clip-Phen ligand is for: Hs683; 8.4 mm, U373MG; 1 mm, HCT-15 > 10 mm, LoVo; 8.6 mm, A549; 5 mm and MCF-7; 4.5 mm.…”

“…[39] This test is based on the measurement of the number of metabolically active living cells able to transform the yellowish MTT product (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide) into the blue product, formazan, via mitochondrial reduction performed by living cells. [39] The amount of formazan obtained at the end of the experiment is measured with a spectrophotometer, and is therefore directly proportional to the number of living cells at that moment. The measurement of the OD (Optical density) provides a quantitative measurement of the effect of the product investigated as compared to control (untreated cells), and enables it to be compared to other reference products.…”

“…The measurement of the OD (Optical density) provides a quantitative measurement of the effect of the product investigated as compared to control (untreated cells), and enables it to be compared to other reference products. [39] The cells are put to grow in flat-bottomed 96-well micro-wells with 100 mL of cell suspension per well and between 1,000 and 5,000 cells/well depending on cell type. Each cell line is seeded in its own cell culture medium.…”