Cell cycle is disturbed in mucopolysaccharidosis type II fibroblasts, and can be improved by genistein

Abstract

Mucopolysaccharidoses (MPSs) are inherited metabolic diseases caused by mutations resulting in deficiency of one of enzymes involved in degradation of glycosaminoglycans (GAGs). These compounds accumulate in cells causing their dysfunctions. Genistein is a molecule previously found to both modify GAG metabolism and modulate cell cycle. Therefore, we investigated whether the cell cycle is affected in MPS cells and if genistein can influence this process. Fibroblasts derived from patients suffering from MPS types I, II, IIIA and IIIB, as well as normal human fibroblasts (the HDFa cell line) were investigated. MTT assay was used for determination of cell proliferation, and the cell cycle was analyzed by using the MUSE® Cell Analyzer. While effects of genistein on cell proliferation were similar in both normal and MPS fibroblasts, fractions of cells in the G0/G1 phase were higher, and number of cells entering the S and G2/M phases was considerably lower in MPS II fibroblasts relative to control cells. Somewhat similar tendency, though significantly less pronounced, could be noted in MPS I, but only at longer times of incubation. However, this was not observed in MPS IIIA and MPS IIIB fibroblasts. Genistein (5, 7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) was found to be able to partially correct the disturbances in the MPS II cell cycle, and to some extent in MPS I, at higher concentrations of this compound. The tendency to increase the fractions of cells entering the S and G2/M phases was also observed in MPS IIIA and IIIB fibroblasts treated with genistein. In conclusion, this is the first report indicating that the cell cycle can be impaired in MPS cells. The finding that genistein can improve the MPS II (and to some extent also MPS I) cell cycle provides an input to our knowledge on the molecular mechanisms of action of this compound.

Mucopolysaccharidosis Type II: One Hundred Years of Research, Diagnosis, and Treatment

“…Originally, these effects were thought to be mediated by the inhibition of the epithelial growth factor (EGF) receptor, with EGF being required for GAG synthesis [190]. More recently, genistein was also reported to partially correct the cell cycle alterations observed in MPS II cells [191].…”

The Antiproliferative Effect of Chakasaponins I and II, Floratheasaponin A, and Epigallocatechin 3-O-Gallate Isolated from Camellia sinensis on Human Digestive Tract Carcinoma Cell Lines

“…The effects of cell cycle distribution were analyzed to determine the mechanism associated with the growth inhibitory effect of chakasaponins I ( 1 ) and II ( 2 ), floratheasaponin A ( 3 ), and (–)-epigallocatechin 3- O -gallate ( 4 ) on HSC-2 cells [20,21]. The cell distribution in G0/G1, S, and G2/M phases shown in blue, red, and green areas, respectively, were determined after a 48 h incubation (Figure 2).…”

Safety study of sodium pentosan polysulfate for adult patients with mucopolysaccharidosis type II

“…Not much is known about Odiparcil ® , but clinical trials are being conducted by Inventiva, testing the agent's potential as a treatment for MPS VI. Perhaps the most prevalent of the available substrate reduction agents is genistein, which works by regulating expression of GAG synthesis genes [75,76]; genistein has also demonstrated the potential to improve cell cycle defects characteristic of MPS II [77]. Similar to rhodamine B, genistein can cross the blood-brain barrier [41,42].…”