Methylsulfonylmethane: A Potential Dietary Supplement targeting sphingosine kinase 1 involved in Glioblastomamultiforme

Abstract

AbstractMethylsulfonylmethane (MSM) is a common dietary supplement mainly used for inflammatory disorders as well as MSM had shown anti-tumor effects on different types of cancers. However, the glioma cell line has not been tested against MSM, and we are reporting it in our study for the first time. This research used an in silico study in which sphingosine kinase 1(SphK1) is used as a therapeutic target which is associated with Glioblastoma multiforme(GBM) SphK1 is pivotal enzyme for sphingolipid metabolism whose high expression level is thought to be associated with cancer alongside other inflammatory diseases and it is a potential drug target for various types of cancer.First, in silico analysis was executed to evaluate the inhibitory effect of MSM on SphK1.Then we further observed the anti-tumor activities of MSM on the C6 glioma cell line. During in silico investigation at the initial stage, we performed molecular docking with Auto Dock Vina followed by molecular dynamics simulation at 100ns with Gromacs Software Package.MSM binds with SphK1 with a docked score of -2.1 kcal mol1. During molecular dynamics simulation complex maintain stability at 10ns but we ran simulation till 100ns to confirm the stability. We performed in depth analysis which includes post trajectory analysis like free energy landscape (FEL), principal constant analysis (PCA) with kernel density (KDE)estimation plots as well as probability distribution plots. Even molecular dynamics simulation shows stability, compactness and interaction of MSM with Sphk1, we calculated MMPBSA binding energy calculation is -13.922 +/- 19.518 kJ/mol-The viability and cellular metabolic activity of the C6 glioma in the presence of MSM showed 393.459 mM/ml of MSM reduced cell viability by 50% (CTC50) value in dose dependent manner. Further analysis like DNA fragmentation assay and Acridine orange and ethidium bromide (AO/EB) staining were carried out, which clearly depicts MSM inducing apoptosis in C6 gliomas. Based on in silico and in vitro results,for the first time we are reporting it in our study and we reach to conclusion that that MSM acts as a potential inhibitor for SphK1 as well as inhibits the growth of glioma cells and acts as a potential dietary supplement for the management of GBM which can cross blood brain barrier (BBB) and not toxic to cells even at high doze.