Moringa oleifera Lam. Isothiocyanate Quinazolinone Derivatives Inhibit U251 Glioma Cell Proliferation through Cell Cycle Regulation and Apoptosis Induction

Abstract

A major active constituent of Moringa oleifera Lam. is 4-[(α-L-rhamnose oxy) benzyl] isothiocyanate (MITC). To broaden MITC’s application and improve its biological activity, we synthesized a series of MITC quinazolinone derivatives and evaluated their anticancer activity. The anticancer effects and mechanisms of the compound with the most potent anticancer activity were investigated further. Among 16 MITC quinazolinone derivatives which were analyzed, MITC-12 significantly inhibited the growth of U251, A375, A431, HCT-116, HeLa, and MDA-MB-231 cells. MITC-12 significantly inhibited U251 cell proliferation in a time- and dose-dependent manner and decreased the number of EdU-positive cells, but was not toxic to normal human gastric mucosal cells (GES-1). Further, MITC-12 induced apoptosis of U251 cells, and increased caspase-3 expression levels and the Bax:Bcl-2 ratio. In addition, MITC-12 significantly decreased the proportion of U251 cells in the G1 phase and increased it in S and G2 phases. Transcriptome sequencing showed that MITC-12 had a significant regulatory effect on pathways regulating the cell cycle. Further, MITC-12 significantly decreased the expression levels of the cell cycle-related proteins CDK2, cyclinD1, and cyclinE, and increased those of cyclinA2, as well as the p-JNK:JNK ratio. These results indicate that MITC-12 inhibits U251 cell proliferation by inducing apoptosis and cell cycle arrest, activating JNK, and regulating cell cycle-associated proteins. MITC-12 has potential for use in the prevention and treatment of glioma.

A Comparative Review of Key Isothiocyanates and Their Health Benefits

“…The effects of MG on glioma cells were shown to be time- and dose-dependent, as reported by Xie et al (2023). They found that MG stimulated tumor cell apoptosis in a manner similar to the previously explained mechanisms without causing harm to normal human gastric mucosal cells [ 76 ]. MIC-mediated activation of apoptotic genes, including caspase, p53, Akt/MAPK, and Bax of the proapoptotic Bcl family, has also been observed in human prostate [ 77 ], liver [ 78 ], and neuroblastoma cancer cells [ 79 ].…”

Moringa oleifera (drumstick tree)—nutraceutical, cosmetological and medicinal importance: a review

“…MITC-12 induced apoptosis of U251 cells and increased the expression levels of caspase-3 and the Bax:Bcl-2 ratio. MITC-12 inhibits the proliferation of U251 cells, by arresting the cell cycle, activating JNK, and regulating cell cycle-related proteins Xie et al (2023) Glucomoringin isothiocyanate from M. oleifera seeds…”

Moringia oleifera Lam. seeds isothiocyanate against skin photoaging by regulating p38MAPK-dependent autophagy signalling pathway

“…Studies have reported that MITC has anticancer, anti-inflammatory, cardiometabolic repair, nervous system protection, blood lipid regulation and diabetes prevention activities [26,27] . MITC are organic compounds with an (R N=C=S) group in their structures, but their biological activity and chemical stability are higher than those of isothiocyanate compounds in other plants due to the presence of aromatic rings and rhamnoses, among which 4-[(α -L-rhamnoxyl) benzyl] isothiocyanate has the highest content and the best activity [28] .…”