Emerging Anticancer Activity of Candidal Glucoseamine-6-Phosphate Synthase Inhibitors upon Nanoparticle-Mediated Delivery

Abstract

Numerous glutamine analogues have been reported as irreversible inhibitors of the glucosamine-6-phosphate (GlcN-6-P) synthase in pathogenic Candida albicans in the last 3.5 decades. Among the reported inhibitors, the most effective N 3-(4-methoxyfumaroyl)-l-2,3-diaminopropanoic acid (FMDP) has been extensively studied in order to develop its more active analogues. Several peptide–FMDP conjugates were tested to deliver FMDP to its subcellularly located GlcN-6-P synthase target. However, the rapid development of fungal resistance to FMDP–peptides required development of different therapeutic approaches to tackle antifungal resistance. In the current state of the global antifungal resistance, subcellular delivery of FMDP via free diffusion or endocytosis has become crucial. In this study, we report on in vitro nanomedical applications of FMDP and one of its ketoacid analogues, N 3-trans-4-oxo-4-phenyl-2-butenoyl-l-2,3-diaminopropanoic acid (BADP). FMDP and BADP covalently attached to polyethylene glycol-coated iron oxide/silica core–shell nanoparticles are tested against intrinsically multidrug-resistant C. albicans. Three different human cancer cell lines potentially overexpressing the GlcN-6-P synthase enzyme are tested to demonstrate the immediate inhibitory effects of nanoparticle conjugates against mammalian cells. It is shown that nanoparticle-mediated delivery transforms FMDP and BADP into strong anticancer agents by inhibiting the growth of the tested cancer cells, whereas their anti-Candidal activity is decreased. This study discusses the emerging inhibitory effect of the FMDP/BADP–nanoparticle conjugates based on their cellular internalization efficiency and biocompatibility.

Inhibition of GFAT1 in lung cancer cells destabilizes PD-L1 protein and improves immune response

“…As a glutamine analog, DON is not specific to GFAT, but it has gone through numerous clinical trials in the past, therefore its toxicity is known and efforts to minimize the side effects are ongoing (28,29). New inhibitors for GFAT are also in development (30)(31)(32). Another advantage of targeting GFAT/HBP is that inhibition of the pathway itself has anti-cancer properties, as we (13)and others have demonstrated (33)(34)(35)(36).…”

Inhibitors of glucosamine-6-phosphate synthase as potential antimicrobials or antidiabetics – synthesis and properties

“…Inhibition of GFPT2 selectively reduced KRAS/LKB1 co-mutant tumour cell growth in culture, xenografts and genetically modified mice 12 . The GlcN-6-P synthase inhibitor: nanoparticle conjugates were found to exhibit remarkable cytotoxicity against human cervical cancer (HeLa) and hypopharyngeal carcinoma cell lines 13 . Moreover, an inhibitor of GlcN-6-P synthase in combination with the established anticancer agent, cisplatin, demonstrated a synergistic effect 14 .…”