engleski

Cytotoxic effects of vitamin B3 derivatives in cultured cells

Vitamin B3 derivatives are today investigated for their antioxidative, anticancer, anti-angiogenic activities as well as cholinesterase inhibitors for potential use in treatment of neurodegenerative disorders such as Alzheimer’s disease. They share a structural similarity with nicotinamide, which participates in vital and important physiological processes in the organism as the nicotinamide adenine dinucleotide (NAD). With that fact in mind, we tested a series of nine vitamin B3 derivatives, previously described as inhibitors of cholinesterases, with the aim to determine their influence on cell viability and homeostasis, membrane integrity and oxidative status. All research was conducted by standard methods: activity of mitochondrial succinate dehydrogenase by the tetrazolium salt MTS, lactate dehydrogenase leakage by fluorescent resazufin and induction of reactive oxygen species and level of glutathione by fluorescent dyes DCFDA and mCB, respectively. As our results showed, four out of nine analogues were cytotoxic and displayed a time-dependent toxicity mechanism on neural-like and kidney cells, indicating cell death by apoptosis. Only one compound triggered significant LDH release at higher concentrations, indicating a necrotic-like impact. More detailed analysis also revealed a significant disturbance in cell homeostasis. Derivatives influenced cell GSH level and the expression of the oxygen sensitive hypoxia inducible transcription factor-1α. Furthermore, the tested analogues modulated nicotinamide-linked pathways such as AMPK-, Akt- and mTOR signalling with an important role in multiple cellular functions by standard western blot technique. Although the concentrations inducing the observed toxic effects were far greater than predicted in medical practice, they should not be neglected in the future design of new nicotinamide structures as potential drugs. This research was supported by the Croatian Science Foundation UIP-2017-05-7260, Croatian-Slovenian Bilateral project BI-HR/20-21 and Slovenian Research Agency P3-0043 in J7-8276.

AD-drugs ; cells ; ChE-inhibitors ; cytotoxicity ; nicotinamide

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