Alkaloids as natural NRF2 inhibitors: chemoprevention and cytotoxic action in cancer

Gjorgieva Ackova, Darinka and Maksimova, Viktorija and Smilkov, Katarina and Buttari, Brigitta and Arese, Marzia and Saso, Luciano (2023) Alkaloids as natural NRF2 inhibitors: chemoprevention and cytotoxic action in cancer. Pharmaceuticals, 16. p. 850. ISSN 1424-8247

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Abstract

Being a controller of cytoprotective actions, inflammation, and mitochondrial function
through participating in the regulation of multiple genes in response to stress-inducing endogenous
or exogenous stressors, the transcription factor Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) is
considered the main cellular defense mechanism to maintain redox balance at cellular and tissue level.
While a transient activation of NRF2 protects normal cells under oxidative stress, the hyperactivation
of NRF2 in cancer cells may help them to survive and to adapt under oxidative stress. This can be
detrimental and related to cancer progression and chemotherapy resistance. Therefore, inhibition
of NRF2 activity may be an effective approach for sensitizing cancer cells to anticancer therapy. In
this review, we examine alkaloids as NRF2 inhibitors from natural origin, their effects on cancer
therapy, and/or as sensitizers of cancer cells to anticancer chemotherapeutics, and their potential
clinical applications. Alkaloids, as inhibitor of the NRF2/KEAP1 signaling pathway, can have direct (berberine, evodiamine, and diterpenic aconitine types of alkaloids) or indirect (trigonelline)
therapeutic/preventive effects. The network linking alkaloid action with oxidative stress and NRF2
modulation may result in an increased NRF2 synthesis, nuclear translocation, as well in a downstream impact on the synthesis of endogenous antioxidants, effects strongly presumed to be the
mechanism of action of alkaloids in inducing cancer cell death or promoting sensitivity of cancer cells
to chemotherapeutic agents. In this regard, the identification of additional alkaloids targeting the
NRF2 pathway is desirable and the information arising from clinical trials will reveal the potential of
these compounds as a promising target for anticancer therapy.

Item Type:	Article
Impact Factor Value:	4.9
Subjects:	Medical and Health Sciences > Basic medicine Medical and Health Sciences > Clinical medicine Medical and Health Sciences > Other medical sciences
Divisions:	Faculty of Medical Science
Depositing User:	Darinka Gorgieva Ackova
Date Deposited:	17 Aug 2023 11:20
Last Modified:	17 Aug 2023 11:20
URI:	https://eprints.ugd.edu.mk/id/eprint/32054

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