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Review
. 2022 Jul 4;23(13):7426.
doi: 10.3390/ijms23137426.

Fenretinide in Cancer and Neurological Disease: A Two-Face Janus Molecule

Rosa Luisa Potenza  1 , Pietro Lodeserto  2 , Isabella Orienti  2
Affiliations
Review

Fenretinide in Cancer and Neurological Disease: A Two-Face Janus Molecule

Rosa Luisa Potenza et al. Int J Mol Sci. .

Abstract

Recently, several chemotherapeutic drugs have been repositioned in neurological diseases, based on common biological backgrounds and the inverse comorbidity between cancer and neurodegenerative diseases. Fenretinide (all-trans-N-(4-hydroxyphenyl) retinamide, 4-HPR) is a synthetic derivative of all-trans-retinoic acid initially proposed in anticancer therapy for its antitumor effects combined with limited toxicity. Subsequently, fenretinide has been proposed for other diseases, for which it was not intentionally designed for, due to its ability to influence different biological pathways, providing a broad spectrum of pharmacological effects. Here, we review the most relevant preclinical and clinical findings from fenretinide and discuss its therapeutic role towards cancer and neurological diseases, highlighting the hormetic behavior of this pleiotropic molecule.

Keywords: anticancer drugs; fenretinide; hormesis; nanomicellar formulations; neuroinflammation; neuroprotection; oxidative stress; repositioning.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic diagram of fenretinide activity in cancer. Pointed arrows represent pathway activation, and blunt arrows represent pathway inhibition. Fenretinide activates PKCδ in the mitochondrial signalosome with consequent activation of PDK2, PDHC, TCA and increased ROS production. High increase of ROS activates the p38 apoptotic pathway with CytC release, caspase-9 activation and induction of apoptosis. Moderate increase of ROS activates the JNK autophagy pathway.Fenretinide induces translocation of RARβ-Nur77 dimer from the nucleus to the cytoplasm where Nur77 binds Bcl-2 allowing their conformational change towards pro-apoptotic structures. Fenretinide inhibition of DES1 increases DhCer/Cer ratio and triggers endoplasmic reticulum stress with blocking of the PI3K/AKT/mTOR and NF-KB signaling pathways, as well as with blocking of eIF2 phosphorylation due to PERK. Moreover, fenretinide inhibits mTORC2 and mTORC1 by structural affinity with mTOR-ATP binding site.
Figure 2
Figure 2
Schematic diagram of fenretinide activity in neurological diseases. Pointed arrows represent pathway activation, and blunt arrows represent pathway inhibition. Fenretinide activates PKCδ in the mitochondrial signalosome with consequent activation of PDK2, PDHC, TCA and increased ROS production. Low doses of fenretinide induce a moderate increase of intracellular ROS with activation of JNK autophagy pathway. Fenretinide decreases oxidative stress by improving the expression of the transcription factor Nrf2 that promotes the transcription of the antioxidant responsive element (ARE). Fenretinide downregulates the production of proinflammatory cytokines in macrophages by decreasing the AA/DHA ratio and enhancing the expression of PPARγ. Fenretinide binds RBP4 in place of retinol thereby decreasing circulating levels of both retinol and RBP4.
Figure 3
Figure 3
Hormetic dose response of fenretinide.
See this image and copyright information in PMC

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