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Apigenin improves cytotoxicity of antiretroviral drugs against HTLV-1 infected cells through the modulation of AhR signaling
Journal article   Open access

Apigenin improves cytotoxicity of antiretroviral drugs against HTLV-1 infected cells through the modulation of AhR signaling

Dominic Sales, Edward Lin, Victoria Stoffel, Shallyn Dickson, Zafar K Khan, Joris Beld and Pooja Jain
NeuroImmune pharmacology and therapeutics, v 2(1), pp 49-62
25 Mar 2023
DOI: https://doi.org/10.1515/nipt-2022-0017
PMID: 37027342
url
https://doi.org/10.1515/nipt-2022-0017View
Published, Version of Record (VoR) Open

Abstract

apigenin HTLV-1 flavonoid antiretroviral therapy aryl hydrocarbon receptor
HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neuroinflammatory autoimmune disease characterized by high levels of infected immortalized T cells in circulation, which makes it difficult for antiretroviral (ART) drugs to work effectively. In previous studies, we established that Apigenin, a flavonoid, can exert immunomodulatory effects to reduce neuroinflammation. Flavonoids are natural ligands for the aryl hydrocarbon receptor (AhR), which is a ligand activated endogenous receptor involved in the xenobiotic response. Consequently, we tested Apigenin's synergy in combination with ART against the survival of HTLV-1-infected cells. First, we established a direct protein-protein interaction between Apigenin and AhR. We then demonstrated that Apigenin and its derivative VY-3-68 enter activated T cells, drive nuclear shuttling of AhR, and modulate its signaling both at RNA and protein level. In HTLV-1 producing cells with high AhR expression, Apigenin cooperates with ARTs such as Lopinavir (LPN) and Zidovudine (AZT), to impart cytotoxicity by exhibiting a major shift in IC that was reversed upon AhR knockdown. Mechanistically, Apigenin treatment led to an overall downregulation of NF-κB and several other pro-cancer genes involved in survival. This study suggest the potential combinatorial use of Apigenin with current first-line antiretrovirals for the benefit of patients affected by HTLV-1 associated pathologies.

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