Indole-3-carbinol in vitro antiviral activity against SARS-Cov-2 virus and in vivo toxicity

Abstract

The effects of indole-3-carbinol (I3C) compound have been described deeply as antitumor drug in multiple cancers. Herein, I3C compound was tested for toxicity and antiviral activity against SARS-CoV-2 infection. Antiviral activity was assessed in vitro in both in VeroE6 cell line and human Lung Organoids (hLORGs) where I3C exhibited a direct anti-SARS-CoV-2 replication activity with an antiviral effect and a modulation of the expression of genes implicated in innate immunity and inflammatory response was observed at 16.67 μM. Importantly, we further show the I3C is also effective against the SARS-CoV-2 Omicron variant. In mouse model, instead, we assessed possible toxicity effects of I3C through two different routes of administration: intragastrically (i.g.) and intraperitoneally (i.p.). The LD50 (lethal dose 50%) values in mice were estimated to be: 1410 and 1759 mg/kg i.g.; while estimated values for i.p. administration were: 444.5 mg/kg and 375 mg/kg in male and female mice, respectively. Below these values, I3C (in particular at 550 mg/kg for i.g. and 250 mg/kg for i.p.) induces neither death, nor abnormal toxic symptoms as well as no histopathological lesions of the tissues analysed. These tolerated doses are much higher than those already proven effective in pre-clinical cancer models and in vitro experiments. In conclusion, I3C exhibits a significant antiviral activity, and no toxicity effects were recorded for this compound at the indicated doses, characterizing it as a safe and potential antiviral compound. The results presented in this study could provide experimental pre-clinical data necessary for the start of human clinical trials with I3C for the treatment of SARS-CoV-2 and beyond.

Aryl Hydrocarbon Receptor Regulates Muc2 Production Independently of IL-22 during Colitis

“…The 40 mg/kg of I3C, which is below the reported toxic levels of 250 mg/kg (i.p.) in mice [50], is the human dose equivalent (HED) to approximately 200 mg for an average 60 kg person [51]. I3C has been shown to be well tolerated in humans even at 400 mg daily [52], which is well within the range used in the current studies.…”

1-L Transcription of SARS-CoV-2 Spike Protein S1 Subunit

“…Moreover, it physically interacts with, and ubiquitylates, the S protein [144]. I3C (Indole-3-carbinol), a natural WWP1 inhibitor from Brassicaceae, displays potent antiviral effects and inhibits viral egress [145]. This E3 ubiquitin ligase also regulates ciliary dynamics via the Hedgehog receptor Smoothened (Smo) [146].…”

Synthetic Methodologies and Therapeutic Potential of Indole-3-Carbinol (I3C) and Its Derivatives

“…I3C is an important phytochemical contained in cruciferous vegetables and is able to exert various activities among which are cardioprotective, antioxidant, anti-inflammatory, antiangiogenesis, and antimicrobial activities, the promotion of tumor cell apoptosis [ 4 , 9 ] and, more recently, an important inhibition of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS)-CoV-2 viral egression, including the Omicron variant [ 10 , 11 ].…”

“…and 250 mg/kg for i.p. values, I3C induces neither death nor abnormal toxic symptoms, as well as no histopathological lesions [ 11 ].…”

“…The role of ubiquitination processes in the survival of the virus have also been very recently confirmed by a study that demonstrated how ubiquitin variants are able to inhibit the production of new viral particles after infection, thus preventing the virus from spreading from one cell to another and wreaking havoc in the body [ 139 ]. Furthermore, treatment of human lung organoids (hLORGs) with I3C at different conditions significantly reduces viral entry and the expression of genes involved in innate immunity and inflammation response [ 11 ]. Overall, these data suggest the potential use of I3C as an antiviral in clinical trials for patients with COVID-19.…”