Quinazolinone derivative BNUA‐3 ameliorated [NDEA+2‐AAF]‐induced liver carcinogenesis in SD rats by modulating AhR‐CYP1B1‐Nrf2‐Keap1 pathway

Abstract

Cytochrome P450 1B1, considered as one of the novel chemotherapeutic targets involved in cancer prevention and therapy is also associated with the conversion of procarcinogens into their active metabolites. The aryl hydrocarbon receptor (AhR) is responsible for mediating different biological responses to a wide variety of environmental pollutants and also causes transcriptional activation of cytochrome P450 enzymes including CYP1B1 and thus plays a pivotal role for initiating cancer and its progression. On the other hand, active carcinogenic metabolites and reactive oxygen species-mediated stress alter different molecular signalling pathways and gene expressions. Quinazoline derivatives are recognized for their diversified biological activities including anticancer properties. The current study was designed for evaluation of chemotherapeutic efficacy of a synthetic quinazolinone derivative BNUA-3 against hepatocellular cancer in Sprague-Dawley (SD) rats. A detailed in vivo analysis was performed by administrating BNUA-3 (15, 30 mg/kg b.w. for 28 days, i.p.) in N-Nitrosodiethylamine + 2-Acetylaminofluorene induced partially hepatectomized liver cancer in SD rats. This was followed by morphological evaluations, biochemical estimations and analysis of different mRNA and protein expressions. The results demonstrated the potency of BNUA-3 in efficient restoration of the altered morphology of liver, its protective effect against lipid peroxidation, enzymic and non-enzymic antioxidants levels in liver tissue which was disrupted after cancer induction. The study also demonstrated downregulation of AhR, CYP1B1 and Keap1 expressions with subsequent augmentation of protective Nrf2, HO-1, NQO1 and GSTA1 expressions thus, revealing the chemotherapeutic potency of BNUA-3 in inhibiting liver carcinogenesis through AhR/CYP1B1/Nrf2/Keap1 pathway.

Carcinogenesis: Failure of resolution of inflammation?

“…AFB 1 upregulates Nrf2 signaling in response to oxidative stress, although expression of the SOD antioxidant is downregulated ( Wang et al, 2017 )(). In liver carcinogenesis Nrf2 activation as a result of AHR and CYP1B1 downregulation led to restoration of liver tissue and reduced oxidative damage ( Bose et al, 2020 ). A novel compound, CDDO-Im, with anti-inflammatory properties also activates Nrf2 to potently inhibit AFB 1 -induced carcinogenesis in 100% of animals ( Eaton & Schaupp, 2014 ; Johnson et al, 2014 ).…”

Molecular dynamics, quantum mechanics and docking studies of some Keap1 inhibitors – An insight into the atomistic mechanisms of their antioxidant potential

“…It was observed that Ala366 was one of the residues that formed hydrophobic interactions with the phenyl ring at the second position of quinazoline at Keap1 active site. This finding might further emphasize the importance of Ala366 towards Keap1 bioactivity [ 43 ].…”

NRF2 Activation by Nitrogen Heterocycles: A Review

“…Quinozaline derivatives are highly potent inducers of the NRF2 target gene NQO1 [ 130 ]. The quinazolinone derivative ( 31 ) ( Table 2 ) upregulates the expression levels of NRF2, HO-1 and NQO1, with a consequent downregulation of the expression of KEAP1, AhR and CYP1B1 [ 131 ]. This modulation of the AhR/CYP1B1/NRF2/KEAP1 signaling pathway by compound 31 accounts for its chemotherapeutic potency in the inhibition of liver carcinogenesis.…”