Cytochrome P450 isoforms 1A1, 1B1 AND 2W1 as targets for therapeutic intervention in head and neck cancer

Daniela Presa,Goreti R Morais,Syed A Khurram,Paul M Loadman,Patricia A Cooper,Maria Sadiq,Klaus Pors,Laurence H Patterson,James Mccaul,Steven D Shnyder,Amir Z A Zubir,Sneha Smarakan,Mark Sutherland

doi:10.1038/s41598-021-98217-z

Daniela Presa, Goreti R Morais + Show 11 more

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https://doi.org/10.1038/s41598-021-98217-z

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Abstract

Epidemiological studies have shown that head and neck cancer (HNC) is a complex multistage process that in part involves exposure to a combination of carcinogens and the capacity of certain drug-metabolising enzymes including cytochrome P450 (CYP) to detoxify or activate such carcinogens. In this study, CYP1A1, CYP1B1 and CYP2W1 expression in HNC was correlated with potential as target for duocarmycin prodrug activation and selective therapy. In the HNC cell lines, elevated expression was shown at the gene level for CYP1A1 and CYP1B1 whereas CYP2W1 was hardly detected. However, CYP2W1 was expressed in FaDu and Detroit-562 xenografts and in a cohort of human HNC samples. Functional activity was measured in Fadu and Detroit-562 cells using P450-Glo™ assay. Antiproliferative results of duocarmycin prodrugs ICT2700 and ICT2706 revealed FaDu and Detroit-562 as the most sensitive HNC cell lines. Administration of ICT2700 in vivo using a single dose of ICT2700 (150 mg/kg) showed preferential inhibition of small tumour growth (mean size of 60 mm3) in mice bearing FaDu xenografts. Significantly, our findings suggest a potential targeted therapeutic approach to manage HNCs by exploiting intratumoural CYP expression for metabolic activation of duocarmycin-based prodrugs such as ICT2700.

Highlights

Head and neck cancers (HNCs) are a heterogeneous group of cancers which can develop in several areas within the head and neck such as the oral cavity, nasopharynx, oropharynx, hypopharynx, larynx, paranasal sinuses and salivary glands[1]
In the frozen tissue samples the majority of normal tissue (80%) displayed no CYP2W1 expression while the primary tumours from the same source consistently showed high expression (Fig. 1C)
Taken together the data indicated that CYP1A1, 1B1 and 2W1 isoforms were, in general, moderately or highly expressed in HNC compared with normal tissues

Summary

Introduction

Head and neck cancers (HNCs) are a heterogeneous group of cancers which can develop in several areas within the head and neck such as the oral cavity, nasopharynx, oropharynx, hypopharynx, larynx, paranasal sinuses and salivary glands[1]. The first molecularly targeted treatment in HNC was cetuximab which acts through binding of the epidermal growth factor receptor (EGFR) This monoclonal antibody has been found to be beneficial for HNC patients with locally advanced and recurrent tumour when administered along with routine chemotherapeutics or radiotherapy. The individual susceptibilities to HNC have been correlated with two functional nonsynonymous polymorphisms, Ile462Val and MspI These could alter CYP1A1 expression and function, potentially influencing the balance between metabolic activation and detoxification of toxicants[12]. As a continuation of our interest in investigating CYPs overexpressed in tumour t issue[26,27,28,29,30] we show CYP1A1, 1B1 and 2W1 expression in HNC as potential targets for therapeutic intervention using CYP-activated duocarmycin bioprecursors developed in-house

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