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

• Published in: Scientific reports Vol. 11; no. 1; p. 18930
• Main Authors: Presa, Daniela, Khurram, Syed A., Zubir, Amir Z. A., Smarakan, Sneha, Cooper, Patricia A., Morais, Goreti R., Sadiq, Maria, Sutherland, Mark, Loadman, Paul M., McCaul, James, Shnyder, Steven D., Patterson, Laurence H., Pors, Klaus
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23-09-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/154; 631/67; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Carcinogens; Cell Line, Tumor; Cohort Studies; Cytochrome; Cytochrome P-450 CYP1A1 - antagonists & inhibitors; Cytochrome P-450 CYP1A1 - metabolism; Cytochrome P-450 CYP1B1 - antagonists & inhibitors; Cytochrome P-450 CYP1B1 - metabolism; Cytochrome P450; Cytochrome P450 Family 2 - antagonists & inhibitors; Cytochrome P450 Family 2 - metabolism; Epidemiology; Female; Head & neck cancer; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - pathology; Heterocyclic Compounds, 3-Ring - pharmacology; Heterocyclic Compounds, 3-Ring - therapeutic use; Humanities and Social Sciences; Humans; Indoles - pharmacology; Indoles - therapeutic use; Isoforms; Metabolic activation; Metabolic rate; Mice; multidisciplinary; Prodrugs; Prodrugs - pharmacology; Prodrugs - therapeutic use; Pyrroles - pharmacology; Pyrroles - therapeutic use; Science; Science (multidisciplinary); Tumors; Xenograft Model Antitumor Assays; Xenografts; United States > US; Detroit Michigan
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-98217-z

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 mm
3
) 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.