Unveiling the role of UGT enzymes in chemoresistance: a path to enhanced cancer pharmacotherapy

Abstract

Aim: Chemotherapeutic resistance is a leading cause of cancer-related mortality worldwide. It has been suggested to be at least partly driven by the activity of uridine diphosphate glucuronosyltransferases (UGTs). However, this hypothesis is primarily supported by indirect evidence with potential confounding factors arising from the use of multienzymatic models among other things. Here we present new HepG2 models transduced with UGT1A1 or UGT2B7 that provide mechanistic insights into the potential role of UGTs in resistance to SN-38, etoposide, and epirubicin.

Methods: The new cellular models were characterised by immunofluorescence, quantitative real-time PCR, and doubling-time assessment. Possible differences in chemotherapeutic efficacy were evaluated using comparative ATP viability assays and an inhibitor-based verification study. Drug combination assays were conducted to determine whether dual-activity modulation could combat enzyme-mediated resistance, using the quantitative Chou-Talalay method to detect synergistic effects. Finally, an advanced physiologically relevant model based on proliferating primary upcyte hepatocytes was characterised and used to verify the results obtained with the transduced models.

Results: The comparative ATP viability assays and verification studies using the UGT inhibitors atazanavir and diclofenac confirmed that both UGT enzymes significantly reduced the tested drugs’ pharmacodynamic activity. Drug combination experiments then showed that UGT1A1 activity can be synergistically targeted by nilotinib and regorafenib via a new dual-activity modulation approach. Finally, the role of UGT1A1 in resistance to SN-38 was confirmed in a complex model based on primary upcyte hepatocytes.

Conclusion: After in vivo confirmation, our findings could potentially be translated into effective and safe combination regimens for oncology patients.

Keywords

UDP-glucuronosyltransferase / drug resistance / cancer / chemotherapy / tyrosine kinase inhibitor

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