Celecoxib Prevents Doxorubicin-Induced Multidrug Resistance in Canine and Mouse Lymphoma Cell Lines.

Edina Karai,Tímea Windt,András Füredi,Kornélia Szebényi,Eszter Szendi,Gergely Szakács,Sára Fehér,Valéria Dékay,Péter Vajdovich

doi:10.3390/cancers12051117

Abstract

Background: Treatment of malignancies is still a major challenge in human and canine cancer, mostly due to the emergence of multidrug resistance (MDR). One of the main contributors of MDR is the overexpression P-glycoprotein (Pgp), which recognizes and extrudes various chemotherapeutics from cancer cells. Methods: To study mechanisms underlying the development of drug resistance, we established an in vitro treatment protocol to rapidly induce Pgp-mediated MDR in cancer cells. Based on a clinical observation showing that a 33-day-long, unplanned drug holiday can reverse the MDR phenotype of a canine diffuse large B-cell lymphoma patient, our aim was to use the established assay to prevent the emergence of drug resistance in the early stages of treatment. Results: We showed that an in vitro drug holiday results in the decrease of Pgp expression in MDR cell lines. Surprisingly, celecoxib, a known COX-2 inhibitor, prevented the emergence of drug-induced MDR in murine and canine lymphoma cell lines. Conclusions: Our findings suggest that celecoxib could significantly improve the efficiency of chemotherapy by preventing the development of MDR in B-cell lymphoma.

Highlights

Despite newly developed therapies and protocols, treatment of lymphomas mostly results in transient remission because of the rapid emergence of therapy resistance [1]
Multidrug resistance was quantitated by the calcein assay and the activity of Pgp was expressed as a dimensionless value (multidrug resistance activity factor (MAF)) [31]
This work demonstrates that celecoxib effectively blocks the emergence of multidrug resistance by preventing the doxorubicin-induced upregulation of P-glycoprotein

Summary

Introduction

Despite newly developed therapies and protocols, treatment of lymphomas mostly results in transient remission because of the rapid emergence of therapy resistance [1]. Occurring canine lymphoma has been considered a comparative animal model to study mechanisms underlying therapy resistance and to investigate novel therapeutic agents for human NHLs [6,7]. Canine lymphoma is usually treated with multiagent chemotherapy, such as the CHOP-protocol (cyclophosphamide (C), doxorubicin (H, hydroxydaunorubicin), vincristine (O, Oncovin), and prednisone (P)). This treatment regimen initially seems successful, tumor recurrence can be expected and the relapsed tumor is often resistant to additional treatment. Methods: To study mechanisms underlying the development of drug resistance, we established an in vitro treatment protocol to rapidly induce Pgp-mediated MDR in cancer cells. Conclusions: Our findings suggest that celecoxib could significantly improve the efficiency of chemotherapy by preventing the development of MDR in B-cell lymphoma

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Discussion

Conclusion