Zidovudine, an anti-viral drug, resensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine by inhibition of the Akt-GSK3β-Snail pathway.

T Namba,R Kodama,T Hoshino,S Moritomo,T Mizushima

doi:10.1038/cddis.2015.172

Abstract

Pancreatic cancer is one of the most difficult malignancies to treat owing to the rapid acquisition of resistance to chemotherapy. Gemcitabine, a first-line treatment for pancreatic cancer, prolongs patient survival by several months, and combination treatment with gemcitabine and other anti-cancer drugs in the clinic do not show any significant effects on overall survival. Thus, identification of a drug that resensitizes gemcitabine-resistant pancreatic cancer to gemcitabine and a better understanding of the molecular mechanisms of gemcitabine resistance are critical to develop new therapeutic options for pancreatic cancer. Here, we report that zidovudine resensitizes gemcitabine-resistant pancreatic cancer to gemcitabine as shown by screening a compound library, including clinical medicine, using gemcitabine-resistant cells. In analyzing the molecular mechanisms of zidovudine effects, we found that the epithelial-to-mesenchymal transition (EMT)-like phenotype and downregulation of human equilibrative nucleoside transporter 1 (hENT1) are essential for the acquisition of gemcitabine resistance, and zidovudine restored these changes. The chemical biology investigations also revealed that activation of the Akt-GSK3β-Snail1 pathway in resistant cells is a key signaling event for gemcitabine resistance, and zidovudine resensitized resistant cells to gemcitabine by inhibiting this activated pathway. Moreover, our in vivo study demonstrated that co-administration of zidovudine and gemcitabine strongly suppressed the formation of tumors by gemcitabine-resistant pancreatic cancer and prevented gemcitabine-sensitive pancreatic tumors from acquiring gemcitabine-resistant properties, inducing an EMT-like phenotype and downregulating hENT1 expression. These results suggested that co-treatment with zidovudine and gemcitabine may become a novel therapeutic strategy for pancreatic cancer by inhibiting chemoresistance-specific signaling.

Highlights

Human equilibrative nucleoside transporter 1 is a widely distributed facilitated diffusion transporter, which uptakes purine and pyrimidine nucleosides into cells.[10]
Analysis of the molecular mechanisms of zidovudine effects revealed that suppression of Human equilibrative nucleoside transporter 1 (hENT1) expression and induction of an epithelial-to-mesenchymal transition (EMT)-like phenotype via activation of the Akt-GSK3β-Snail[1] pathway are essential for gemcitabine resistance
To investigate whether the EMT phenotype, which has been well established as being related to gemcitabine resistance, is induced in PK1-GR and KLM1-GR cells and whether zidovudine affects the EMT phenotype, we examined the mRNA and protein expression levels of markers for epithelial cells (E-cadherin) and mesenchymal cells (Snail[1], Slug, and α-smooth muscle action (α-SMA)).[17]

Summary

Introduction

Human equilibrative nucleoside transporter 1 (hENT1) is a widely distributed facilitated diffusion transporter, which uptakes purine and pyrimidine nucleosides into cells.[10]. The Notch pathway is involved in gemcitabine-induced EMT.[15,17] EMT is related to cancer aggressiveness, such as metastasis and chemoresistance, in several types of cancer, including pancreatic cancer.[16,18] targeting EMT cells or preventing the induction of EMT may be new targets for anti-cancer therapeutic methods. We report that zidovudine enhanced gemcitabine-induced cell death in highly gemcitabineresistant pancreatic cancer cells. Analysis of the molecular mechanisms of zidovudine effects revealed that suppression of hENT1 expression and induction of an EMT-like phenotype via activation of the Akt-GSK3β-Snail[1] pathway are essential for gemcitabine resistance. Zidovudine inhibited these chemoresistant phenotypes by suppressing this activated pathway. Zidovudine and gemcitabine co-treatment is a new chemotherapeutic strategy for pancreatic cancer by targeting gemcitabine resistance

Methods

Results

Conclusion