Gemcitabine resistance in triple-negative breast cancer cells can be reverted by Drosophila melanogaster deoxyribonucleoside kinase in the nucleus or cytosol

Abstract

The development of drug resistance to chemotherapeutic agents has consistently presented a challenge in terms of the treatment of patients with triple-negative breast cancer (TNBC). In the present study, gemcitabine (dFdC)-resistant TNBC cells were established, and the effects of lentivirus-deoxyribonucleoside kinase (dNK) and a mutated form of dNK (lentivirus-dNKmut) on reversing the acquired drug resistance in dFdC-resistant TNBC cells were explored. Quantitative PCR and western blotting experiment results suggested that Drosophila melanogaster (Dm)-dNK was stably expressed in the lentivirus-infected MDA-MB-231 and MDA-MB-231R cells in the nucleus or cytosol, and autoradiography experiments revealed similar levels of enzymatic activity in the cells expressing dNK or dNKmut. In vitro cytotoxicity assay revealed that the IC ₅₀ values of dFdC were decreased 30~50-fold in the dFdC-resistant MDA-MB-231 cells following lentiviral transfection with dNK or dNKmut, and this effect was associated with a significantly increased rate of apoptosis compared with the cells transfected with the negative control lentivirus. In conclusion, Dm-dNK in the nucleus or cytosol may be a potential candidate for reversing acquired dFdC resistance in TNBC cells, which may form the basis of novel strategies for the treatment of patients with drug-resistant TNBC.