Gemcitabine resistance in triple‑negative breast cancer cells can be reverted by <em>Drosophila melanogaster</em> 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.

Non-viral Suicide Gene Therapy: Cytosine Deaminase Gene Directed by VEGF Promoter and 5-fluorocytosine as a Gene Directed Enzyme/prodrug System in Breast Cancer Model

“…The VEGF promoter was obtained from 4T1 cell lines and inserted into the pEGFP-N1 expression plasmid. Another plasmid was constructed under the control of the CMV promoter, as a standard promoter [51], to make an appropriate comparison between the function of the VEGF promoter and the standard CMV promoter. The results of bystander effect test and real-time PCR showed that the VEGF promoter function can act close to the CMV promoter of the standard pEGFP-N1 plasmid.…”

Recent Advances in Drug Discovery for Triple-Negative Breast Cancer Treatment

“…To overcome the drug resistance induced by nucleoside kinase deficiency, various therapeutic approaches have been postulated. In this context, a multisubstrate deoxyribonucleoside kinase of Drosophila melanogaster in the nucleus or cytosol has been reported as a potential candidate suicide gene for reversing acquired dFdC resistance in TNBC cells [30].…”

Serum exosomal miR‐3662 down‐regulates the expression of RBMS3 to promote malignant progression and gemcitabine resistance of breast cancer cells

“…Gemcitabine, a pyrimidine nucleoside analog anticancer drug, is effective in most solid tumors, and cisplatin combined with gemcitabine is the preferred chemotherapy strategy in patients with metastatic TNBC (Hu et al., 2015; Miao et al., 2020; Poggio et al., 2018). Although gemcitabine is clinically effective, chemoresistance remains a barrier to cancer treatment (Zhao et al., 2020). Factors affecting gemcitabine resistance were previously explored.…”