Abstract
Inhibition of the glycolytic pathway is a critical strategy in anticancer therapy because of the role of aerobic glycolysis in cancer cells. The glycolytic inhibitor 2-Deoxy-d-glucose (2-DG) has shown potential in combination with other anticancer agents. Buforin IIb is an effective antimicrobial peptide (AMP) with broad-spectrum anticancer activity and selectivity. The efficacy of combination treatment with 2-DG and buforin IIb in prostate cancer remains unknown. Here, we tested the efficacy of buforin IIb as a mitochondria-targeting AMP in the androgen-independent human prostate cancer cell line DU145. Combining 2-DG with buforin IIb had a synergistic toxic effect on DU145 cells and mouse xenograft tumors. Combination treatment with 2-DG and buforin IIb caused stronger proliferation inhibition, greater G1 cell cycle arrest, and higher apoptosis than either treatment alone. Combination treatment dramatically decreased L-lactate production and intracellular ATP levels, indicating severe inhibition of glycolysis and ATP production. Flow cytometry and confocal laser scanning microscopy results indicate that 2-DG may increase buforin IIb uptake by DU145 cells, thereby increasing the mitochondria-targeting capacity of buforin IIb. This may partly explain the effect of combination treatment on enhancing buforin IIb-induced apoptosis. Consistently, 2-DG increased mitochondrial dysfunction and upregulated Bax/Bcl-2, promoting cytochrome c release to initiate procaspase 3 cleavage induced by buforin IIb. These results suggest that 2-DG sensitizes prostate cancer DU145 cells to buforin IIb. Moreover, combination treatment caused minimal hemolysis and cytotoxicity to normal WPMY-1 cells. Collectively, the current study demonstrates that dual targeting of glycolysis and mitochondria by 2-DG and buforin IIb may be an effective anticancer strategy for the treatment of some advanced prostate cancer.
Highlights
Despite a progressive decrease in death rate in the past two decades, cancer remains a major public health problem globally [1]
Our results suggest that inhibition of glycolysis by 2-DG is a promising agent to increase the therapeutic efficacy of antimicrobial peptide (AMP) buforin IIb in prostate cancer
Prostate cancer (PCa) cell line DU145 and the normal prostate epithelial cell line WPMY-1 were used to assess the effect of combination treatment with 2-DG and buforin IIb on cell viability using the CCK8 assay
Summary
Despite a progressive decrease in death rate in the past two decades, cancer remains a major public health problem globally [1]. The standard treatment for advanced PCa is based on hormonal strategies, such as androgen ablation therapy and/or androgen receptor (AR) antagonists, which are used to prevent AR signaling associated with the development and progression of PCa [3]. Despite a good initial response, most patients eventually. Current treatments are only slightly effective in such patients. Several chemotherapeutic drugs, such as docetaxel and cabazitaxel, are approved for the treatment of advanced PCa, their efficacy is limited. Docetaxel is frequently associated with hematological toxicities such as neutropenia, and the use of mitoxantrone is limited by severe adverse events [5]. New treatment strategies against PCa are needed
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