N1-guanyl-1,7-diaminoheptane sensitizes bladder cancer cells to doxorubicin by preventing epithelial-mesenchymal transition through inhibition of eukaryotic translation initiation factor 5A2 activation.
Bottom Line: Drug resistance greatly reduces the efficacy of doxorubicin-based chemotherapy in bladder cancer treatment; however, the underlying mechanisms are poorly understood.It significantly inhibited activity of eIF5A2, suppressed doxorubicin-induced epithelial-mesenchymal transition in BIU-87 cells, and promoted mesenchymal-epithelial transition in J82 and UM-UC-3 cells.Combination therapy with GC7 may enhance the therapeutic efficacy of doxorubicin in bladder cancer by inhibiting eIF5A2 activation and preventing epithelial-mesenchymal transition.
Affiliation: Department of Radiation Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.Show MeSH
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Mentions: Activation of eIF5A2 is specifically inhibited by GC7 through inhibiting the hypusination of eIF5A2 by DHPS. However, the cytotoxicity of GC7 towards bladder cells is rarely reported. To determine the GC7 concentration appropriate for coadministration with doxorubicin, we tested the effect of a series of GC7 concentrations on bladder cell viability using the CCK8 assay. Between 0 and 50 μM, GC7 exerted little cytotoxicity in bladder cancer cells; however, higher concentrations of GC7 (e.g., 100 μM) significantly inhibited the viability of the three cell lines (Fig. 1a–c). Although 50 μM GC7 exhibited little cytotoxicity on bladder cancer cells, rare hypusinated eIF5A2 (mature form) was detected in the presence of 50 μM GC7 (Fig. 1d–f) after incubation with [1, 8-3H]-spermidine. Western blot analyses revealed GC7 did not exert any effects on the expression levels of eIF5A2 (Fig. 1d–f) in bladder cancer cells. Therefore, 50 μM GC7, which exerted a low toxicity but effectively inhibited eIF5A2 activation, was used for further cotreatments with doxorubicin.
Affiliation: Department of Radiation Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.