Toxicology and applied pharmacology · 2025
CB-5083 and luteolin synergistically induce the apoptosis of bladder cancer cells via multiple mechanisms.
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Sun Shuben, Liu Ping, Xie Guohai, Zheng Junhua
Аннотация
PURPOSE: Bladder cancer (BC) is a common urological malignancy for which effective treatments are lacking. In recent years, valosin-containing protein (VCP) has emerged as a potential target for the treatment of cancers. CB-5083 is a VCP inhibitor that has been evaluated in phase I clinical trials. However, drug resistance and severe side effects hamper the application of CB-5083. Mounting evidence suggests that combined treatment is a useful strategy to improve anticancer efficiency with lower toxicity. The aim of this study was to evaluate the combined effects of CB-5083 and luteolin (Lut), a natural flavonoid, on BC cells.
METHODS: Cellular viability was measured via MTT assays. The cell cycle distribution, degree of cell death and mitochondrial membrane potential were assayed via flow cytometry. mRNA levels were assayed via qRT-PCR. Protein levels were measured via western blotting. RNA interference was applied to knockdown genes. Xenograft experiments were conducted to evaluate the toxicity in vivo.
RESULTS: Cotreatment with CB-5083 and luteolin synergistically reduced the viability of BC cells. In addition, cotreatment with CB-5083 and Lut synergistically induced cell cycle arrest at the G1 phase and apoptosis in BC cells. Mechanistically, CB-5083/Lut cooperatively reduced the expression of Bcl-xl and Mcl-1 in BC cells. Moreover, CB-5083 and Lut synergistically induced endoplasmic reticulum (ER) stress in BC cells. The genetic or pharmacological inhibition of ER stress markedly reduced the degree of apoptosis induced by CB-5083, Lut or their combination in BC cells. In addition, combined treatment with CB-5083 and Lut synergistically repressed the growth of BC cells in vivo.
CONCLUSION: Our data suggest that combined treatment with CB-5083 and Lut might be applied to treat BC.
METHODS: Cellular viability was measured via MTT assays. The cell cycle distribution, degree of cell death and mitochondrial membrane potential were assayed via flow cytometry. mRNA levels were assayed via qRT-PCR. Protein levels were measured via western blotting. RNA interference was applied to knockdown genes. Xenograft experiments were conducted to evaluate the toxicity in vivo.
RESULTS: Cotreatment with CB-5083 and luteolin synergistically reduced the viability of BC cells. In addition, cotreatment with CB-5083 and Lut synergistically induced cell cycle arrest at the G1 phase and apoptosis in BC cells. Mechanistically, CB-5083/Lut cooperatively reduced the expression of Bcl-xl and Mcl-1 in BC cells. Moreover, CB-5083 and Lut synergistically induced endoplasmic reticulum (ER) stress in BC cells. The genetic or pharmacological inhibition of ER stress markedly reduced the degree of apoptosis induced by CB-5083, Lut or their combination in BC cells. In addition, combined treatment with CB-5083 and Lut synergistically repressed the growth of BC cells in vivo.
CONCLUSION: Our data suggest that combined treatment with CB-5083 and Lut might be applied to treat BC.