Additive antitumor effect of arsenic trioxide combined with intravesical bacillus Calmette–Guerin immunotherapy against bladder cancer through blockade of the IER3/Nrf2 pathway - 20/09/18
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Graphical abstract |
Synergistic antitumor effects of arsenic trioxide plus bacillus Calmette–Guerin on bladder cancer by promoting IL-6/IL-8 secretion and increasing the proportion of CD4+ T cells through inhibiting the IER3/Nrf2 pathway
Highlights |
• | To study the effect of As2O3 on bladder cancer via IER3/Nrf2 pathway is innovative. |
• | As2O3 increases expressions of IL-6 and IL-8 in DC cells. |
• | As2O3 up-regulates the proportion of CD4+ cells and ratio of CD4+/CD8+ in T cells. |
• | As2O3 enhances intravesical BCG therapy for bladder cancer. |
• | As2O3 and BCG promote apoptosis of bladder cancer cells. |
Abstract |
Background |
As an inorganic compound used to treat various cancers and other diseases, arsenic trioxide (As2O3) has been reported to induce cellular apoptosis in certain kinds of cancers including bladder cancer. The aim of the present study was to elucidate the crucial cooperative role of As2O3 and intravesical bacillus Calmette-Guerin (BCG) immunotherapy and its ability to protect against bladder cancer by targeting the IER3/Nrf2 pathway.
Method |
Initially, an orthotopic bladder cancer model was established in mice by means of intravesical instillation of the human bladder cancer cell line 5637. The expression of IL-6/IL-8 in dendritic cells (DCs) and the proportion of CD4+ cells and ratio of CD4+/CD8+ T cells were subsequently determined. RT-qPCR and Western blot assay methods were employed to determine the expressions of IER3, Nrf2, NQO1, IL-6 and IL-8. Finally, tumor cell apoptosis and the volume and weight of the in vivo tumors were evaluated in an attempt to determine the contributory role of As2O3 in combination with BCG immunotherapy in treating bladder cancer.
Results |
The additive effect of As2O3 and BCG was demonstrated to promote the expressions of IL-6/IL-8 among DCs. Additionally, the proportion of CD4+ cells, ratio of CD4+/CD8+ T cells and rate of tumor cell apoptosis were all elevated, while decreased in vivo tumor volume and weight were detected. Of importance, we determined the role that ad-shNrf2 (adenoviral vectors expressing shRNA against Nrf2) played in inhibiting the effects of As2O3 on bladder cancer.
Conclusion |
Taken together, the key findings of the present study provide evidence defining the effect of As2O3 on inducing the inhibitory effect of BCG on the development of bladder cancer via the IER3/Nrf2 pathway, highlighting the potential of As2O3 as a treatment option for bladder cancer through its enhancement of intravesical BCG.
Le texte complet de cet article est disponible en PDF.Keywords : Arsenic trioxide, IER3/Nrf2, Pathway, Bacillus Calmette–Guerin, Bladder cancer
Plan
Vol 107
P. 1093-1103 - novembre 2018 Retour au numéro
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