- β -catenin signal pathway in prostate cancer cells. - The efficacy of the combination of BZM and mitoxantrone (MTX) in treating prostate cancer remains unknown.. - Results: BZM significantly enhanced MTX-induced antiproliferation in vivo and in vitro. - BZM significantly attenuated MTX-induced apoptosis. - Conclusions: This study demonstrates that BZM enhances MTX-induced anti-tumor effects by inhibiting the Wnt/ β - Catenin signaling pathway in prostate cancer cells.. - Aber- rant activation of Wnt/ β -Catenin signaling is involved in several cancers, including colorectal cancers [3], hepato- cellular carcinomas [4], melanoma [5], pancreas cancer [6], adrenocortical carcinoma [7], and prostate cancer. - To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.. - The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.. - However, the efficacy of the combination of BZM and MTX for prostate cancer treatment remains undeter- mined. - Human prostate cancer LNCaP, 22RV1, PC-3 cells were obtained from ATCC (Manassas, VA, USA). - CFSE- labelled prostate cancer cells were treated with indicated treatments for 24 h. - To construct the mice Xenograft model, prostate cancer cells were implanted subcutaneously into the flanks of 6-week-old male SCID mice. - To investigate the effect of BZM treatment on MTX- induced anti-tumor activity in vivo, we generated sub- cutaneous xenograft tumors with LNCaP cells in SCID mice. - BZM enhanced MTX-induced anti-proliferation but attenuates MTX-induced apoptosis. - LNCaP and 22RV1 cells were treated with vehicle, BZM, MTX, or a combination of MTX and BZM for 24 h. - 2 BZM enhanced MTX-induced anti-proliferation activity. - These findings indicate that BZM enhances MTX-induced anti-proliferation, and attenuates MTX-induced apoptosis.. - BZM enhanced MTX-induced anti-proliferation but attenuated MTX-induced apoptosis in vivo. - BZM enhanced MTX-induced downregulation of nuclear β -catenin accumulation. - LNCaP and 22RV1 cells were treated with BZM, MTX, or a combination of MTX and BZM for 24 h. - 3 BZM attenuated MTX-induced apoptosis. - Proteasome activity was required for MTX-induced apoptosis. - The UPS plays an important role in the cellular process of apoptosis [31], and we hypothesized that BZM attenu- ates MTX-induced apoptosis by interfering with the pro- teasome activity required for MTX-induced apoptosis.. - MG132 treatment significantly attenuated MTX-induced apoptosis either in the early or late phase (Fig. - proteasome activity is required for MTX-induced apop- tosis, and proteasome inhibitors attenuate MTX-induced apoptosis. - We also investigated whether MG132 en- hanced MTX-induced anti-proliferation, LNCaP and 22RV1 cells were treated with vehicle, MTX, MG132, or a combination of MTX and MG132. - MG132 treatment significantly enhanced MTX-induced anti-proliferation compared with the individual drugs (Fig. - Here, we demonstrated that com- bination treatment with MTX and BZM is associated with greater anti-tumor effects compared to MTX or BZM monotherapy in prostate cancer. - BZM significantly enhanced MTX-induced anti-proliferation both in vivo and in vitro. - However, the combination of BZM and MTX attenuated MTX-induced apoptosis. - Moreover, the combination of BZM and MTX significantly. - 4 BZM attenuated MTX-induced apoptosis but enhanced anti-proliferation in vivo . - BZM induces cell death [33, 34] and anti-proliferation [35] in prostate cancer cells.. - MTX is a type-2 DNA topoisomerase inhibitor that is used as a therapy for metastatic prostate cancer alone or in combination with other drugs [10, 11]. - In this study, we found that BZM significantly enhanced the MTX-induced anti-tumor activity. - Although BZM significantly reduced MTX-induced apoptosis, the combination of BZM and MTX inhibited tumor growth and prolonged survival both in vivo and in vitro. - β-Catenin accumulated in the nucleus of enzalutamide-resistant cells and interaction of the Wnt/β-Catenin pathway overcomes resistance to enza- lutamide in castration-resistant prostate cancer [41]. - Inhibition of Wnt signaling can prevent prostate cancer progression [8]. - While several FDA-approved drugs reportedly inhibit Wnt/ β -Catenin signaling [43], inhibition of this pathway is a novel application for prostate cancer. - 5 BZM aggravated MTX-induced inhibition of Wnt/ β -Catenin signaling. - In this study, MTX increased proteasome activity in prostate cancer cells, in- dicating that proteasome activity may be required for MTX-induced apoptosis. - BZM and MG132 attenuated MTX-induced apoptosis, which may be due to a de- crease in proteasome activity.. - This study demonstrates that BZM enhances MTX- induced anti-tumor effects by inhibiting the Wnt/ β - Catenin signaling pathway in prostate cancer cells.. - The online version contains supplementary material available at https://doi.. - org/10.1186/s . - BZM attenuated MTX-induced Cell cycle ar- rest. - 6 Proteasome activity was required for MTX-induced apoptosis. - LNCaP and 22RV1 cells were treated with vehicle, MTX (1 μ M) for 24 h. - 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