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Immunotherapy has emerged as a promising modality for cancer treatment. Dendritic cell immunoreceptor (DCIR), a C-type lectin receptor, is expressed mainly by dendritic cells (DCs) and mediates inhibitory intracellular signaling. Inhibition of DCIR activation may enhance antitumor activity. DCIR is encoded by CLEC4A in humans and by Clec4a2 in mice. Gene gun-mediated delivery of short hairpin RNA (shRNA) targeting Clec4a2 into mice bearing bladder tumors reduces DCIR expression in DCs, inhibiting tumor growth and inducing CD8+ T cell immune responses. Various oncolytic adenoviruses have been developed in clinical trials. Previously, we have developed Ad.LCY, an oncolytic adenovirus regulated by Oct4 and hypoxia, and demonstrated its antitumor efficacy. Here, we generated a Clec4a2 shRNA-expressing oncolytic adenovirus derived from Ad.LCY, designated Ad.shDCIR, aimed at inducing more robust antitumor immune responses. Our results show that treatment with Ad.shDCIR reduced Clec4a expression in DCs in cell culture. Furthermore, Ad.shDCIR exerted cytolytic effects solely on MBT-2 bladder cancer cells but not on normal NIH 3T3 mouse fibroblasts, confirming the tumor selectivity of Ad.shDCIR. Compared to Ad.LCY, Ad.shDCIR induced higher cytotoxic T lymphocyte (CTL) activity in MBT-2 tumor-bearing immunocompetent mice. In addition, Ad.shDCIR and Ad.LCY exhibited similar antitumor effects on inhibiting tumor growth. Notably, Ad.shDCIR was superior to Ad.LCY in prolonging the survival of tumor-bearing mice. In conclusion, Ad.shDCIR may be further explored as a combination therapy of virotherapy and immunotherapy for bladder cancer and likely other types of cancer. [ABSTRACT FROM AUTHOR]

Evodiamine (EVO) exhibits anti-cancer activity through the inhibition of cell proliferation; however, little is known about its underlying mechanism. To determine whether ferroptosis is involved in the therapeutic effects of EVO, we investigated critical factors, such as lipid peroxidation levels and glutathione peroxidase 4 (GPX4) expression, under EVO treatment. Our results showed that EVO inhibited the cell proliferation of poorly differentiated, high-grade bladder cancer TCCSUP cells in a dose- and time-dependent manner. Lipid peroxides were detected by fluorescence microscopy after cancer cell exposure to EVO. GPX4, which catalyzes the conversion of lipid peroxides to prevent cells from undergoing ferroptosis, was decreased dose-dependently by EVO treatment. Given the features of iron dependency and lipid-peroxidation-driven death in ferroptosis, the iron chelator deferoxamine (DFO) was used to suppress EVO-induced ferroptosis. The lipid peroxide level significantly decreased when cells were treated with DFO prior to EVO treatment. DFO also attenuated EVO-induced cell death. Co-treatment with a pan-caspase inhibitor or necroptosis inhibitor with EVO did not alleviate cancer cell death. These results indicate that EVO induces ferroptosis rather than apoptosis or necroptosis. Furthermore, EVO suppressed the migratory ability, decreased the expression of mesenchymal markers, and increased epithelial marker expression, determined by a transwell migration assay and Western blotting. The TCCSUP bladder tumor xenograft tumor model confirmed the effects of EVO on the inhibition of tumor growth and EMT. In conclusion, EVO is a novel inducer for activating the ferroptosis of bladder cancer cells and may be a potential therapeutic agent for bladder cancer. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To establish the normal range of urine prothymosin-alpha in humans and to investigate its role as a specific tumor marker for the detection and follow-up of transitional cell carcinoma of the urinary bladder before and after curative treatment. Methods: Urine samples were obtained from 151 healthy volunteers, 60 patients with urinary tract infection, 238 patients with bladder transitional cell carcinoma (96 with tumor and 142 tumor free), and 22 patients with non-transitional cell carcinoma tumors. The urine prothymosin-alpha levels were quantified by enzyme-linked immunosorbent assay and then appropriately analyzed and compared among the different study groups. Results: The mean value of urine prothymosin-alpha in healthy volunteers was 0.68 ± 0.13 ng/mL. Regardless of the presence of urinary tract infection, the urine prothymosin-alpha level in patients with newly diagnosed, as yet untreated, bladder cancer was significantly greater than that in those who were tumor free after curative treatment (P = 0.050 and P = 0.026 for the presence and absence of urinary tract infection, respectively). At follow-up, the urine prothymosin-alpha level was constantly elevated when residual or recurrent tumor was present after treatment. Although the urine prothymosin-alpha level in patients with non-transitional cell carcinoma tumors was not significantly different from that of healthy volunteers, it was definitely lower than the level in patients with bladder tumors (P = 0.003). Conclusions: Our findings have revealed that urine prothymosin-alpha has the potential of being a useful tumor marker for the detection and follow-up of bladder cancer. [Copyright &y& Elsevier]