Arenobufagin enhances T-cell anti-tumor immunity in colorectal cancer by modulating HSP90ß accessibility.

BACKGROUND: Colorectal cancer (CRC) is a significant public health issue, ranking as one of the predominant cancer types globally in terms of incidence. Intriguingly, Arenobufagin (Are), a compound extracted from toad venom, has demonstrated the potential to inhibit tumor growth effectively. PURPOSE: This study aimed to explore Are's molecular targets and unravel its antitumor mechanism in CRC. Specifically, we were interested in its impact on immune checkpoint modulation and correlations with HSP90ß-STAT3-PD-L1 axis activity. METHODS: We investigated the in vivo antitumor effects of Are by constructing a colorectalcancer subcutaneous xenograft mouse model. Subsequently, we employed single-cell multi-omics technology to study the potential mechanism by which Are inhibits CRC. Utilizing target-responsive accessibility profiling (TRAP) technology, we identified heatshock protein 90ß (HSP90ß) as the direct target of Are, and confirmed this through a microscale thermophoresis experiment (MST). Further downstream mechanisms were explored through techniques such as co-immunoprecipitation, Western blotting, qPCR, and immunofluorescence. Concurrently, we arrived at the same research conclusion at the organoid level by co-cultivating with immune cells. RESULTS: We observed that Are inhibits PD-Ll expression in CRC tumor xenografts at low concentrations. Moreover, TRAP revealed that HSP90ß's accessibility significantly decreased upon Are binding. We demonstrated a decrease in the activity of the HSP90ß-STAT3-PD-Ll axis following low-concentration Are treatment in vivo. The PDO analysis showed improved enrichment of lymphocytes, particularly T cells, on the PDOs following Are treatment. CONCLUSION: Contrary to previous research focusing on the direct cytotoxicity of Are towards tumor cells, our findings indicate that it can also inhibit tumor growth at lower concentrations through the modulation of immune checkpoints. This study unveils a novel anti-tumor mechanism of Are and stimulates contemplation on the dose-response relationship of natural products, which is beneficial for the clinical translational application of Are.

Effect of Aidi injection plus transarterial chemoembolization on primary hepatic carcinoma: a systematic review and Meta-analysis.

OBJECTIVE: To assess the efficacy and safety of Aidi injection plus transarterial chemoembolization (TACE) in patients with primary hepatic carcinoma. METHODS: A comprehensive research of seven electronic databases was performed for comparative studies evaluating Aidi injection combined with TACE for primary hepatic carcinoma until September 2016. Two authors independently extracted data and assessed the methodological quality of the included trials using the Cochrane risk of bias tool from the Cochrane Handbook version 5.1.0. Data was synthesized by using RevMan 5.3 software. RESULTS: Forty-nine studies involving 3435 patients met the inclusion criteria, most of which were low methodological quality. Compared with TACE alone, Aidi injection plus TACE can significantly improve the efficiency rate [RR = 1.33, 95%CI (1.24, 1.43), P < 0.000 01], clinical beneficial rate [RR = 1.25, 95% CI (1.17, 1.33), P < 0.000 01], survival rate [6 months, RR = 1.19, 95% CI (1.09, 1.29), P < 0.0001], 12 months, [RR = 1.37, 95% CI (1.24, 1.52), P < 0.000 01], 18 months, [RR = 2.00, 95% CI (1.26, 3.20), P < 0.004], 24 months, [RR = 1.44, 95% CI (1.22, 1.70), P < 0.0001], 36 months, [RR = 1.50, 95% CI (1.07, 2.11), P = 0.02 < 0.05], quality of life [RR = 1.84, 95% CI (1.64, 2.05), P < 0.000 01] and immune function [CD3+, MD = 11.12, 95% CI (7.93, 14.30), P < 0.000 01], CD4+, [MD = 10.37, 95% CI (7.29, 13.45), P < 0.000 01], CD4+/CD8+, [MD = 0.30, 95% CI (0.07, 0.53), P = 0.01 < 0.05], NK, [MD = 7.49, 95% CI (6.64, 8.34), P < 0.000 01]. A significant improvement was also found in improvement of symptoms [RR = 1.64, 95%CI (1.38, 1.94), P < 0.000 01], leukopenia [RR = 0.60, 95% CI (0.54, 0.66), P < 0.000 01], thrombocytopenia [RR = 0.46, 95% CI (0.34, 0.61), P < 0.000 01], nausea and vomiting incidence [RR = 0.66, 95% CI (0.54, 0.81), P < 0.0001), liver damage rate [RR = 0.57, 95% CI (0.42, 0.77), P = 0.0003 < 0.05), and kidney damage rate [RR = 0.18, 95% CI (0.05, 0.68), P = 0.01 < 0.05]. CONCLUSION: The results suggested that Aidi injection plus TACE significantly improve the clinical effect of TACE, and reduce the incidence of adverse events. However, rigorous multicenter trials with larger size are warranted to further confirm the findings.