Liver cancer is one of common types of cancer with poor prognosis and limited therapies. Heat shock proteins (HSP) are molecular chaperones that have important roles in tumorigenesis, and emerging as therapeutic targets. Artemisinin and rhein are natural agents from Artemisia annua L. and Rheum undulatum L., respectively. Both rhein and artemisinin have anticancer effects; however, the molecular targets of rhein remain to be identified. It is also unclear whether rhein can synergize with artemisinin derivatives to inhibit liver cancer.We aim to identify the targets of rhein in the treatment of hepatocarcinoma and determine the effects of combining rhein and artemisinin derivatives on liver cancer cells.The targets of rhein were detected by mass spectrometry and validated by rhein-proteins interaction assays. The effects of rhein on the chaperone activity of HSP72/HSC70/GRP78 were determined by luciferase refolding assays. Cell viability and apoptosis were determined by CCK8 and flow cytometry assays. For in vivo study, xenograft tumor models were established and treated with rhein and artesunate. Tumor growth was monitored regularly.Mass spectrometry analysis of rhein-binding proteins in HepG2 cells revealed that HSP72, HSC70 and GRP78 were more profoundly pulled down by rhein-crosslinked sepharose 4B beads compared to the control beads. Further experiments demonstrated that rhein directly interacted with HSP72/HSC70/GRP78 proteins, and inhibit their activity of refolding denatured luciferase. Meanwhile, rhein induced proteasomal degradation of HIF1α and β-catenin. Artesunate or dihydroartemisinin in combination with knockdown of both HSP72 and HSC70 significantly inhibited cell viability. The HSP70/HSC70/GRP78 inhibitors VER-155,008 and rhein phenocopied HSP72/HSC70 knockdown, synergizing with artesunate or dihydroartemisinin to inhibit hepatocarcinoma cell viability. Combinatorial treatment with rhein and artemisinin derivatives significantly induced hepatocarcinoma cell apoptosis, and inhibited tumor growth in vivo.The current study demonstrates that rhein is a novel HSP72/HSC70/GRP78 inhibitor that suppresses the chaperone activity of HSP70s. Dual inhibition of HSP72 and HSC70 can enhance the sensitivity of hepatocarcinoma cells to artemisinin derivatives. Combined treatment with artemisinin derivative and rhein significantly inhibits hepatocarcinoma. Artemisinin derivatives in combination with dual inhibition of HSP72 and HSC70 represents a new approach to improve cancer therapy. 

Targeting HSP70 chaperones by rhein sensitizes liver cancer to artemisinin derivatives

Immunotherapy shows promise as a treatment option for various cancers. However, there is growing concern over potential complications from hepatitis B virus (HBV) reactivation after checkpoint blockade immunotherapy. Although most of the previous clinical trials on immune checkpoint inhibitors (ICIs) excluded patients with HBV, a few case reports and retrospective studies of HBV reactivation have been published. The aim of this study is to assess the risk of hepatitis B virus reactivation (HBVr) in patients receiving ICIs for advanced cancer.English and Chinese language literature published prior to April 30, 2023, was searched in PubMed, EMBASE, Web of Science, Cochrane, SinoMed, CNKI and Wanfang Data for studies reporting HBVr rates in cancer patients treated with ICIs. A pooled risk estimate was calculated for HBVr rates with 95% confidence intervals (CI).Data from 34 studies including 7126 patients were retrieved and analyzed. The pooled HBVr rate in cancer patients treated with ICIs was 1.3% (I2 = 90.44%, 95% CI: 0.2-2.9%, P < 0.001). Subgroup analysis revealed that patients diagnosed with hepatocellular carcinoma (HCC), HBV carriers, and patients from Asian regions or in developing countries have a higher rate of HBVr.Our meta-analysis demonstrated a low risk of HBVr in patients treated with ICIs for advanced cancer. ICI treatment may be safely used in patients with existing HBV infection or chronic hepatitis B, accompanied by regular monitoring and appropriate antiviral prophylaxis if necessary. 

Hepatitis B reactivation in cancer patients receiving immune checkpoint inhibitors: a systematic review and meta-analysis

Background and objective Cisplatin (DDP) plus vinorelbine (NVB) constitute the first-line regimen (NP regimen) for non-small cell lung cancer (NSCLC). Oxaliplatin (OXA) is another effective drug in treatment of NSCLC with mild toxicities to gastrointestinal tract, kidney and bone marrow. The aim of this study is to evaluate the efficiency and safety between NVB plus OXA (NO) regimen and NP regimen for advanced NSCLC. Methods We searched CBM, CNKI, VIP, Cochrane Library, PubMed, EMBASE, ASCO etc. conference proceedings and internet information. Randomized controlled trials of NO versus NP for advanced NSCLC were included; we evaluated the quality of the included studies and analyzed data by Cochrane Collaboration’s RevMan 5.0 software. Results Fourteen randomized trials involving 1 270 patients were included. There were no statistical differences between NO and NP in overall response rate, disease control rate, 1-year survival rate, anemia and thrombocytopenia. Gastrointestinal toxicity, leucopenia, alopecia and kidney toxicity were more serious in NP (P < 0.05), but neuritis was more serious in NO, with significant difference (P < 0.05). Conclusion The clinical efficacy of NO and NP for advanced NSCLC was similar, but the side effects were different. The toxicity of NO has the tendency to be more tolerable.

[Vinorelbine plus oxaliplatin versus vinorelbine plus cisplatin for advanced non-small cell lung cancer: a systematic review].

MESP1-knockdown inhibits the proliferation and epithelial mesenchymal transition of hepatocellular carcinoma and enhances the tumor-suppressive effect of 5-fluorouracil

This study was designed to evaluate the prognosis and pharmacological therapy sensitivity of epithelial mesenchymal transition-related genes (EMTRGs) that obtained from the EMTome database in hepatocellular carcinoma (HCC) using bioinformatical method. The expression status of EMTRGs were also investigated using the clinical information of HCC patients supported by TCGA database and the ICGC database to establish the TCGA cohort as the training set and the ICGC cohort as the validation set. Analyze the EMTRGs between HCC tissue and liver tissue in the TCGA cohort in the order of univariate COX regression, LASSO regression, and multivariate COX regression, and construct a risk model for EMTRGs. In addition, enrichment pathways, gene mutation status, immune infiltration, and response to drugs were also analyzed in the high-risk and low-risk groups of the TCGA cohort, and the protein expression status of EMTRGs was verified. The results showed a total of 286 differentially expressed EMTRGs in the TCGA cohort, and EZH2, S100A9, TNFRSF11B, SPINK5, and CCL21 were used for modeling. The TCGA cohort was found to have a worse outcome in the high-risk group of HCC patients, and the ICGC cohort confirmed this finding. In addition, EMTRGs risk score was shown to be an independent prognostic factor in both cohorts by univariate and multivariate COX regression. The results of GSEA analysis showed that most of the enriched pathways in the high-risk group were associated with tumor, and the pathways enriched in the low-risk group were mainly associated with metabolism. Patients in various risk groups had varying immunological conditions, and the high-risk group might benefit more from targeted treatments. To sum up, the EMTRGs risk model was developed to forecast the prognosis for HCC patients, and the model might be useful in assisting in the choice of treatment drugs for HCC patients. 

EMT-related gene risk model establishment for prognosis and drug treatment efficiency prediction in hepatocellular carcinoma

Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies in China. Most HCC patients are first diagnosed at an advanced stage, and systemic treatments are the mainstay of treatment. Summary: In recent years, immune checkpoint inhibitors have made a breakthrough in the systemic treatment of middle-advanced HCC, breaking the single therapeutic pattern of molecular-targeted agents. To better guide the clinical treatment for effective and safe use of immunotherapeutic drugs, the Chinese Association of Liver Cancer and Chinese Medical Doctor Association has gathered multidisciplinary experts and scholars in relevant fields to formulate the “Chinese Clinical Expert Consensus on Immunotherapy for Hepatocellular Carcinoma (2021)” based on current clinical studies and clinical medication experience for reference in China. Key Messages: The consensus contained 17 recommendations, including the preferred regimen for first- and second-line immunotherapy, evaluation and monitoring before/during/after treatment, management of complications, precautions for special patients, and potential population for immunotherapy.

https://www.karger.com/Article/Pdf/526038

Chinese Expert Consensus on Immunotherapy for Hepatocellular Carcinoma (2021 Edition)

BACKGROUND vinorelbine/cisplatin is an important regimen for advanced non-small lung cancer (NSCLC), but the side effect is severe . This study aims to compare the efficacy and toxicity of vinorelbine/cisplatin and vinorelbine/oxaliplatin regimens in the treatment of advanced NSCLC. METHODS One hundred and twenty six inoperatable or recurrent patients with stage III and IV NSCLC were randomized into vinorelbine/cisplatin group and vinorelbine/oxaliplatin group. All of them were treated by the two regimens responsively for 2 or 3 cycles. RESULTS The overall response rate was 48.4%(30/62) for vinorelbine/cisplatin group and 42.2% (27/64) for vinorelbine/oxaliplatin group, the partial response rate was 45.2% (28/62) and 40.6% (26/64) respectively. There was no statistically significant difference of overall response rate between two groups (P > 0.05). The major side effects were leukopenia and gastrointestinal reaction, 25 patients (40.3%) in vinorelbine/cisplatin group and 10 patients (15.6%) in vinorelbine/oxaliplatin group had grade III+IV leucopenia (P < 0.05). Eleven patients (17.7%) in vinorelbine/cisplatin group and 3 patients (4.7%) in vinorelbine/oxaliplatin group had grade III+IV gastrointestinal reaction (P < 0.05). Seven patients (11.7%) in vinorelbine/cisplatin group and 60 patients (93.8%) in vinorelbine/oxaliplatin group had neurotoxicity (P < 0.05). CONCLUSIONS Both vinorelbine/cisplatin and vinorelbine/oxaliplatin regimens are effective for advanced NSCLC. Compared with vinorelbine/cisplatin regimen, vinorelbine/oxaliplatin regimen has less bone marrow toxicity and gastrointestinal toxicity but higher neurotoxicity.

[Randomly clinical study of vinorelbine/cisplatin and vinorelbine/oxaliplatin regimens in the treatment of advanced non-small cell lung cancer].

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Chinese Expert Consensus on Immunotherapy for Hepatocellular Carcinoma (2021 Edition)

[Randomly clinical study of vinorelbine/cisplatin and vinorelbine/oxaliplatin regimens in the treatment of advanced non-small cell lung cancer].