Sanguinarine Represses the Growth and Metastasis of Non-small Cell Lung Cancer by Facilitating Ferroptosis.

OBJECTIVE: Ethnopharmacological relevance: Sanguinarine (SAG), a natural benzophenanthridine alkaloid derived from the root of Sanguinaria canadensis Linn. (Bloodroot), possesses a potential anticancer activity. Lung carcinoma is the chief cause of malignancy-related mortality in China. Non-small cell lung carcinoma (NSCLC) is the main subtype of lung carcinoma and accounts for about eighty-five percent of this disease. Current treatment in controlling and curing NSCLC remains deficient. AIM: The role and underlying mechanism of SAG in repressing the growth and metastasis of NSCLC were explored. MATERIALS AND METHODS: The role of SAG in regulating the proliferation and invasion of NSCLC cells was evaluated in vitro and in a xenograft model. After treatment with SAG, Fe2+ concentration, reactive oxygen species (ROS) levels, malondialdehyde (MDA), and glutathione (GSH) content in NSCLC cells were assessed to evaluate the effect of SAG on facilitating ferroptosis. RESULTS: SAG exhibited a dose- and time-dependent cytotoxicity in A549 and H3122 cells. SAG treatment effectively repressed the growth and metastasis of NSCLC in a xenograft model. We, for the first time, verified that SAG triggered ferroptosis of NSCLC cells, as evidenced by increased Fe2+ concentration, ROS level, and MDA content, and decreased GSH content. Mechanistically, SAG decreased the protein stability of glutathione peroxide 4 (GPX4) through E3 ligase STUB1-mediated ubiquitination and degradation of endogenous GPX4. GPX4 overexpression restored the proliferation and invasion of NSCLC cells treated with SAG through inhibiting ferroptosis. CONCLUSION: SAG inhibits the growth and metastasis of NSCLC by regulating STUB1/GPX4-dependent ferroptosis.

The Efficacy of Long-Term Chinese Herbal Medicine Use on Lung Cancer Survival Time: A Retrospective Two-Center Cohort Study with Propensity Score Matching.

OBJECTIVE: To explore the efficacy of long-term use of Chinese herbal medicine (CHM) on survival time of lung cancer. METHODS: We conducted a retrospective cohort study on lung cancer patients. A propensity score matching (PSM) was performed to balance the covariates. Progression-free survival (PFS) was the primary endpoint and overall survival (OS) was the secondary endpoint. Patients who received CHM therapy from the initial date of diagnosis of lung cancer were included in the CHM group. Patients who were not treated with CHM during the same interval were categorized in the control group. A Cox regression model was used to explore the prognostic factors related to lung cancer. Hazard ratios of different subgroups were also analyzed. RESULTS: A total of 1134 patients were included in our study: 761 patients were in the CHM group and 373 patients were in the control group. After PSM, the mPFS and mOS in the CHM group were 70.4 months and 129.1 months, respectively, while the mPFS and mOS in the control group were 23.8 months and 99.7 months, respectively. The results of survival analysis on each stage demonstrated that patients may benefit from the long-term CHM treatment especially for patients with early stage. One-year to ten-year progression-free survival rates in the CHM group were higher than those in the control group (p < 0.001). COX multivariate regression analysis indicated that CHM treatment, female, low age at diagnosis, early tumor stage, and surgery were independent protective factors against recurrence and metastasis of lung cancer. Subgroup analysis showed that CHM treatment could reduce the risk of recurrence and metastasis in each subgroup (p < 0.01). CONCLUSION: Long-term CHM treatment with the Fuzheng Quxie Formula, which can be flexibly applied in the course of lung cancer treatment, not only has a positive influence on the progression-free survival time of lung cancer patients, but also reduces the risk of recurrence and metastasis of lung cancer.

Chinese Herbal Prescription Fu-Zheng-Qu-Xie Prevents Recurrence and Metastasis of Postoperative Early-Stage Lung Adenocarcinoma: A Prospective Cohort Study Followed with Potential Mechanism Exploration.

Chinese herbal Fu-Zheng-Qu-Xie (FZQX) prescription has been found to improve the immune function and survival of patients with early-stage lung cancer. However, the therapeutic efficacy needs to be evaluated objectively, and the precise mechanism remains unclear. In the present study, a double-center, prospective cohort study was carried out to assess the clinical efficacy of the FZQX prescription in preventing the recurrence and metastasis of postoperative early-stage lung adenocarcinoma. Our results indicated that the FZQX prescription could significantly reduce the 3-year postoperative recurrence rate and improve the life quality. Moreover, the peripheral blood indices showed that the positive immune index (CD4 +T/CD8 +T) increased and the negative immune indices (CD8 +T, Myeloid-derived suppressor cells (MDSCs), Treg) decreased after treatment with the FZQX prescription. Since the positive regulatory effect of the FZQX prescription on immune function, a series of experiments were conducted to verify the tumor-suppressive effect and elucidate the underlying mechanisms. Through the MDSC clearance xenograft model, we confirmed that the FZQX prescription could effectively suppress tumor growth with lesser side effects in vivo, and MDSCs may be involved in the biological process of the FZQX prescription's intervention in lung cancer progression. By establishing the coculture system of MDSCs/LLC to simulate the immune microenvironment of lung cancer, the tumor suppression effect of the FZQX prescription was further validated by in vitro experiments. Besides, it was confirmed that the FZQX prescription could regulate MDSCs to remodel the immunosuppressive tumor microenvironment, thus exerting its preventive effect on relapse of lung cancer. Finally, the pathway activator and inhibitor were further used to explore the potential molecular mechanism. Results demonstrated that the IL-1ß/NF-κB signaling pathway was one of the critical signaling pathways of FZQX prescription regulating MDSCs to prevent the recurrence and metastasis of lung adenocarcinoma.

ShenQi FuZheng Injection combined with chemotherapy in the treatment of colorectal cancer: A meta-analysis.

OBJECTIVE: This study aims to investigate cellular immunity and clinical efficacy of ShenQi FuZheng Injection (SFI) in the associated chemotherapy of colorectal cancer (CRC). METHODS: PubMed, Cochrane Library, EMBASE, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Full-text Database (VIP), WanFang Database and Chinese Biomedical Literature Database (CBM) searches were undertaken to identify randomized controlled trials of SFI plus chemotherapy versus chemotherapy alone in CRC patients. The quality of each trial was assessed according to the Jadad's scale, and Review Manager 5 was used to statisitically analyze the outcomes. RESULTS: Eight studies involving 722 patients were included in this review. The meta-analyses suggested there was a significantly higher overall response rate (OR 1.89; CI: 1.10-3.24; p = 0.02), grades of KPS (OR 2.35; CI: 1.55-3.56; p<0.01), CD3+cells (MD 10.29; CI: 8.46-12.12; p<0.01), CD4+cells (MD 7.06; CI: 5.33-8.794; p<0.01), CD4/CD8+cells (MD 0.32; CI: 0.25-0.40; p<0.01), NK+ (MD 7.20; CI: 2.02-12.37, p = 0.006), WBC (MD 1.24; CI: 0.59-1.89; p<0.01), HB (MD 14.55; CI: 7.47-21.63; p<0.01), and PLT (MD 19.05; CI: 4.29-33.81; p = 0.01), but lower severe toxicity for leukocytopenia (OR 0.37; CI: 0.17-0.80; p = 0.01), thrombocytopenia (OR 0.32; CI: 0.14-0.74; p = 0.008), gastrointestinal toxicity (OR 0.48; CI: 0.24-0.96; p = 0.04), when chemotherapy combined with SFI was compared with chemotherapy alone. There were similarities between two groups in liver dysfunction (OR 0.44; CI: 0.18-1.08; p = 0.07) and CD8+ (MD 0.54; CI: -1.89-2.96; p = 0.66). Also, there was presence of heterogeneity in the CD8 results; after the sensitivity analysis, the result of CD8+ was reversed (MD 1.57; CI: 0.32-2.81; p = 0.01). There was no significant publication bias across studies according to the Egger's (P = 0.19) and Begg's test (P = 0.23). CONCLUSION: SFI enhances chemotherapy efficiency as they are combined and used in the treatment of colorectal cancer patients. At the same time, SFI also improves patients' immunity function.