Effects of Fufang Banmao Capsule Associated with Sorafenib on Liver Function, Immune Status, Quality of Life Improvement, and Survival in Patients with Advanced Hepatocellular Carcinoma: A Retrospective Cohort Study.

Objective: A case-control study was carried out to explore the influences of Fufang Banmao capsule (FBC) associated with sorafenib on liver function, immune status, life quality, and survival in patients with advanced hepatocellular carcinoma (HCC). Methods: During January 2019 to October 2021, in our hospital, the clinical data of 144 patients with advanced HCC treated were collected and measured retrospectively. The patients were cured with transcatheter arterial chemoembolization (TACE) in the control group, and the patients were cured with FBC associated with sorafenib in the observation group. The clinical effect, liver function index, humoral immunity index (IgG, IgM, and IgA), cellular immunity index (CD3, CD4, CD4/CD8, and CD8), tumor marker alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA199), and life quality were compared before and after treatment. Results: Regarding the therapeutic effects, the observation group had CR4, PR 48, SD 18, and PD2; the total remission rate was 97.22%. There were 2 individuals with CR, 32 with PR, 22 with SD, and 16 with PD in the observation group. 77.79% of the total remissions occurred. The total remission rate in the observation group was higher, and the difference was statistically significant (P < 0.05). A comparison of liver function index levels before and after treatment was done. As a result of treatment, the levels of AST, ALT, and TBIL lessened. In addition, the levels of AST, ALT, and TBIL in the observation group were lower as well, and the difference was statistically significant (P < 0.05). In the control group, the levels of serum IgG, IgM, and IgA were lower after treatment than before treatment, but in the observation group, the levels were higher. Additionally, the levels of IgG, IgM, and IgA were higher, and the difference was statistically significant (P < 0.05). With regard to the cellular immune indexes, compared to those before treatment, the CD3, CD4 and CD4/CD8 of the patients in the control group were lower, CD8 was higher, while CD3, CD4, and CD4/CD8 in the observation group were higher, CD8 was lower, and the difference was statistically significant (P < 0.05). AFP and CA199 levels lessened after treatment in the control group, indicating that the markers were reducing tumor growth, and the difference was statistically significant (P < 0.05). The value of CEA lessened, and the difference was statistically significant (P < 0.05). There was a marked decrease in AFP, CEA, and CA199 serum levels in the observation group compared to those before treatment, and the difference was statistically significant (P < 0.05). After treatment, the contents of AFP, CEA, and CA199 in the observation group were lower, and the difference was statistically significant (P < 0.05). In terms of the life quality after treatment, 36 patients (50.00%) had augmented KPS score and 38 patients (52.78%) had augmented ZPS score in the observation group, which was noticeably higher compared to the control group, and the difference was statistically significant (P < 0.05). The progression-free survival (PFS) of the observation group was 31.67 months (95% confidence interval was 0.09657∼0.3019), and the PFS of the control group was 26.73 months (95% confidence interval was 3.313∼10.36). The PFS time of the observation group was noticeably longer, and the difference was statistically significant (P < 0.05). Conclusion: FBC associated with sorafenib can noticeably strengthen the clinical effect of patients with advanced HCC, enhance the liver function and immune function of patients with advanced HCC, accelerate the speed of rehabilitation and ease clinical symptoms, reduce the level of tumor markers, strengthen the quality of life, and prolong the survival time of patients.

Cinobufagin restrains the growth and triggers DNA damage of human hepatocellular carcinoma cells via proteasome-dependent degradation of thymidylate synthase.

Anti-tumor candidate drugs from natural products have gained increasing attention. Cinobufagin is a natural product isolated from the traditional chinese medicine Chansu. Herein, we find that cinobufagin inhibits the proliferation and colony-forming ability of human hepatoma HepG2 and SK-HEP-1 cells. Furthermore, cinobufagin induces G2-phase cell cycle arrest and DNA damage in cancer cells. Thymidylate synthase (TYMS), the major target of chemotherapeutic drugs 5-FU or other fluoropyrimidines, which catalyzes the conversion of dUMP to dTMP and provides the sole de novo source of thymidylate for DNA synthesis. We demonstrate that cinobufagin suppresses TYMS expression via proteasome-dependent degradation in human hepatoma cells, moreover, depletion of TYMS restrains the proliferation and colony formation of tumor cells, and the results of western blotting and immunofluorescence assay indicate DNA damage is induced in tumor cells transfected with TYMS-targeting siRNA (siTYMS), additionally, knockdown of TYMS enhances the inhibitory effect of cinobufagin on the proliferative potential of HepG2 and SK-HEP-1 cells. It is worth noting that cinobufagin in combination with 5-FU exhibits antagonism or synergism combined effects on the proliferation of human hepatoma cells, indicating that Chansu-related preparations such as cinobufacini injection and Huachansu capsules applied to clinical practice should be used with caution in combination with 5-FU for the treatment of liver cancer. Collectively, cinobufagin exerts good anti-hepatoma activity through inhibition of growth and induction of DNA damage by promoting the degradation of TYMS. Our results provide evidence that cinobufagin might be a potential agent for the treatment of cancers such as hepatocellular carcinoma. It can also promote the scientific development of Chansu, and has great significance for enriching the application of TCM in the development of new anti-tumor drugs.

A network pharmacology approach to investigate the anticancer mechanism of cinobufagin against hepatocellular carcinoma via downregulation of EGFR-CDK2 signaling.

Hepatocellular carcinoma (HCC) is one of the deadliest cancers with high mortality and poor prognosis, and the investigation on new approaches and effective drugs for HCC therapy is of great significance. In our study, we demonstrate that treatment with cinobufagin, a natural compound isolated from traditional chinese medicine Chansu, reduces proliferation and the colony formation capacity of the human hepatoma cells in vitro, in addition, cinobufagin induces mitotic arrest in human hepatoma cells. The results of a network pharmacology-based analysis show that EGFR, MAPK1, PTK2, CDK2, MAPK3, ESR1, CDK1, PRKCA, AR, and CSNK2A1 are the key targets involved in the anti-tumor activities of cinobufagin, additionally, several signaling pathways such as proteoglycans in cancer, pathways in cancer, HIF-1 signaling pathway, VEGF signaling pathway, ErbB signaling pathway, and PI3K-AKT signaling pathway are identified as the potential pathways involved in the inhibitory effects of cinobufagin against HCC. Furthermore, at the molecular level, we find that cinobufagin decreases EGFR expression and CDK2 activity in human hepatoma cells. Inhibition of EGFR or CDK2 expression could not only suppress the growth of tumor cells but also enhance the inhibitory effects of cinobufagin on the proliferative potential of human hepatoma cells. We also demonstrate that EGFR positively regulates CDK2 expression. Furthermore, EGFR inhibitor gefitinib or CDK2 inhibitor CVT-313 synergistically enhances anticancer effects of cinobufagin in human hepatoma cells. Taken together, these findings indicate that cinobufagin may exert antitumor effects by suppressing EGFR-CDK2 signaling, and our study suggests that cinobufagin may be a novel, promising anticancer agent for the treatment of HCC.

C-type natriuretic peptide in individuals with normal left ventricular systolic function.

OBJECTIVE: The objective of this study was to evaluate production or release of CNP in individuals without CHF. METHODS: Nineteen patients with symptomatic paroxysmal supraventricular tachycardia (PSVT) and normal left ventricular systolic function were enrolled into the study. Blood samples were collected from the coronary sinus (CS), the femoral artery (FA), and the peripheral vein (PV) before pacing, after rapid RA pacing, and post electrophysiological study (EPS) and/or radiofrequency (RF) ablation. RESULTS: The CNP level in the CS, compared to FA and PV, was significantly higher before pacing (CS, 3.2+/-0.8; FA, 2.6+/-0.7; PV, 2.5+/-0.5 pg/ml; CS vs. either FA or PV, both p<0.001), after the pacing (CS, 3.2+/-1.3; FA, 2.4+/-0.6 pg/ml; p=0.004), and post the EPS and/or RF ablation (CS, 3.1+/-0.7; FA, 2.6+/-0.9; PV, 2.5+/-0.8 pg/ml; CS vs. either FA or PV, both p<0.01). CONCLUSION: The myocardium regularly produces or releases CNP in patients with normal LV systolic function. Brief periods of rapid RA pacing, PSVT, or EPS does not change the production and/or release.