Dihydrotanshinone-I and Carcinoma--Hepatocellular

The incidence and mortality of hepatocellular carcinoma (HCC) are globally on the rise. Dihydrotanshinone I, a natural product isolated from. Cell proliferations in hepatoma cells (Huh-7 and HepG2) were evaluated by MTT and colony formation assays. Immunofluorescence (IF) of 53BP1 and flow cytometry analysis were performed to detect DNA damage and cell apoptosis. Furthermore, network pharmacological analysis was applied to explore the potential therapeutic targets and pathway of dihydrotanshinone I.. The results showed that dihydrotanshinone I effectively inhibited the proliferation of Huh-7 and HepG2 cells. Moreover, dihydrotanshinone I dose-dependently induced DNA-damage and apoptosis

Topics: Carcinoma, Hepatocellular; Cell Proliferation; DNA Damage; ErbB Receptors; Humans; Liver Neoplasms

Liver cancer is one of the leading causes of cancer-related death worldwide. Dihydrotanshinone I (DHI) was shown to inhibit the growth of several types of cancer. However, research related to hepatoma treatment using DHI is limited.. Here, we explored the inhibitory effect of DHI on the growth of hepatoma cells, and investigated the underlying molecular mechanisms.. The proliferation of Hep3B, SMCC-7721 and SK-Hep1 hepatoma cells was evaluated using the MTS and Edu staining assay. Hepatoma cell death was analyzed with a LIVE/DEAD Cell Imaging Kit. The relative expression and phosphorylation of proto-oncogene tyrosine-protein kinase Src (Src) and signal transducer and activator of transcription-3 (STAT3) proteins in hepatoma cells, as well as the expression of other protein components, were measured by western blotting. The structural interaction of DHI with Src proteins was evaluated by molecular docking, molecular dynamics simulation, surface plasmon resonance imaging and Src kinase inhibition assay. Src overexpression was achieved by infection with an adenovirus vector encoding human Src. Subsequently, the effects of DHI on tumor growth inhibition were further validated using mouse xenograft models of hepatoma.. In vitro studies showed that treatment with DHI inhibited the proliferation and promoted cell death of Hep3B, SMCC-7721 and SK-Hep1 hepatoma cells. We further identified and verified Src as a direct target of DHI by using molecular stimulation, surface plasmon resonance image and Src kinase inhibition assay. Treatment with DHI reduced the in vitro phosphorylation levels of Src and STAT3, a transcription factor regulated by Src. In the xenograft mouse models, DHI dose-dependently suppressed tumor growth and Src and STAT3 phosphorylation. Moreover, Src overexpression partly abrogated the inhibitory effects of DHI on the proliferation and cell death in hepatoma cells.. Our results suggest that DHI inhibits the growth of hepatoma cells by direct inhibition of Src.

Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Furans; Mice; Molecular Docking Simulation; Phenanthrenes; Phosphorylation; Quinones; src-Family Kinases; STAT3 Transcription Factor

Hepatocellular carcinoma (HCC) is resistant to current immunotherapy. This poor outcome mainly results from the immunosuppressive characteristics of tumor microenvironment (TME). Accumulating evidence indicates that some chemotherapy agents trigger immunogenic cell death (ICD), providing a promising strategy to remodel the immunosuppressive TME. The role of Plumbagin (PLB, a naphthoquinone compound from Plumbago zeylanica L.) as the ICD inducer for HCC cells was confirmed in this study. Dihydrotanshinone I (DIH, a phenanthraquinone compound of Salvia miltiorrhiza) functioned as the ICD enhancer by generating the reactive oxygen species (ROS). A poly(D,L-lactic-co-glycolic acid) (PLGA)-based nanoparticle (NP) was used to co-encapsulate PLB, DIH and NH

Topics: Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Furans; Lactic Acid; Liver Neoplasms; Mice; Nanoparticles; Naphthoquinones; Phenanthrenes; Quinones; Tumor Microenvironment

P-Glycoprotein (Pgp) overexpression and alterations in p53 oncogene expression are known to affect chemotherapeutic efficacy in the treatment of human hepatocellular carcinoma (HCC). The present study has demonstrated the anti-HCC potential of cryptotanshinone (1), dihydrotanshinone (2), tanshinone I (3), and tanshinone IIA (4), the active lipophilic constituents of Salvia miltiorrhiza, using MTT and caspase-3 activity assays and poly(ADP-ribose) polymerase cleavage in HepG2, Hep3B, and PLC/PRF/5 cells. THLE-3, a normal human immortalized liver cell line, was used to demonstrate the selective growth inhibitory effect of 3 for a HCC cell line. Compound 1 suppressed doxorubicin efflux, a process mediated by P-glycoprotein, in a Pgp-overexpressed HepG2 subclone (R-HepG2 cells). Despite its moderate cytostatic and pro-apoptotic effects and minimal influence on doxorubicin efflux, 4 provided the best synergism with doxorubicin as determined by the Combination Index, the Loewe additivity model, and the Bliss independence criterion.

Topics: Abietanes; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carcinoma, Hepatocellular; Doxorubicin; Drug Resistance, Neoplasm; Humans; Models, Biological; Molecular Structure; Phenanthrenes; Plants, Medicinal; Salvia miltiorrhiza

The role of reactive oxygen species (ROS) and p38 mitogen-activated protein kinases (MAPK) in tanshinones-induced apoptosis was investigated in HepG2 cells in this study. The major tanshinones (cryptotanshinone, dihydrotanshinone, tanshinone I, tanshinone IIA), isolated from Salvia miltiorrhiza, inhibit cell growth and induce caspase-dependent apoptosis concentration-dependently, with dihydrotanshinone being the most potent. All four tanshinones were found to induce ROS generation, but only dihydrotanshinone can induce activation of p38 MAPK. The p38 MAPK activation by dihydrotanshinone was inhibited by N-acetyl cysteine pretreatment. It is thus concluded that ROS-mediated p38 MAPK activation plays a vital role in dihydrotanshinone-induced apoptosis in HepG2 cells.

Topics: Abietanes; Acetylcysteine; Antineoplastic Agents, Phytogenic; Antioxidants; Apoptosis; bcl-2-Associated X Protein; Carcinoma, Hepatocellular; Caspases; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cytochromes c; Dose-Response Relationship, Drug; Enzyme Activation; Furans; Humans; Imidazoles; Inhibitory Concentration 50; JNK Mitogen-Activated Protein Kinases; L-Lactate Dehydrogenase; Liver Neoplasms; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Phenanthrenes; Phosphorylation; Poly(ADP-ribose) Polymerases; Protein Kinase Inhibitors; Protein Transport; Pyridines; Quinones; Reactive Oxygen Species; Time Factors