Dihydrotanshinone-I and Liver-Neoplasms

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

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

Cryptotanshinone (CPT) and dihydrotanshinone (DHT) are diterpenoid anthraquinone compounds extracted from traditional Chinese herbal medicine (TCM). Recent studies have shown that CPT regulates the signal transduction pathways via microRNA (miRNA) alterations. However, few studies have investigated the role of DHT in miRNA alterations affecting cell-signaling pathways. This study aimed to investigate the miRNA alterations and post-transcriptional regulation activities of DHT in comparison to CPT.. HepG2 and HT-29 cells were treated with DHT or CPT for 72 h. MiRNA, transcription factor encoding mRNA, and downstream gene expression were determined using real-time quantitative PCR. Protein expression was analyzed using western blotting.. The results revealed that CPT and DHT targeted cell proliferation and apoptosis signaling pathways via miR-15a-5p, miR-27a-5p, miR-100-5p, and miR-200a-5p alterations.In silico target predictions showed that downregulation of epidermal growth factor receptor (EGFR) mRNA expression by DHT might also suppress the expression of STAT family proteins and lead to anti-proliferation effects. We also found that, compared to CPT, DHT might possess higher potency in cell growth regulation via multi-miRNA and transcription factor alterations.. This study revealed that CPT and DHT targeted cell proliferation and apoptosis signaling pathways via alterations in miRNAs and transcription factors. In addition, the findings of this study suggest that DHT is more potent than CPT in cancer chemopreventive activities. Therefore, DHT at a low dose is a TCM compound with less toxic side effects and may contribute to the development of natural medicine as a potential cancer chemopreventive agent.

Topics: Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Regulatory Proteins; Cell Cycle Proteins; Cell Proliferation; Colonic Neoplasms; Furans; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Hep G2 Cells; HT29 Cells; Humans; Liver Neoplasms; MicroRNAs; Phenanthrenes; Quinones; Signal Transduction; Transcription Factors; Transcriptome

Miltirone (1), an abietane-type diterpene quinone isolated from Salvia miltiorrhiza, possesses anticancer activity in p-glycoprotein (P-gp)-overexpressing human cancer cells. Results of the current study suggest a dual effect of miltirone on P-gp inhibition and apoptotic induction in a human hepatoma HepG2 cell line and its P-gp-overexpressing doxorubicin-resistant counterpart (R-HepG2). Miltirone (1) elicited a concentration-dependent cytotoxicity, with a similar potency (EC50 ≈ 7-12 μM), in HepG2 and R-HepG2 cells. Miltirone (1) (1.56-6.25 μM) produced synergistic effects on doxorubicin (DOX)-induced growth inhibition of R-HepG2 (synergism: 0.3 < combination index < 0.5). Molecular docking studies illustrated that miltirone (1) interacted with the active site of P-gp with a higher binding affinity than DOX, suggesting that it was a P-gp inhibitor. Flow cytometric analysis confirmed miltirone (1) as a competitive inhibitor of P-gp. At non-necrotic concentrations (1.56-25 μM), miltirone (1) activated caspase-dependent apoptotic pathways and triggered the generation of reactive oxygen species (ROS) and ROS-mediated mitogen-activated protein kinase (MAPK) signaling pathways (e.g., p38 MAPK, stress-activated protein kinase/c-Jun N-terminal kinase, and extracellular regulated kinase 1/2) in both HepG2 and R-HepG2 cells. Thus, we conclude that miltirone (1) is a dual inhibitor of P-gp and cell growth in human drug-resistant hepatoma cells.

Topics: Apoptosis; ATP Binding Cassette Transporter, Subfamily B; Caspases; Cell Cycle; Cell Proliferation; Doxorubicin; Drug Resistance, Neoplasm; Hep G2 Cells; Humans; JNK Mitogen-Activated Protein Kinases; Liver Neoplasms; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Molecular Structure; Phenanthrenes; 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