epothilone-a and Carcinoma--Hepatocellular

Liver carcinoma generally presents as an immunosuppressive microenvironment that promotes tumor evasion. The intercellular crosstalk of immune cells significantly influences the construction of an immunosuppressive microenvironment. This study aimed to investigate the important interactions between immune cells and their targeting drugs in liver carcinoma, by using single-cell and bulk transcriptomic data.. Single-cell and bulk transcriptomic data were retrieved from Gene Expression Omnibus (GSE159977, GSE136103, and GSE125449) and The Cancer Genome Atlas (TGCA-LIHC), respectively. Quality control, dimension reduction, clustering, and annotation were performed according to the Scanpy workflow based on Python. Cell-cell interactions were explored using the CellPhone database and CellChat. Trajectory analysis was executed using a partition-based graph abstraction method. The transcriptomic factors (TFs) were predicted using single-cell regulatory network inference and clustering (SCENIC). The target genes from TFs were used to establish a related score based on the TCGA cohort; this score was subsequently validated by survival, gene set enrichment, and immune cell infiltration analyses. Drug prediction was performed based on the Cancer Therapeutics Response Portal and PRISM Repurposing datasets.. Thirty-one patients at four different states, including health, hepatitis, cirrhosis, and cancer, were enrolled in this study. After dimension reduction and clustering, twenty-two clusters were identified. Cell-cell interaction analyses indicated that macrophage-naive CD4 + T cell interaction significantly affect cancerous state. In brief, macrophages interact with naive CD4 + T cells via different pathways in different states. The results of SCENIC indicated that macrophages present in cancer cells were similar to those present during cirrhosis. A macrophage-naive CD4 + T cell (MNT) score was generated by the SCENIC-derived target genes. Based on the MNT score, five relevant drugs (inhibitor of polo-like kinase 1, inhibitor of kinesin family member 11, dabrafenib, ispinesib, and epothilone-b) were predicted.. This study reveals the crucial role of macrophage-naive CD4 + T cell interaction in the immunosuppressive microenvironment of liver carcinoma. Tumor-associated macrophages may be derived from cirrhosis and can initiate liver carcinoma. Predictive drugs that target the macrophage-naive CD4 + T cell interaction may help to improve the immunosuppressive microenvironment and prevent immune evasion. The relevant mechanisms need to be further validated in experiments and cohort studies.

Topics: Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell Communication; Epothilones; Humans; Kinesins; Liver Cirrhosis; Liver Neoplasms; Macrophages; T-Lymphocytes; Transcriptome; Tumor Microenvironment

High mortality rates in ovarian and liver cancer are largely a result of resistance to currently used chemotherapy. Here, we investigated genotoxic and pro-oxidant effects of metformin (MET) and epothilone A (A) in combination with respect to apoptosis in HepG2 and SKOV-3 cancer cells. Reactive oxygen species (ROS) was studied using 2',7'-dichlorodihydrofluoresein diacetate, and samples were analyzed for the presence and absence of the N-acetylcysteine (NAC). Expression of genes involved in programmed cell death, oxidative and alkylating DNA damage was measured. Probes were analyzed in the presence of Akt or nuclear factor-κB inhibitor. Compared to either drug alone, combination of epothilone A and metformin was more potent; decreased Akt level; and elevated percentage of apoptotic cells, induced cell cycle arrest at G1 phase and elevated the sub-G1 cell population by increasing the mRNA level of caspase-3, poly (ADP-ribose) polymerase-1 and H2AX. The anticancer effect of the drug combination was partially reversed by NAC supplementation, suggesting that ROS generation is required to induce apoptosis. The present study demonstrates that novel combination such as epothilone A and MET show promise in expanding ovarian and liver cancer therapy.

Topics: Adenocarcinoma; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Hepatocellular; Caspase 3; Cell Line, Tumor; DNA Damage; Drug Resistance, Neoplasm; Epothilones; Female; Gene Expression Regulation, Neoplastic; Histones; Humans; Hypoglycemic Agents; Liver Neoplasms; Metformin; Neoplasm Proteins; Ovarian Neoplasms; Oxidative Stress; Poly (ADP-Ribose) Polymerase-1; Proto-Oncogene Proteins c-akt

Type 2 diabetes mellitus patients are at increased risk of many forms of malignancies, especially of the pancreas, colon and hepatocellular cancer. Unfortunately, little is known of the possible interaction between antidiabetic drugs and anticancer agents. The present study investigates the influence of metformin (MET) and sitagliptin (SITA) on the in vitro anticancer activity of the microtubule depolymerization inhibitor agent epothilone A (EpoA). Hepatocellular liver carcinoma cell line (HepG2) viability and apoptosis were determined by the MTT test and by double staining with PO-PRO-1 and 7-aminoactinomycin D, respectively, after treatment with EpoA, metformin or sitagliptin. The levels of nuclear factor NF-κB and p53 were evaluated in the presence and absence of inhibitors. While EpoA and MET inhibited HepG2 cell proliferation, SITA did not. EpoA and SITA induced higher p53 levels than MET. All tested drugs increased the level of NF-κB. Only MET enhanced the proapoptotic effect of EpoA. The EpoA+MET combination evoked the highest cytotoxic effect on HepG2 cells and led to apoptosis independent of p53, decreasing the level of NF-κB. These findings support the link between NF-κB and p53 in the modulation of apoptotic effects in HepG2 cells treated by EpoA. Our studies indicate that the combination of EpoA and MET applied in subtoxic doses has a stronger cytotoxic effect on liver cancer cells than each of the compounds alone. The therapeutic advantages of the combination of EpoA with MET may be valuable in the treatment of patients with diabetes mellitus type 2 (T2DM) and liver cancer.

Topics: Antineoplastic Agents; Apoptosis; Benzoxazoles; Carcinoma, Hepatocellular; Dactinomycin; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Epothilones; Hep G2 Cells; Humans; Hypoglycemic Agents; Liver Neoplasms; Metformin; NF-kappa B; Sitagliptin Phosphate; Tumor Suppressor Protein p53

Hepatocellular carcinoma (HCC) is one of the most common and challenging malignant disease. The prognosis is poor in patients with advanced disease. Although sorafenib prolongs survival in these patients, improvement remains modest. We used doxorubicin and sorafenib as controls and screened eight new agents including ixabepilone, gefitinib, cetuximab, brivanib, dasatinib, sunitinib, BMS-690514, and BMS-536924 against nine HCC cell lines and evaluated their interactions. We studied growth inhibition of 10 drugs against nine HCC cell lines. Single-agent activity was tested using an MTS assay. Combination studies were carried out in both resistant and sensitive cells to determine the combination index. The IC50 of each agent varied widely among nine cell lines. Ixabepilone was more potent than doxorubicin. HT-17 cells were more sensitive to gefitinib and cetuximab than the other eight cell lines. BMS-536924 showed good efficacy (IC50 ≤ 1 µmol/l) on all three α-fetoprotein (AFP)-producing cell lines (HepG2, Hep3B, Huh-7). Three cell lines showed moderate sensitivity to dasatinib (IC50 ≤ 1 µmol/l). Dasatinib showed the most frequent and strongest synergism with ixabepilone, gefitinib, brivanib, BMS-690514, or BMS-536924. Ixabepilone, sorafenib, brivanib, dasatinib, and BMS-536924 are active against HCC cell lines. The heterogeneity of the sensitivity of each cell line emphasizes the need for individualized treatment. The sensitivity to BMS-536924 is closely associated with the production of AFP. AFP may be a biomarker predicting response to the insulin-like growth factor-1 receptor inhibitor in HCC patients. Additional studies are warranted. The synergism between dasatinib and other agents also provides future research directions to understand drug resistance and improve outcome.

Topics: Alanine; alpha-Fetoproteins; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carcinoma, Hepatocellular; Cetuximab; Dasatinib; Doxorubicin; Drug Screening Assays, Antitumor; Epothilones; Gefitinib; Humans; Indoles; Inhibitory Concentration 50; Liver Neoplasms; Niacinamide; Phenylurea Compounds; Piperidines; Pyridones; Pyrimidines; Pyrroles; Quinazolines; Sorafenib; Sunitinib; Thiazoles; Triazines

In this study, the cytotoxic effects of patupilone (epothilone B; EPO906) were assessed in a panel of hepatocellular carcinoma (HCC) cell lines, and were compared with doxorubicin and the microtubule-stabilizing taxanes.. The following HCC cell lines were used: PLC/PRF/5, HepG2, Hep3B, SNU-387, SNU-398, SNU-423, SNU-449, and SNU-475. Cells were treated with various concentrations of patupilone, paclitaxel, docetaxel, or doxorubicin for 72 h; 50% inhibitory concentrations (IC(50)) were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay. P-glycoprotein expression was assessed using standard Western blotting techniques.. Patupilone was found to be the most potent drug in all 8 HCC cell lines. All cell lines except SNU-449 were 4- to19-fold more sensitive to patupilone than to paclitaxel and docetaxel, and 59- to 208-fold more sensitive than to doxorubicin. SNU-449, the most resistant cell line and the only one overexpressing P-glycoprotein, was 3- to 39-fold more resistant to paclitaxel, docetaxel, and doxorubicin than were other cell lines. The IC(50) of patupilone in SNU-449 was 1.14 nmol, which was 108- to 529-fold lower than those of the other agents.. Patupilone was more potent than taxanes and doxorubicin in HCC cell lines and may result in reduced clinical resistance by overcoming P-glycoprotein overexpression. A clinical study in HCC is warranted.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carcinoma, Hepatocellular; Cell Line, Tumor; Docetaxel; Doxorubicin; Drug Resistance, Neoplasm; Epothilones; Humans; Liver Neoplasms; Paclitaxel; Taxoids

Different Sorangium cellulosum strains not only showed diversity in their cell and fruiting body morphologies, but also differences of bio-activities and components of the metabolites. All the Sorangial strains studied in this paper had no activity on Gram-negative bacteria, some were able to repress Gram-positive bacteria. However, all the strains were able to repress growth of fungi and tumor cells strongly and widely. Thin layer chromatography assay of metabolites showed multi-components in the metabolites, and most of them have abilities of repressing fungi and tumor cells in different degrees. Four strains were found to be able to produce compounds with activity of promoting polymerization of microtubule. Based on Rf value on TLC, the bio-active component produced by So33-1 strain was similar to Epothilone A, while that of So81 was much different. The results of this paper suggested that Sorangium cellulosum is a much beneficial resource for screening nature compounds with bio-activities against eukaryotes.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Epothilones; Humans; Liver Neoplasms; Microtubules; Myxococcales; Species Specificity