withanolides and Liver-Neoplasms

withanolides has been researched along with Liver-Neoplasms* in 7 studies

Other Studies

7 other study(ies) available for withanolides and Liver-Neoplasms

ArticleYear
Vimentin as a potential therapeutic target in sorafenib resistant HepG2, a HCC model cell line.
    Clinical and molecular hepatology, 2020, Volume: 26, Issue:1

    Hepatocellular carcinoma (HCC) is the most common liver cancer with high mortality rate in patients suffering from liver diseases. The drug of choice used in advanced-stage of HCC is sorafenib. However, adaptive resistance has been observed in HCC patients undergoing long-term sorafenib treatment, lowering its effectiveness. Hence, it is important to overcome drug resistance to improve overall management of HCC. Here, we have identified a candidate biomarker for sorafenib resistance in a HCC model cell line, HepG2.. Initially, comparative proteomic profiling of parental HepG2 [HepG2 (P)] and sorafenib-resistant HepG2 [HepG2 (R)] cells was performed via MALDI (matrix-assisted laser desorption/ionization) which revealed the deregulation of vimentin in HepG2 (R) cells. Gene and protein level expression of vimentin was also observed through quantitative real-time polymerase chain reaction (qRT PCR) and fluorescence-activated cell sorting (FACS), respectively. Furthermore, withaferin A was used to study regulation of vimentin expression and its significance in sorafenib resistance.. Both gene and protein level of vimentin expression was found to be downregulated in HepG2 (R) in comparison to HepG2 (P). Interestingly, the study demonstrated that withaferin A further lowered the expression of vimentin in HepG2 (R) cells in a dose-dependent manner. Also, inhibition of vimentin lowered ABCG2 expression and decreased cell viability in parental as well as sorafenib resistant HepG2 cells.. Hence, our study for the first time highlighted the probable therapeutic potential of vimentin in sorafenib resistant HepG2, a HCC model cell line.

    Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily G, Member 2; Carcinoma, Hepatocellular; Cell Survival; Chromatography, High Pressure Liquid; Down-Regulation; Drug Resistance, Neoplasm; Hep G2 Cells; Humans; Liver Neoplasms; Proteomics; Sorafenib; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Vimentin; Withanolides

2020
Adenylate kinase 4 modulates oxidative stress and stabilizes HIF-1α to drive lung adenocarcinoma metastasis.
    Journal of hematology & oncology, 2019, 01-29, Volume: 12, Issue:1

    Adenylate kinase 4 (AK4) has been identified as a biomarker of metastasis in lung cancer. However, the impacts of AK4 on metabolic genes and its translational value for drug repositioning remain unclear.. Ingenuity upstream analyses were used to identify potential transcription factors that regulate the AK4 metabolic gene signature. The expression of AK4 and its upstream regulators in lung cancer patients was examined via immunohistochemistry. Pharmacological and gene knockdown/overexpression approaches were used to investigate the interplay between AK4 and its upstream regulators during epithelial-to-mesenchymal transition (EMT). Drug candidates that reversed AK4-induced gene expression were identified by querying a connectivity map. Orthotopic xenograft mouse models were established to evaluate the therapeutic efficacy of drug candidates for metastatic lung cancer.. We found that HIF-1α is activated in the AK4 metabolic gene signature. IHC analysis confirmed this positive correlation, and the combination of both predicts worse survival in lung cancer patients. Overexpression of AK4 exaggerates HIF-1α protein expression by increasing intracellular ROS levels and subsequently induces EMT under hypoxia. Attenuation of ROS production with N-acetylcysteine abolishes AK4-induced invasion potential under hypoxia. Pharmacogenomics analysis of the AK4 gene signature revealed that withaferin-A could suppress the AK4-HIF-1α signaling axis and serve as a potent anti-metastatic agent in lung cancer.. Overexpression of AK4 promotes lung cancer metastasis by enhancing HIF-1α stability and EMT under hypoxia. Reversing the AK4 gene signature with withaferin-A may serve as a novel therapeutic strategy to treat metastatic lung cancer.

    Topics: A549 Cells; Adenocarcinoma of Lung; Adenylate Kinase; Animals; Carcinoma, Non-Small-Cell Lung; Epithelial-Mesenchymal Transition; Follow-Up Studies; Gene Knockdown Techniques; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Liver Neoplasms; Lung Neoplasms; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Invasiveness; Oxidative Stress; Reactive Oxygen Species; Transfection; Tumor Hypoxia; Withanolides; Xenograft Model Antitumor Assays

2019
4β-Hydroxywithanolide E Modulates Alternative Splicing of Apoptotic Genes in Human Hepatocellular Carcinoma Huh-7 Cells.
    Scientific reports, 2017, 08-04, Volume: 7, Issue:1

    Alternative splicing is a mechanism for increasing protein diversity from a limited number of genes. Studies have demonstrated that aberrant regulation in the alternative splicing of apoptotic gene transcripts may contribute to the development of cancer. In this study, we isolated 4β-Hydroxywithanolide E (4bHWE) from the traditional herb Physalis peruviana and investigated its biological effect in cancer cells. The results demonstrated that 4bHWE modulates the alternative splicing of various apoptotic genes, including HIPK3, SMAC/DIABLO, and SURVIVIN. We also discovered that the levels of SRSF1 phospho-isoform were decreased and the levels of H3K36me3 were increased in 4bHWE treatment. Knockdown experiments revealed that the splicing site selection of SMAC/DIABLO could be mediated by changes in the level of H3K36me3 in 4bHWE-treated cells. Furthermore, we extended our study to apoptosis-associated molecules, and detected increased levels of poly ADP-ribose polymerase cleavage and the active form of CASPASE-3 in 4bHWE-induced apoptosis. In vivo experiments indicated that the treatment of tumor-bearing mice with 4bHWE resulted in a marked decrease in tumor size. This study is the first to demonstrate that 4bHWE affects alternative splicing by modulating splicing factors and histone modifications, and provides a novel view of the antitumor mechanism of 4bHWE.

    Topics: Alternative Splicing; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Biomarkers; Carcinoma, Hepatocellular; Cell Cycle; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Histones; Humans; Liver Neoplasms; Male; Mice; Protein Processing, Post-Translational; Withanolides; Xenograft Model Antitumor Assays

2017
Metabonomics applied in exploring the antitumour mechanism of physapubenolide on hepatocellular carcinoma cells by targeting glycolysis through the Akt-p53 pathway.
    Scientific reports, 2016, 07-15, Volume: 6

    Metabolomics can be used to identify potential markers and discover new targets for future therapeutic interventions. Here, we developed a novel application of the metabonomics method based on gas chromatography-mass spectrometry (GC/MS) analysis and principal component analysis (PCA) for rapidly exploring the anticancer mechanism of physapubenolide (PB), a cytotoxic withanolide isolated from Physalis species. PB inhibited the proliferation of hepatocellular carcinoma cells in vitro and in vivo, accompanied by apoptosis-related biochemical events, including the cleavage of caspase-3/7/9 and PARP. Metabolic profiling analysis revealed that PB disturbed the metabolic pattern and significantly decreased lactate production. This suggests that the suppression of glycolysis plays an important role in the anti-tumour effects induced by PB, which is further supported by the decreased expression of glycolysis-related genes and proteins. Furthermore, the increased level of p53 and decreased expression of p-Akt were observed, and the attenuated glycolysis and enhanced apoptosis were reversed in the presence of Akt cDNA or p53 siRNA. These results confirm that PB exhibits anti-cancer activities through the Akt-p53 pathway. Our study not only reports for the first time the anti-tumour mechanism of PB, but also suggests that PB is a promising therapeutic agent for use in cancer treatments and that metabolomic approaches provide a new strategy to effectively explore the molecular mechanisms of promising anticancer compounds.

    Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Cell Proliferation; Glycolysis; Hep G2 Cells; Humans; Liver Neoplasms; Metabolomics; Mitochondria; Models, Biological; Proto-Oncogene Proteins c-akt; Signal Transduction; Tumor Suppressor Protein p53; Withanolides

2016
Withaferin A inhibits matrix metalloproteinase-9 activity by suppressing the Akt signaling pathway.
    Oncology reports, 2013, Volume: 30, Issue:2

    Withaferin A (Wit A), a steroidal lactone isolated from Withania somnifera, exhibits anti-inflammatory, immuno-modulatory and anti-angiogenic properties and antitumor activities. In the present study, we investigated the effects of Wit A on protease-mediated invasiveness of the human metastatic cancer cell lines Caski and SK-Hep1. We found that treatment with Wit A resulted in marked inhibition of the TGF‑β‑induced increase in expression and activity of matrix metalloproteinase (MMP)‑9 in Caski cell line. These effects of Wit A were dose-dependent and showed a correlation with suppression of MMP‑9 mRNA expression levels. Treatment with Wit A resulted in an ~1.6-fold induction of MMP-9 promoter activity, which was also suppressed by treatment with Wit A in Caski cells. We found that treatment with Wit A resulted in inhibition of TGF‑β‑induced phosphorylation of Akt, which was involved in the downregulation of expression of MMP-9 at the protein level. Introduction with constitutively active (CA)‑Akt resulted in a partial increase in the secretion of TGF-β-induced MMP-9 blocked by treatment with Wit A in Caski cells. According to these results, Wit A may inhibit the invasive and migratory abilities of Caski cells through a reduction in MMP-9 expression through suppression of the pAkt signaling pathway. These findings indicate that use of Wit A may be an effective strategy for control of metastasis and invasiveness of tumors.

    Topics: Cell Line, Tumor; Cell Movement; Cell Survival; Down-Regulation; Female; Humans; Liver Neoplasms; Matrix Metalloproteinase 9; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; Transcription, Genetic; Transforming Growth Factor beta; Uterine Cervical Neoplasms; Withanolides

2013
Cytotoxic withanolides from the leaves of Moroccan Withania frutescens.
    Pharmaceutical biology, 2013, Volume: 51, Issue:8

    Withania species are a rich source of interesting phytochemical substances (withanolides) which have shown several biological properties.. To investigate the cytotoxic potential of Withania frutescens (L.) Pauquy (Solanaceae) leaf extracts and isolated active compounds against cultured tumor cell lines.. The crude methanol extract of W. frutescens leaves was partitioned with dichloromethane, ethyl acetate and n-butanol. MeOH extract and its fractions were tested for their cytotoxic activity against cancer cell lines (HepG2 and HT29) using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. Bioassay-guided fractionation was performed for the active CH₂Cl₂ fraction employing column chromatography and preparative high-performance liquid chromatography. Structural elucidation of the isolated active compounds was carried out mainly by 1D and 2D NMR and mass spectrometry. The compounds were then tested for their cytotoxic activity.. The CH₂Cl₂ fraction was the most active against HT29 cell line. The fractionation procedure resulted in the isolation of 4β,17α,27-trihydroxy-1-oxo-22-R-witha-2,5,24-trienolide (1), 5β,6β-epoxy-4β,17α,27-trihydroxy-1-oxowitha-2,24-dienolide (2) and 2,3-dihydroxywithaferin A-3β-O-sulfate (3). The latter exhibited the strongest cytotoxic activity against HT29 cancer cell lines (IC₅₀ of 1.78 ± 0.09 µM) which was comparable to that of 5-fluorouracil (5-FU) used as the positive antimitotic control.. Compounds 2 and 3 were isolated from W. frutescens for the first time. Data obtained suggest that the sulfated steroidal lactone (3) can be considered as a compound with potential application in the new anticancer drugs development field.

    Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Chromatography, High Pressure Liquid; Colonic Neoplasms; Fluorouracil; Hep G2 Cells; HT29 Cells; Humans; Inhibitory Concentration 50; Liver Neoplasms; Magnetic Resonance Spectroscopy; Mass Spectrometry; Morocco; Plant Leaves; Solvents; Withania; Withanolides

2013
Withaferin A inhibits breast cancer invasion and metastasis at sub-cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation.
    International journal of cancer, 2011, Dec-01, Volume: 129, Issue:11

    Withaferin A (WFA) is purified from the plant Withania somnifera and inhibits the vimentin cytoskeleton. Vimentin overexpression in cancer correlates with metastatic disease, induction of epithelial to mesenchymal transition and reduced patient survival. As vimentin functions in cell motility, we wanted to test the hypothesis that WFA inhibits cancer metastasis by disrupting vimentin function. These data showed that WFA had weak cytotoxic and apoptotic activity at concentrations less than or equal to 500 nM, but retained potent anti-invasive activity at these low doses. Imaging of breast cancer cell lines revealed that WFA induces perinuclear vimentin accumulation followed by rapid vimentin depolymerization. A concomitant induction of vimentin ser56 phosphorylation was observed, which is consistent with vimentin disassembly. Structure activity relationships were established using a set of chemically modified WFA analogs and showed that the predicted vimentin-binding region of WFA is necessary to induce vimentin ser56 phosphorylation and for its anti-invasive activity. Pharmacokinetic studies in mice revealed that WFA reaches peak concentrations up to 2 μM in plasma with a half-life of 1.36 hr following a single 4 mg/kg dose. In a breast cancer metastasis mouse model, WFA showed dose-dependent inhibition of metastatic lung nodules and induced vimentin ser56 phosphorylation, with minimal toxicity to lung tissue. Based upon these studies, we conclude that WFA is a potent breast cancer anti-metastatic agent and the anti-metastatic activity of WFA is, at least in part, mediated through its effects on vimentin and vimentin ser56 phosphorylation.

    Topics: Animals; Antineoplastic Agents; Blotting, Western; Breast Neoplasms; Cell Differentiation; Cell Line, Tumor; Cell Movement; Female; Humans; Liver Neoplasms; Lung Neoplasms; Mice; Mice, Inbred BALB C; Neoplasm Invasiveness; Phosphorylation; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Serine; Vimentin; Withanolides

2011