pregna-4-17-diene-3-16-dione and Liver-Neoplasms

Environmental factors such as exposure to ionizing radiations, certain environmental pollutants, and toxic chemicals are considered as risk factors in the development of breast cancer. Triple-negative breast cancer (TNBC) is a molecular variant of breast cancer that lacks therapeutic targets such as progesterone receptor, estrogen receptor, and human epidermal growth factor receptor-2 which makes the targeted therapy ineffective in TNBC patients. Therefore, identification of new therapeutic targets for the treatment of TNBC and the discovery of new therapeutic agents is the need of the hour. In this study, CXCR4 was found to be highly expressed in majority of breast cancer tissues and metastatic lymph nodes derived from TNBC patients. CXCR4 expression is positively correlated with breast cancer metastasis and poor prognosis of TNBC patients suggesting that suppression of CXCR4 expression could be a good strategy in the treatment of TNBC patients. Therefore, the effect of Z-guggulsterone (ZGA) on the expression of CXCR4 in TNBC cells was examined. ZGA downregulated protein and mRNA expression of CXCR4 in TNBC cells and proteasome inhibition or lysosomal stabilization had no effect on the ZGA-induced CXCR4 reduction. CXCR4 is under the transcriptional control of NF-κB, whereas ZGA was found to downregulate transcriptional activity of NF-κB. Functionally, ZGA downmodulated the CXCL12-driven migration/invasion in TNBC cells. Additionally, the effect of ZGA on growth of tumor was investigated in the orthotopic TNBC mice model. ZGA presented good inhibition of tumor growth and liver/lung metastasis in this model. Western blotting and immunohistochemical analysis indicated a reduction of CXCR4, NF-κB, and Ki67 in tumor tissues. Computational analysis suggested PXR agonism and FXR antagonism as targets of ZGA. In conclusion, CXCR4 was found to be overexpressed in majority of patient-derived TNBC tissues and ZGA abrogated the growth of TNBC tumors by partly targeting the CXCL12/CXCR4 signaling axis.

Topics: Animals; Cell Line, Tumor; Chemokine CXCL12; Humans; Liver Neoplasms; Mice; NF-kappa B; Pregnenediones; Receptors, CXCR4; Signal Transduction; Triple Negative Breast Neoplasms

An ancient saffron-based polyherbal formulation, Dawa-ul-Kurkum (DuK), has been used to treat liver ailments and other diseases and was recently evaluated for its anticancer potential against hepatocellular carcinoma (HCC) by our research team. To gain further insight into the lead molecule of DuK, we selected ten active constituents belonging to its seven herbal constituents (crocin, crocetin, safranal, jatamansone, isovaleric acid, cinnamaldehyde, coumaric acid, citral, guggulsterone and dehydrocostus lactone). We docked them with 32 prominent proteins that play important roles in the development, progression and suppression of HCC and those involved in endoplasmic reticulum (ER) stress to identify the binding interactions between them. Three reference drugs for HCC (sorafenib, regorafenib, and nivolumab) were also examined for comparison. The in silico studies revealed that, out of the ten compounds, three of them-

Topics: Carcinoma, Hepatocellular; Crocus; Humans; Liver Neoplasms; Pregnenediones

To investigate the effects of guggulsterone on the proliferation and apoptosis of human hepatoma HepG2 cells in vitro and relevant mechanisms.. Human hepatocellular carcinoma HepG2 cells and normal human liver L-02 cells were treated with different concentrations of guggulsterone (5-100 μmol/L) for 24-72 h. Cell proliferation was tested by MTT assay. Cell cycle and apoptosis were investigated using flow cytometry (FACS). Bcl-2 and Bax mRNA and protein expression was detected by real-time PCR and Western blot, respectively. TGF-β1, TNF-α, and VEGF contents were determined by ELISA.. Guggulsterone significantly inhibited HepG2 cell proliferation in a dose- and time-dependent manner. FACS showed that guggulsterone arrested HepG2 cell cycle at G0/G1 phase. Guggulsterone induced apoptosis was also observed in HepG2 cells, with 24.91% ± 2.41% and 53.03% ± 2.28% of apoptotic cells in response to the treatment with 50 μmol/L and 75 μmol/L guggulsterone, respectively. Bax mRNA and protein expression was significantly increased and Bcl-2 mRNA and protein expression was decreased. ELISA analysis showed that the concentrations of TGF-β1 and VEGF were significantly decreased and TNF-α concentration was increased.. Guggulsterone exerts its anticancer effects by inhibiting cell proliferation and inducing apoptosis in HepG2 cells. Guggulsterone induces apoptosis by activation of the intrinsic mitochondrial pathway.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; bcl-2-Associated X Protein; Carcinoma, Hepatocellular; Cell Cycle Checkpoints; Cell Proliferation; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Liver Neoplasms; Mitochondria; Pregnenediones; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Time Factors; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Guggulsterone (GGS) has anti-tumor and anti-angiogenesis potential by suppressing nuclear factor-κB and STAT3 activity. Although GGS has been suggested as a potential therapeutic agent for treating various cancers, the underlying molecular mechanisms are unknown. Therefore, we investigated whether GGS sensitizes hepatocellular carcinoma cells (HCC) to apoptosis mediated by tumor necrosis factor-related apoptosis inducing ligand (TRAIL). The apoptotic mechanism induced by treatment with a GGS/TRAIL combination involved the loss of mitochondrial transmembrane potential and consequent activation of caspases. GGS also induced upregulation of the death receptor DR5 for TRAIL. The effects seemed to be associated with eIF2α and CHOP activation, which are related to the endoplasmic reticulum (ER) stress response and apoptosis. This relationship was suggested by the observation that CHOP downregulation by specific siRNA attenuated both GGS-mediated DR5 upregulation and the cytotoxicity induced by GGS/TRAIL co-treatment. Moreover, salubrinal, a specific eIF-2α phosphorylation-inducing agent, enhanced the expression of CHOP and DR5 induced by GGS and sensitized cells to GGS/TRAIL-induced apoptosis. Thus, GGS-induced eIF2α phosphorylation seems to be important for CHOP and DR5 upregulation. Furthermore, these events were accompanied by an increase in the generation of reactive oxygen species. Pretreatment with N-acetyl-L-cysteine and glutathione inhibited GGS-induced ER-stress, and CHOP and DR5 upregulation and almost completely blocked GGS/TRAIL-induced apoptosis. These results collectively indicate that DR5 induction via eIF-2α and CHOP is crucial for the marked synergistic effects induced by TRAIL and GGS. Taken together, these results indicate that a GGS/TRAIL combination could represent a novel important tool for cancer therapy.

Topics: Apoptosis; Carcinoma, Hepatocellular; Caspases; Cell Line, Tumor; Drug Synergism; Endoplasmic Reticulum Stress; Enzyme Activation; Humans; Liver Neoplasms; Pregnenediones; Reactive Oxygen Species; Receptors, TNF-Related Apoptosis-Inducing Ligand; TNF-Related Apoptosis-Inducing Ligand; Transcription Factor CHOP; Up-Regulation