acacetin and Ovarian-Neoplasms

Ovarian cancer is a devastating gynecological malignancy and frequently presents as an advanced carcinoma with disseminated peritoneum metastasis. Acacetin exerts anti-cancerous effects in several carcinomas. Here, we sought to investigate acacetin function in ovarian cancer malignancy triggered by peritoneal mesothelial cells.. Peritoneal mesothelial cells were treated with acacetin, and then the conditioned medium was collected to treat ovarian cancer cells. Then, cell proliferation was analyzed by MTT assay. Transwell analysis was conducted to evaluate cell invasion. Protein expression was determined by western blotting. ELISA and qRT-PCR were applied to analyze inflammatory cytokine levels. The underlying mechanism was also explored.. Acacetin suppressed cell proliferation and invasion, but enhanced cell apoptosis. Furthermore, mesothelial cell-evoked malignant characteristics were inhibited when mesothelial cells were pre-treated with acacetin via restraining cell proliferation and invasion, concomitant with decreases in proliferation-related PCNA, MMP-2 and MMP-9 levels. Simultaneously, acacetin reduced mesothelial cell-induced transcripts and production of pro-inflammatory cytokine IL-6 and IL-8 in ovarian cancer cells. Mechanically, acacetin decreased lysophosphatidic acid (LPA) release from mesothelial cells, and subsequent activation of receptor for advanced glycation end-products (RAGE)-PI3K/AKT signaling in ovarian cancer cells. Notably, exogenous LPA restored the above pathway, and offset the efficacy of acacetin against mesothelial cell-evoked malignancy in ovarian cancer cells, including cell proliferation, invasion and inflammatory cytokine production.. Acacetin may not only engender direct inhibition of ovarian cancer cell malignancy, but also antagonize mesothelial cell-evoked malignancy by blocking LPA release-activated RAGE-PI3K/AKT signaling. Thus, these findings provide supporting evidence for a promising therapeutic agent against ovarian cancer.

Topics: Apoptosis; Cell Line; Cell Line, Tumor; Cell Movement; Cell Proliferation; Coculture Techniques; Epithelium; Female; Flavones; Humans; Lysophospholipids; Ovarian Neoplasms; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Receptor for Advanced Glycation End Products; Signal Transduction

Dysregulation of the dynamic balance between cell proliferation and cell death leads to several malignancies including cancer. Biflavones are known to possess anti-proliferative activity against numerous cancer cell lines. The current study was undertaken to understand the mechanism of action of the biflavonoid (I-3,II-3)-biacacetin on MDA-MB-231. Biacacetin induces dose-dependent cell death in MDA-MB-231 cells from concentrations as low as 0.5 μM, which was further confirmed by an increase in sub-G1 cells. Furthermore, the cell death induced by biacacetin was found to be mitochondria-dependent, since cells devoid of mitochondria were viable in the presence of biacacetin even at the highest concentration tested (25 μM). Fluorescence studies clearly indicated nuclear changes and apoptotic body formation that are characteristic of apoptosis. These results were further corroborated by studies that demonstrate biacacetin to regulate several key markers of apoptosis like Caspase 3, p53, Bax, and poly-ADP-ribose polymerase-1. Furthermore, biacacetin did not induce cell death in normal macrophage cell line, RAW at concentrations up to 15 μM. In addition to MDA-MB-231 cells, biacacetin also induces apoptotic cell death in the highly chemo-resistant cell line, OVISE, where the cells stained positive for annexin. Biacacetin also induces cell death in the highly malignant fibrosarcoma cell line HT1080. Furthermore, biacacetin also induces significant cell death (50%) in 3D tumor spheroids, at a concentration of 25 μM. Taken together, these results provide an understanding of biacacetin-mediated cell death and thereby provides a strong basis for the use of such compounds as novel templates for anti-cancer therapeutics.

Topics: Apoptosis; Breast Neoplasms; Cell Cycle; Cell Proliferation; Female; Flavones; Humans; Mitochondria; Ovarian Neoplasms; Signal Transduction; Tumor Cells, Cultured

Acacetin (5,7-dihydroxy-4'-methoxyflavone) is a flavone compound, some of which have anti-cancerous effects. Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis and tumor growth. In this study, we found that acacetin decreased the steady level of VEGF mRNA level and inhibited VEGF transcriptional activation. To further determine the potential mechanism of acacetin in inhibiting VEGF expression, we showed that acacetin inhibited HIF-1α expression and AKT activation. Over-expression of HIF-1α or AKT restored acacetin-decreasing VEGF transcriptional activation, indicating that AKT and HIF-1 are the essential downstream targets of acacetin for inhibiting VEGF expression in the cells. Moreover, acacetin significantly inhibited ovarian cancer cell-induced angiogenesis and tumor growth in vivo through inhibiting HIF-1α and VEGF expression. Acacetin did not change HIF-1α mRNA level, but inhibited HIF-1α protein level through increasing its degradation and decreasing its stability. These results indicate that acacetin may be a useful natural compound for ovarian cancer prevention and treatment.

Topics: Angiogenesis Inhibitors; Animals; Cell Proliferation; Chick Embryo; Female; Flavones; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Neovascularization, Pathologic; Ovarian Neoplasms; Proto-Oncogene Proteins c-akt; RNA, Messenger; Transcriptional Activation; Vascular Endothelial Growth Factor A