Flavokawain B induces apoptosis of human oral adenoid cystic cancer ACC-2 cells via up-regulation of Bim and down-regulation of Bcl-2 expression.
ABSTRACT Novel effective drugs are still urgently needed in the prevention and treatment of oral adenoid cystic carcinoma (ACC). In this study, we have assessed the antitumor potential and molecular mechanisms of flavokawain B (FKB) as a kava chalcone on the ACC-2 cell line in vitro. The results demonstrated that FKB could significantly inhibit the cell proliferation of ACC-2 in a dose-dependent manner that was associated with induced apoptosis and cell cycle G2-M arrest, and the half maximal inhibitory concentration (IC(50)) of flavokawain-B treatment for 48 h was estimated to be 4.69 ± 0.43 µmol/L. Mechanistically, FKB could induce the release of cytochrome c from mitochondria into the cytosol, and activate the cleavage of caspase-3 and, eventually, the poly(ADP-ribose) polymerase (PARP), in a dose-dependent manner, leading to marked apoptotic effect of ACC-2 cells. The apoptotic action of FKB was associated with the increased expression of proapoptotic proteins: Bim, Bax, Bak and a decreased expression of antiapoptotic Bcl-2. Among them, Bim expression was significantly induced by FKB, and knockdown of Bim expression by short-hairpin RNAs attenuated the inhibitory effect induced by FKB on ACC-2 cells. These results suggest Bim may be one of the potential transcriptional targets, and suggests the potential usefulness of FKB for the prevention and treatment of ACC.
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ABSTRACT: Flavokawain B (FKB) possesses strong anti-neoplastic activity against many cancer cells. Here we assessed its antitumor activity and molecular mechanisms in lung cancer H460 cells in vitro. FKB significantly inhibited cell proliferation and caused arrest of the cell cycle G2-M of H460 cells in a dose-dependent manner. FKB also inducted apoptosis, which was associated with cytochrome c release, caspase-7 and caspase-9 activation and Bcl-xL/Bax dys-regulation. FKB significantly down-regulated survivin and XIAP, and the inhibitory effect induced by FKB was greatly attenuated by through over-expression of survivin or Bax(-/-) MEFs. Furthermore, FKB activated the mitogen-activated protein kinases and the JNK inhibitor SP600125 significantly decreased the growth-inhibitory and apoptotic effects of FKB. Together, these results suggest the anti-lung cancer potential of flavokawain B for the prevention and treatment of lung cancer.Biotechnology Letters 06/2012; 34(10):1781-8. DOI:10.1007/s10529-012-0976-6 · 1.74 Impact Factor
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ABSTRACT: Induction of apoptosis in tumor cells has become the major focus of anti-tumor therapeutics development. Juglone, a major chemical constituent of Juglans mandshurica Maxim, possesses several bioactivities, including anti-tumor. In the present study, HeLa cells were incubated with juglone at various concentrations. The proliferation inhibition of juglone on HeLa cells was tested by the MTT assay. Occurrence of apoptosis was detected by Hoechst 33258 staining, flow cytometry, and transmission electron microscopy. The expression of apoptotic-related proteins was examined by Western blot. The results showed that juglone inhibits the growth of HeLa cells in dose-dependent manner. Topical morphological changes of apoptotic body formation after juglone treatment were observed. The percentages of early apoptosis of Annexin V-FITC were 5.23%, 7.95%, 10.69%, and 20.92% with the concentrations of juglone (12.5, 25, 50, and 100 µmol/L), respectively. After cells were treated with juglone at the different dose for 24 h, the expression of Bcl-2 was significantly down-regulated and the expression of Bax was significantly up-regulated compared with the control. These events paralleled with activation of caspase-9, -8, -3, and PARP cleavage. The results suggest that juglone may be effective for the treatment of HeLa cells.Canadian Journal of Physiology and Pharmacology 11/2012; 90(11):1553-8. DOI:10.1139/y2012-134 · 1.55 Impact Factor
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ABSTRACT: Osteosarcoma (OS) is the most common primary bone malignancy with a high propensity for local invasion and distant metastasis. Limited by the severe toxicity of conventional agents, the therapeutic bottleneck of osteosarcoma still remains unconquered. Flavokawain B (FKB), a kava extract, has been reported to have significant anti-tumor effects on several carcinoma cell lines both in vitro and in vivo. Its efficacy and low toxicity profile make FKB a promising agent for use as a novel chemotherapeutic agent. In the current study, we investigated the anti-proliferative and apoptotic effects of FKB against human osteosarcomas. Exposure of OS cells to FKB resulted in apoptosis, evidenced by loss of cell viability, morphological changes and the externalization of phosphatidylserine. Apoptosis induced by FKB resulted in activation of Caspase-3/7, -8 and -9 in OS cell lines, 143B and Saos-2. FKB also down-regulated inhibitory apoptotic markers, including Bcl-2 and Survivin and led to concomitant increases in apoptotic proteins, Bax, Puma and Fas. Therefore, the induction of apoptosis by FKB involved both extrinsic and intrinsic pathways. FKB also caused G2/M phase cell cycle arrest, which was observed through reductions in the levels of cyclin B1, cdc2 and cdc25c and increases in Myt1 levels. Furthermore, migration and invasion ability was decreased by FKB in a dose-dependent manner. The cytotoxicity profile showed FKB had significant lower side effects on bone marrow cells and small intestinal epithelial cells compared with Adriamycin. Taken together, our evidence of apoptosis and cell cycle arrest by FKB treatment with less toxicity than the standard treatments provides an innovative argument for the use of FKB as a chemotherapeutic and chemopreventive compound. In vivo experiments utilizing FKB to reduce tumorigenesis and metastatic potential will be crucial to further justify clinical application.Molecular Cancer 06/2013; 12:55. DOI:10.1186/1476-4598-12-55 · 5.40 Impact Factor