Flavokawain B, a kava chalcone, inhibits growth of human osteosarcoma cells through G2/M cell cycle arrest and apoptosis

Abstract

BackgroundOsteosarcoma (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.ResultsIn 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.ConclusionsTaken 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.

Crude Extracts, Flavokawain B and Alpinetin Compounds from the Rhizome of Alpinia mutica Induce Cell Death via UCK2 Enzyme Inhibition and in Turn Reduce 18S rRNA Biosynthesis in HT-29 Cells

“…A previous study had reported that FKB inhibited proliferation of HCT 116 cells at an IC 50 of 25 μM [16], which is consistent with the present finding. Moreover, FKB has been shown to inhibit 50% cell growth of SK-LMS-1 and 143B cells at a very low concentration of 2.2 μM (1.25 μg/mL) and 1.97 μM (3.5 μg/mL), respectively [17,18]. These IC 50 values are, however 6 fold lower than that observed in colorectal cancer (HT-29 and HCT 116 cells), which in fact, is within acceptable concentration limits.…”

Brucea javanica Leaf Extract Activates Caspase-9 and Caspase-3 of Mitochondrial Apoptotic Pathway in Human Oral Squamous Cell Carcinoma

“…(11)(12)(13)(14)(15)(16) Natural products have played a major role in apoptosis induction of osteosarcoma cells. (17,18) Due to the apoptosis induction by these natural products, several apoptosis-related proteins were induced, including Caspase 3, Caspase 7, Caspase 8 and Caspase 9, B cell lymphoma (Bcl)-2 and Survivin, Bcl-2-associated x protein (Bax), p53 upregulated modulator of apoptosis (Puma) and Fas. (18) In our current study, we pursued a further investigation Figure 3.…”

Quantitative Structure–Cytotoxicity Relationship of Chalcones

“…Several studies with murine xenograft models have shown that administration of chalcones significantly reduced the tumor volume by inducing apoptosis (3)(4)(5)(6)(7)(8)(9)(10). The tumor specificity of chalcones has been reported in comparing sensitivity of hepatocarcinoma HepG2 cells to normal liver AML12 cells (11); osterosarcoma to bone marrow and smallintestinal epithelial cells (12); murine acute lymphoblastic leukemia cells L-1210 to normal human lymphocytes (13); and human prostate cancer cells PC3 and DU145 to normal human prostate epithelial cells (14). Although chalcones have been reported to induce apoptosis of human oral carcinoma cell line (HSC-3) (15) and cultured primary and metastatic oral cancer cell lines (16), the tumor specificity against these has not been investigated as far as we are aware of.…”