Flavokawain B
(Synonyms: 黄卡瓦胡椒素B,Flavokavain B) 目录号 : GC41261Induces cancer cell apoptosis
Cas No.:1775-97-9
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Flavokawain B is a natural chalcone first isolated from extracts of kava roots. It induces apoptosis in androgen receptor-negative, hormone-refractory prostate cancer cell lines (IC50s = 32, 48, 6.2, and 3.9 µM for LAPC4, LNCaP, PC-3, and DU145 cells, respectively, treated for 48 hours), with increased expression of the proapoptotic protein Bim. Flavokawain B increases Bim expression and inhibits growth of DU145 xenografts in mice. It also increases Bim expression, promotes apoptosis, and induces cell cycle arrest in uterine leiomyosarcoma cells. However, flavokawain B is hepatotoxic, triggering oxidative stress, inhibiting NF-κB signaling, and activating MAPK pathways, culminating in HepG2 and L-02 cell death (LD50s = 15 and 32 µM, respectively).
Cas No. | 1775-97-9 | SDF | |
别名 | 黄卡瓦胡椒素B,Flavokavain B | ||
Canonical SMILES | COC1=CC(O)=C(C(/C=C/C2=CC=CC=C2)=O)C(OC)=C1 | ||
分子式 | C17H16O4 | 分子量 | 284.3 |
溶解度 | DMF: 30 mg/mL,DMSO: 50 mg/mL,Ethanol: 10 mg/mL | 储存条件 | 4°C, protect from light |
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1 mM | 3.5174 mL | 17.5871 mL | 35.1741 mL |
5 mM | 0.7035 mL | 3.5174 mL | 7.0348 mL |
10 mM | 0.3517 mL | 1.7587 mL | 3.5174 mL |
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Inhibition of glioma growth by Flavokawain B is mediated through endoplasmic reticulum stress induced autophagy
Autophagy 2018;14(11):2007-2022.PMID:30025493DOI:10.1080/15548627.2018.1501133.
Flavokawain B (FKB), a natural kava chalcone, displays potent antitumor activity in various types of cancer. The mechanism of action, however, remains unclear. Here, we evaluated the efficacy of FKB in the treatment of human glioblastoma multiforme (GBM) as well as the molecular basis for its inhibitory effects in cancer. Approximately 60% of GBM cells became senescent after treatment with FKB as assessed in the senescence-associated (SA)-GLB1/SA-β-galactosidase assay. The cellular process of autophagy potentially contributed to the establishment of senescence. Transmission electron microscopy revealed the formation of autophagic vesicles under FKB treatment, and MAP1LC3B (microtubule associated protein 1 light chain 3 beta)-II was increased. Transfection of ATG5 or ATG7 small interfering RNAs (siRNAs) inhibited FKB-induced autophagy in U251 cells. Western blot revealed that molecular components of the endoplasmic reticulum stress pathway were activated, including ATF4 (activating transcription factor 4) and DDIT3 (DNA damage inducible transcript 3), while levels of TRIB3 (tribbles pseudokinase 3) increased. In addition, based on the phosphorylation status, the AKT-MTOR-RPS6KB1 pathway was inhibited, which induced autophagy in GBM cells. Inhibition of autophagy by autophagy inhibitors 3-methyladenine and chloroquine or knockdown of ATG5 or ATG7 caused FKB-treated U251 cells to switch from senescence to apoptosis. Finally, knockdown of ATG5 or treatment with chloroquine in combination with FKB, significantly inhibited tumor growth in vivo. Our results demonstrated that FKB induced protective autophagy through the ATF4-DDIT3-TRIB3-AKT-MTOR-RPS6KB1 signaling pathway in GBM cells, indicating that the combination treatment of FKB with autophagy inhibitors may potentially be an effective therapeutic strategy for GBM. Abbreviations: 3-MA: 3-methyladenine; 4-PBA: 4-phenylbutyrate; AKT: AKT serine/threonine kinase; ATF4: activating transcription factor 4; ATG: autophagy related; CASP3: caspase 3; CCK-8: cell counting kit-8; CDKN1A: cyclin-dependent kinase inhibitor 1A; CQ: chloroquine; DDIT3: DNA damage inducible transcript 3; DMEM: Dulbecco's modified Eagle's medium; EIF2A: eukaryotic translation initiation factor 2A; EIF2AK3: eukaryotic translation initiation factor 2 alpha kinase 3; ER: endoplasmic reticulum; FKB: Flavokawain B; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GBM: glioblastoma multiforme; GFP: green fluorescent protein; HSPA5: heat shock protein family A (Hsp70) member 5; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; PARP1: poly(ADP-ribose) polymerase; 1RPS6KB1: ribosomal protein S6 kinase B1; SA-GLB1: senescence-associated galactosidase beta 1; siRNA: short interfering RNA; SQSTM1: sequestosome 1; TEM: transmission electron microscopy; TRIB3: tribbles pseudokinase 3; TUNEL: deoxynucleotidyl transferase-mediated dUTP nick-end labeling.
Flavokawain B alleviates LPS-induced acute lung injury via targeting myeloid differentiation factor 2
Acta Pharmacol Sin 2022 Jul;43(7):1758-1768.PMID:PMC9253132DOI:10.1038/s41401-021-00792-4.
Acute lung injury (ALI) is a sudden onset systemic inflammatory response. ALI causes severe morbidity and death and currently no effective pharmacological therapies exist. Natural products represent an excellent resource for discovering new drugs. Screening anti-inflammatory compounds from the natural product bank may offer viable candidates for molecular-based therapies for ALI. In this study, 165 natural compounds were screened for anti-inflammatory activity in lipopolysaccharide (LPS)-challenged macrophages. Among the screened compounds, Flavokawain B (FKB) significantly reduced LPS-induced pro-inflammatory IL-6 secretion in macrophages. FKB also reduced the formation of LPS/TLR4/MD2 complex by competitively binding to MD2, suppressing downstream MAPK and NF-κB signaling activation. Finally, FKB treatment of mice reduced LPS-induced lung injury, systemic and local inflammatory cytokine production, and macrophage infiltration in lungs. These protective activities manifested as increased survival in the ALI model, and reduced mortality upon bacterial infection. In summary, we demonstrate that the natural product FKB protects against LPS-induced lung injury and sepsis by interacting with MD2 and inhibiting inflammatory responses. FKB may potentially serve as a therapeutic option for the treatment of ALI.
Cyclization of Flavokawain B reduces its activity against human colon cancer cells
Hum Exp Toxicol 2020 Mar;39(3):262-275.PMID:31640425DOI:10.1177/0960327119882986.
Chalcones are naturally occurring compounds exhibiting biological activity through multiple mechanisms. Flavokawain B is one of chalcones found in kava plant. In our studies, we focused on the anticancer activity of Flavokawain B in colorectal cancer cells LoVo and its resistant to doxorubicin subline-LoVo/Dx. Strong cytotoxic activity of Flavokawain B and its ability to inhibit the proliferation in both cell lines was detected. These effects accompanied with induction cell cycle arrest in G2/M phase and the presence of SubG1 fraction. Flavokawain B at low concentration led to increase of caspase-3 activity. The chalcone-induced apoptosis was also confirmed by DNA fragmentation. In our work, the conversion of Flavokawain B to corresponding flavanone-5,7-dimetoxyflavanone-was shown to be more extensive in cancer than in non-cancer cells. We found that the cyclization of the chalcone was related to the significant decrease in the cytotoxicity. Cell proliferation and cell cycle progression were not impaired significantly in the studied cancer cells incubated with 5,7-dimethoxyflavanone. We did not observe apoptosis in the cells incubated with flavanone. The results from biological studies agreed with the theoretical activity that emerges from structural parameters.
Flavokawain B inhibits the growth of acute lymphoblastic leukemia cells via p53 and caspase-dependent mechanisms
Leuk Lymphoma 2015;56(8):2398-407.PMID:25641429DOI:10.3109/10428194.2014.976819.
The development of novel chemotherapeutic drugs is needed for the treatment of patients with acute lymphoblastic leukemia (ALL). In this study, the anti-leukemic effect and the potential molecular mechanisms of action of Flavokawain B on ALL were investigated. Flavokawain B was found to significantly inhibit the cellular proliferation of B-ALL and T-ALL cell lines in a dose-dependent manner. It also induced cellular apoptosis by increasing the expression of p53, Bax and Puma, and activating the cleavage of caspase-3 and poly ADP-ribose polymerase (PARP). Furthermore, the enhancement of p53-dependent apoptosis by Flavokawain B could be rescued by pifithrin-α, a pharmacological inhibitor of p53 transcriptional activity. Moreover, the proliferation of leukemia blast cells from 16 patients with ALL was inhibited by Flavokawain B, and tumor growth in xenograft mice was also suppressed by this drug. In conclusion, our results demonstrate the therapeutic potential of Flavokawain B for the treatment of ALL.
Flavokawain B Weakens Gastric Cancer Progression via the TGF- β 1/SMAD4 Pathway and Attenuates M2 Macrophage Polarization
J Immunol Res 2022 Jul 16;2022:4903333.PMID:35879950DOI:10.1155/2022/4903333.
This study was designed to observe the treatment effects of Flavokawain B (FKB) on gastric cancer both in SGC-7901 cells and nude mice. When SGC-7901 cells were exposed to 10 μg/mL FKB, cellular proliferative and apoptotic capacities and cell cycle were detected utilizing CCK-8 and flow cytometry assays. The results showed that FKB treatment induced cell apoptosis and G2/M arrest and suppressed cell proliferation for SGC-7901 cells. Western blot results showed that FKB upregulated proapoptotic proteins as well as downregulated antiapoptotic and cell cycle-related proteins in SGC-7901 cells. SMAD4, TGF-β1, and TSPAN12 proteins were tested in FKB-induced SGC-7901 cells. Following exposure to FKB, SMAD4, TGF-β1, and TSPAN12 expression was augmented in SGC-7901 cells. si-SMAD4 transfection weakened cell apoptosis and accelerated cell proliferation. Furthermore, FKB reversed the change in apoptotic and cell cycle-related proteins induced by si-SMAD4. A nude mouse tumorigenesis model was constructed, which was treated by FKB. In the nude mouse tumorigenesis model, FKB activated the TSPAN12 expression and TGF-β1/SMAD4 pathway. Also, FKB treatment prolonged the survival time of nude mice and lowered tumor weight. iNOS and CD86 expression was significantly enhanced, and Arg-1 and CD206 expression was significantly decreased in THP-1 cells cultured in conditioned media from FKB-treated SGC-7901 cells. Additionally, FKB-treated SGC-7901 cells weakened macrophage migration. Collectively, this evidence suggested that FKB accelerated apoptosis and suppressed the proliferation of gastric cancer cells and attenuated M2 macrophage polarization, thereby exerting an anticancer effect on gastric cancer.