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Oroxylin A is a flavonoid extracted from the root of Scutellaria baicalensis Georgi. Our previous research demonstrated that oroxylin A have various anti-tumor effects including apoptosis, cell cycle arrest, drug-resistant reversion, and others. This paper explores the mechanism how oroxylin A induce apoptosis by regulating uncoupling protein 2 (UCP2) in human colon cancer cells. We found that the inhibition of UCP2 by UCP2 siRNA significantly increased the sensitivity of cells to drugs, reactive oxygen species (ROS) generation and the opening of mitochondrial permeability transition pore (MPTP) of CaCo-2 cells. We also found that UCP2 inhibition could lead to ROS-mediated MPTP activation. Furthermore, we demonstrated that oroxylin A triggered MPTP-dependent pro-apoptotic protein release from mitochondria to matrix and then induced apoptotic cascade by inhibiting UCP2. Intriguingly, the inhibition of UCP2 by oroxylin A was able to block Bcl-2 translocation to the mitochondria, keeping MPTP at open-state. In conclusion, we have demonstrated that UCP2 plays a key role in mitochondrial apoptotic pathway; UCP2s inhibition by oroxylin A triggers the MPTP opening, and promotes the apoptosis in CaCo-2 cells. J. Cell. Physiol. 230: 1054-1063, 2015. © 2014 Wiley Periodicals, Inc., A Wiley Company [ABSTRACT FROM AUTHOR]

Aim To investigate the potential anticancer effects of the natural flavonoid wogonin on human hepatocellular carcinoma ( HCC) cells and tumor xenografts and the contribution of the unfolded protein response ( UPR) and AKT pathways to the cytotoxicity of wogonin. Methods The HCC cell lines HepG2, SMMC-7721 and Hep3B were treated with wogonin. 3-(4 5-Dimethylthiazol-2-yl)-2 5-diphenyltetrazolium bromide assays were used to evaluate the cell viability. Flow cytometry assays were used to identify the cell death types and measure the concentrations of intracellular H2O2 and Ca2+. Western blotting assays were used to detect the protein expression levels of members in the UPR and AKT pathways. Relative quantitative real-time polymerase chain reaction assays were used to analysis the m RNA expression levels of chop and trb3. Furthermore, the male BALB/c nude mice with SMMC-7721 xenografts were treated with wogonin. The tumor volume, tumor weight and bodyweight were monitored during the tumorigenicity assays. Results Wogonin significantly inhibited the viability of HCC cells by inducing apoptosis and necrosis. This cytotoxicity was at least partially attributed to the activation of the UPR pathway and consequent inactivation of AKT signaling, which resulted from the production of intracellular H2O2 and causal release of endoplasmic reticulum Ca2+. Moreover, wogonin evidently repressed the growth of xenografts but slightly influenced the bodyweight of mice. Conclusion Wogonin is a prospect for improving the systemic chemotherapy strategy on HCC by concurrently rectifying the aberrant UPR and AKT signaling pathways, which are crucial to the biology of HCC. [ABSTRACT FROM AUTHOR]

Abstract: Background: Cellular metabolism, particularly glycolysis, is altered during the metastatic process and is highly associated with tumor progression and apoptosis resistance. Oroxylin A, a natural plant flavonoid, exhibits chemopreventive and therapeutic anti-inflammatory and anticancer potential. However, the anticancer effects of oroxylin A on non-small cell lung carcinoma (NSCLC) remain poorly understood. Methods: In vitro studies were performed using 2D and 3D conditions. The effects on anoikis-sensitization and glycolysis-inhibition of oroxylin A in human non-small cell lung cancer A549 cells were examined. In vivo murine lung metastasis experiments were utilized to assess the anti-metastatic capacity of oroxylin A. Results: ROS-mediated activation of c-Src following detachment caused anoikis resistance in A549 cells. Oroxylin A sensitized A549 cells to anoikis by inactivating the c-Src/AKT/HK II pathway in addition to inducing the dissociation of HK II from mitochondria. Prior to sensitizing A549 cells to anoikis, oroxylin A decreased the ATP level and inhibited glycolysis. Furthermore, oroxylin A inhibited lung metastasis of A549 cells in vivo in nude mice. Conclusions: Oroxylin A sensitized anoikis, which underlies distinct glucose-deprivation-like mechanisms that involved c-Src and HK II. General significance: The findings in this study indicated that oroxylin A could potentially be utilized in the development of improved metastatic cancer treatments. [Copyright &y& Elsevier]

We recently established that LYG-202, a new flavonoid with a piperazine substitution, exerts an anti-tumor effect in vivo and in vitro. In the present study, we demonstrate that LYG-202 induces G1/S phase arrest and apoptosis in human colorectal carcinoma HCT-116 cells. Data showed that the blockade of the cell cycle was associated with increased p21WAF1/Cip1 and Rb levels and reduced expression of cyclin D1, cyclin E, and CDK4. Moreover, PARP cleavage, activation of caspase-3, caspase-8, and caspase-9, and an increased ratio of Bax/Bcl-2 were detected in LYG-202-induced apoptosis. Additionally, activation of p53 resulted in the up-regulation of its downstream targets PUMA and p21WAF1/Cip1, as well as the down-regulation of its negative regulator MDM2, suggesting that the p53 pathway may play a crucial role in LYG-202-induced cell cycle arrest and apoptosis. Furthermore, siRNA knockdown of p53 attenuated the G1 cell cycle arrest and apoptosis induced by LYG-202, as the effects of LYG-202 on up-regulation of p21WAF1/Cip1 and down-regulation of Bcl-2 and pro-caspase-3 were partly inhibited in p53 siRNA transfected cells compared with control siRNA transfected cells. Collectively, these data indicate that LYG-202 exerts its anti-tumor potency by activating the p53-p21 pathway for G1/S cell cycle arrest and apoptosis in colorectal cancer cells. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Most cancer cells generate energy through aerobic glycolysis to enable their rapid growth and proliferation, which is a phenomenon known as Warburg effect. Inhibition of aerobic glycolysis reduces lactate and ATP generation in cancer cells, and ultimately kills tumor cells. Increasing evidence suggests that wogonin, a flavonoid isolated from Scutellaria baicalensis Georgi , exhibits potent anti-tumor effects in vivo and in vitro. However, the role of wogonin in the aerobic glycolysis of tumor cells has not yet been elucidated. In this study, the effect of wogonin on glucose uptake, lactate generation and ATP content is assessed in colon, ovarian and hepatocellular cancer cells. The results indicate that wogonin reduces glycolysis and cell proliferation in cancer cells expressing wild-type p53 but not mutated p53. Wogonin increases the expression of p53 and p53-inducible glycolysis and apoptosis regulator (TIGAR), while decreases glucose transporter 1 (GLUT1) and some key glycolytic enzymes. Expressing wild-type and mutant-type p53 in HCT116 p53−/− cells proved that the inhibitory effect of wogonin on glycolysis in cancer cells is dependent on wild type p53. Mechanistically, wogonin induced the phosphorylation and acetylation of p53 and inhibited the expression of MDM2 to enhance the stability of p53. Furthermore, wogonin suppressed the growth and glycolysis of transplanted wild-type p53 expressing A2780 cells on nude mice, but did not affect mutant-type p53 expressing HT-29 cells. In conclusion, these findings explain the broad anti-tumor effect of wogonin, and offer a novel avenue for the therapeutic strategy in cancer. [ABSTRACT FROM AUTHOR]

Abstract: We recently established that GL-V9, a newly synthetic flavonoid derivative, is an active cytotoxic component. In this study, we demonstrated that GL-V9 inhibited cells growth via inducing apoptosis and G2/M cell cycle arrest in human hepatocellular carcinoma HepG2 cells. Following the treatment of HepG2 cells with GL-V9, we observed poly (ADP-ribose) polymerase (PARP) cleavage and activation of caspase-3 and caspase-9, while caspase-8 remained unchanged. The expression ratio of Bcl-2/Bax was also decreased in GL-V9-treated cells. Meanwhile, the cell cycle-related proteins, such as cyclin B1, CDK1 and cdc25 were down-regulated in GL-V9-induced G2/M cell cycle arrest. Furthermore, we showed that GL-V9-induced apoptosis in HepG2 cells was achieved through mitochondrial pathway. It also regulated changes of mitochondrial membrane potential and increased the production of intracellular reactive oxygen species. Besides, the growth inhibitory effect of GL-V9 was examined in vivo using murine implanted tumor model. These studies indicate that GL-V9 shows promise as a therapeutic agent against human heptoma. [Copyright &y& Elsevier]

Abstract: HQS-3 is a newly baicalein derivative with a benzene substitution. We investigated the anticancer effect of HQS-3 in vivo and in vitro. HQS-3 significantly decreased tumor growth in mice inoculated with Heps and HepG2 cells; and had little influence on the state and weight of animals. After treatment with 20mg/kg HQS-3, the inhibitory rate of tumor weight in mice inoculated with Heps and HepG2 cells were 63.62% and 68.03%, respectively. Meanwhile, HQS-3 inhibited the viability of various kinds of tumor cells with IC50 values in the range of 22.98–54.32μM after 48h treatment measured by MTT-assay. HQS-3 remarkably inhibited viability of hepatoma cells in a concentration- and time-dependent manner and induced apoptosis in HepG2 cells by DAPI staining and Annexin V/PI double staining. The apoptosis-induction effect of HQS-3 was attributed to its ability to modulate the activity of caspase-9, caspase-3 and PARP. Moreover, the expression of bax protein was increased while the bcl-2 protein was decreased, leading to an increase in Bax/Bcl-2 ratio. The accumulation of ROS induced by HQS-3 in HepG2 cells was also observed. The further results suggested that HQS-3 induced mitochondrial-mediated apoptosis by increasing ROS level and inhibiting the expression of anti-oxidative protein SOD2. HQS-3 exerted anti-tumor activity both in vitro and in vivo via inducing tumor cells apoptosis, and these results suggested that it deserves further investigation as a novel chemotherapy for human tumors. [Copyright &y& Elsevier]

Abstract: Hepatocellular carcinoma (HCC) is a refractory malignancy with a high incidence and large mortality. Current strategy for the chemotherapy of HCC focuses on developing agents with better efficacy and lower toxicity. In this study, we demonstrated that the natural flavonoid oroxylin A preferentially inhibited the viability of HCC cell line HepG2 but not the normal hepatic cell line L02. In HepG2 but not L02 cells, oroxylin A induced substantial production of intracellular H2O2 and inordinate activation of the PERK-eIF2α-ATF4-CHOP branch of the unfolded protein response (UPR) pathway, which resulted in the induction of TRB3 and causal reduction of p-AKT1/2/3 (Ser473). Moreover, these effects were eliminated by either the stable knockdown of CHOP or the pretreatment and then co-incubation with the specific H2O2 scavenger catalase. These results indicated that the H2O2-triggered overactivation of the UPR pathway and causal inactivation of AKT signaling contributed to the preferential cytotoxicity of oroxylin A in malignant HepG2 cells. Therefore, present study proposed an underlying molecular mechanism that implicated the selective antitumor effect of oroxylin A and recommended oroxylin A as a prospect for improving the current chemotherapeutic strategy for the treatment of HCC. [Copyright &y& Elsevier]