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Chalcones have been described to represent cancer chemopreventive food components that are rich in fruits and vegetables. In this study, we examined the anti-oral cancer effect of flavokawain B (FKB), a naturally occurring chalcone isolated from Alpinia pricei (shell gingers), and revealed its molecular mechanism of action. Treatment of human oral carcinoma (HSC-3) cells with FKB (1.25-10 μg/mL; 4.4-35.2 μM) inhibited cell viability and caused G(2)/M arrest through reductions in cyclin A/B1, Cdc2, and Cdc25C levels. Moreover, FKB treatment resulted in the induction of apoptosis, which was associated with DNA fragmentation, mitochondria dysfunction, cytochrome c and AIF release, caspase-3 and caspase-9 activation, and Bcl-2/Bax dysregulation. Furthermore, increased Fas activity and procaspase-8, procaspase-4, and procaspase-12 cleavages were accompanied by death receptor and ER-stress, indicating the involvement of mitochondria, death-receptor, and ER-stress signaling pathways. FKB induces apoptosis through ROS generation as evidenced by the upregulation of oxidative-stress markers HO-1/Nrf2. This mechanism was further confirmed by the finding that the antioxidant N-acetylcysteine (NAC) significantly blocked ROS generation and consequently inhibited FKB-induced apoptosis. Moreover, FKB downregulated the phosphorylation of Akt and p38 MAPK, while their inhibitors LY294002 and SB203580, respectively, induced G(2)/M arrest and apoptosis. The profound reduction in cell number was observed in combination treatment with FKB and Akt/p38 MAPK inhibitors, indicating that the disruption of Akt and p38 MAPK cascades plays a functional role in FKB-induced G(2)/M arrest and apoptosis in HSC-3 cells.

Twenty six 18β-glycyrrhetinic acid (GA) (1) derivatives 2-27 including twelve new GA derivatives 10, 11, 13-17, 21-25 were synthesized and evaluated for cytotoxicities against NTUB1 cells (human bladder cancer cell lines). seco-Compounds 9, 25, and 27 are the most potent compounds of this series, inhibiting cell growth of human NTUB1 cells with an IC(50) values of 2.34 ± 0.28, 4.76 ± 1.15, and 3.31 ± 0.61 μM, respectively. Exposure of NTUB1 to 25 for 24h significantly increased the production of reactive oxygen species (ROS). Flow cytometric analysis exhibited that treatment of NTUB1 with 25 did not induce cell cycle arrest but accompanied by an increase of apoptotic cell death in a dose-dependant manner after 24h. Mitochondrial membrane potential (MMP) decreased significantly in a dose-dependant manner when the NTUB1 cells were exposed to 25 for 24h. Marked collapse of the MMP suggested that dysfunction of the mitochondria may be involved in the oxidative burst and apoptosis induced by 25. Western blot analysis shows that NTUB1 cells treated with 25 increased the level of p-p53 in a dose-dependant manner. Further, NAC treatment prevented p53 phosphorylation stimulated by 25. These results suggested that 25 induced a mitochondrial-mediated apoptosis in NTUB1 cells through activation of p53, which are mainly mediated ROS generated by 25., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

A known triterpenoid, β-amyrin (1), and a known and a new phloroglucinol, cohulupone (2) and garcinielliptone P (3), were isolated from the pericarp and heartwood and seed of Garcinia subelliptica, respectively. A new xanthonolignoid, hyperielliptone HF (4), was isolated from the heartwood of Hypericum geminiflorum. The new compounds were established by analysis of their spectroscopic data. Compounds 1-3 showed an inhibitory effect on xanthine oxidase (XO). Treatment of NTUB1, a human bladder cancer cell, with 1 or 1 cotreated with cisplatin for 24 h resulted in a decreased viability of cells. Exposure of NTUB1 to 1 or 1 cotreated with cisplatin for 24 h significantly increased the level of production of reactive oxygen species (ROS). Flow cytometric analysis indicated that treatment of NTUB1 with 1 or 1 cotreated with cisplatin led to the cell cycle arrest, accompanied by an increase in the extent of apoptotic cell death in 1 or 1 combined with cisplatin-treated NTUB1 after 24 h. These data suggested that the presentation of cell cycle arrest and apoptosis in 1 or 1 combined with cisplatin-treated NTUB1 for 24 h was mediated through an increased amount of ROS in cells exposed to 1 or 1 cotreated with cisplatin.

Bioguided fractionation of the CHCl(3) extracts obtained from Celastrus kusanoi stems led to isolation of two new terpenoids, 3beta-hydroxy-11,14-oxo-abieta-8,12-diene (1) and 3beta-trans-(3,4-dihydroxycinnamoyloxy)-11alpha-methoxy-12-ursene (2), and four known compounds characterized by spectroscopic methods. Compounds 1 and 2 and known triterpenoid erythrodiol (3) exhibited cytotoxic activity against bladder cancer cells (NTUB1) with IC(50) values of 58.2 +/- 2.3, 160.1 +/- 60.9, and 18.3 +/- 0.5 microM, respectively. Exposure of NTUB1 to 3 (5 and 10 microM) for 24 h significantly increased the level of production of reactive oxygen species (ROS). Flow cytometric analysis showed that treatment of NTUB1 with 3 led to the cell cycle arrest at G0/G1 accompanied by an increase in the extent of apoptotic cell death after 24 h. These data suggest that the presentation of G1 phase arrest and apoptosis in 3-treated NTUB1 for 24 h was mediated through an increased amount of ROS in cells exposed to 3.

Chalcones found in fruits and vegetables have promising cancer chemopreventive properties. This study attempts to identify the anticancer efficacies of chalcone flavokawain B (FKB) in the rhizomes of Alpinia pricei Hayata by examining key molecular events in non‐small‐cell lung cancer (A549) cells. Our results indicated that in human A549 cells, FKB (0–15 μg/ml) decreases cell viability and colony formation, dysregulates the Bax:B‐cell lymphoma 2 ratio and increases apoptotic DNA fragmentation. Mitochondrial (caspase‐9/‐3 and poly ADP ribose polymerase [PARP]) signaling was found to be involved in FKB‐induced apoptosis. In addition, FKB‐induced reactive oxygen species (ROS) generation, and N‐acetylcysteine attenuated FKB‐induced apoptotic cell death. Moreover, FKB triggered autophagy, as evidenced by the improved acidic vesicular organelle formation, lipidated light chain 3 (microtubule‐related light chain 3) accumulation, and ATG7 expression and the decreased mammalian target of rapamycin phosphorylation. Furthermore, FKB suppressed ROS‐mediated ATG4B expression. Inhibiting autophagy using 3‐methyladenine/chloroquine diminished FKB‐induced cell death, indicating that autophagy is triggered as a death mechanism by FKB. In summary, FKB has a crucial role in the execution and propagation of ROS‐mediated apoptotic and autophagic cell death of lung adenocarcinoma cells. [ABSTRACT FROM AUTHOR]

Ursolic acid and most of its derivatives are cytotoxic to bladder cancer cells. An ursolic acid derivative, isopropyl 3 β -hydroxyurs-12-en-28-oat (UA17), previously reported that it exhibited potent cytotoxicity against bladder cancer cells, NTUB1 cells. In this study, we further investigated the underlying mechanism of UA17 and evaluated its potential clinical use. UA17 may exert the onset of a p53-mediated p38 MAPK activation to up-regulate GADD153. GADD153, in turn, down-regulated Bcl-2 protein to cause mitochondrial membrane potential loss and apoptosis through intracellular ROS generation. In addition, UA17 markedly decreased the levels of cyclins (D1 and E), cyclin-dependent kinases (CDK2 and CDK4), and caused increase of p21 and p27 levels. To assess the suitability of UA17 as a chemotherapeutic agent against NTUB1 cells, its cytotoxic effects have been further evaluated in the combination with cisplatin. The addition of UA17 to cisplatin induces possibly additive cell growth inhibition which correlated to the accumulation of S phase cells and a corresponding decrease in accumulation of G1 phase cells, accompanied an increased accumulation of sub-G1 phase cells. Furthermore, UA17/cisplatin combination exhibited increase of p21, cyclin E, and p-p53 level, and decrease of p27 and cyclin D1 proteins, and slightly diminishing the level of CDK2. P-p38 up-regulation induced by UA17/cisplatin combination through generation of ROS and Bcl-2 down-regulation induced by UA17/cisplatin combination increased cell death. Finally, the antitumorigenic effects of UA17 or UA17/cisplatin combination were further supported by their inhibition on growth of bladder tumor cells in a therapeutic murine MBT-2 bladder tumor model. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Antrodia camphorata (AC) is well known in Taiwan as a traditional Chinese medicinal fungus. However, the anticancer activity of AC against human HER-2/neu-overexpressing ovarian cancers is poorly understood. Materials and methods: The aim of this study is to investigate whether a submerged fermentation culture of AC can inhibit human ovarian carcinoma cell (SKOV-3) proliferation by suppressing the HER-2/neu signaling pathway. Cell viability, colony formation, DCFH-DA fluorescence microscopy, western blotting, HER-2/neu immunofluorescence imaging, flow cytometry, and TUNEL assays were carried out to determine the anti-cancer effects of AC. Results: MTT and colony formation assays showed that AC induced a dose-dependent reduction in SKOV-3 cell growth. Immunoblot analysis demonstrated that HER-2/neu activity and tyrosine phosphorylation were significantly inhibited by AC. Furthermore, AC treatment significantly inhibited the activation of PI3K/Akt and their downstream effector β-catenin. We also observed that AC caused G2/M arrest mediated by down-regulation of cyclin D1, cyclin A, cyclin B1, and Cdk1 and increased p27 expression. Notably, AC induced apoptosis, which was associated with DNA fragmentation, cytochrome c release, caspase-9/-3 activation, PARP degradation, and Bcl-2/Bax dysregulation. An increase in intracellular reactive oxygen species (ROS) was observed in AC-treated cells, whereas the antioxidant N-acetylcysteine (NAC) prevented AC-induced cell death, HER-2/neu depletion, PI3K/Akt inactivation, and Bcl-2/Bax dysregulation, indicating that AC-induced cell death was mediated by ROS generation. Conclusions: These results suggest that AC may exert anti-tumor activity against human ovarian carcinoma by suppressing HER-2/neu signaling pathways. [Copyright &y& Elsevier]

Simple Summary: Among various kinds of treatment strategies for cancers, combination therapy has attracted significant attention due to its beneficial effects than the individual effects of the same compounds. Based on this idea, this study has investigated the synergistic effects of combination treatment of a natural anti-cancer agent flavokawain B (FKB) and a chemotherapeutic agent Doxorubicin on human gastric cancer cells and the underlying molecular mechanisms were deciphered through in vitro and in vivo approaches. Experimental data obtained in this study provided promising application prospects of FKB + Doxrubicin combination treatment in human gastric cancer cells. Chalcone flavokawain B (FKB) possesses a chemopreventive and anti-cancer activity. Doxorubicin is a chemotherapeutic DNA intercalating agent widely used in malignancy treatment. The present study investigated whether synergistic effects exist between the combination of FKB (1.25–5 µg/mL) and doxorubicin (0.5 µg/mL) on the apoptosis and autophagy in human gastric cancer (AGS) cells, and the possible in vitro and in vivo mechanisms. The MTT assay measured cell viability. Various apoptotic-, autophagy-associated protein expression was determined by the Western blot technique. FKB+doxorubicin synergy was estimated by the Chou-Talalay combination index (CI) method. In vivo studies were performed on BALB/c mice. Results showed that compared to FKB/doxorubicin treatments, low doses of FKB+doxorubicin suppressed AGS cell growth. FKB potentiated doxorubicin-induced DNA fragmentation, apoptotic cell death, and enhanced doxorubicin-mediated mitochondrial, death receptor pathways. FKB+doxorubicin activated increased LC3-II accumulation, p62/SQSTM1 expression, and AVO formation as compared to the FKB/doxorubicin alone treatments indicating autophagy in these cells. The death mechanism in FKB+doxorubicin-treated AGS cells is due to the activation of autophagy. FKB+doxorubicin-mediated dysregulated Bax/Bcl-2, Beclin-1/Bcl-2 ratios suggested apoptosis, autophagy induction in AGS cells. FKB+doxorubicin-induced LC3-II/AVOs downregulation was suppressed due to an apoptotic inhibitor Z-VAD-FMK. Whereas, 3-methyladenine/chloroquine weakened FKB+doxorubicin-induced apoptosis (decreased DNA fragmentation/caspase-3). Activation of ERK/JNK may be involved in FKB+doxorubicin-induced apoptosis and autophagy. FKB+doxorubicin-triggered ROS generation, but NAC attenuated FKB+doxorubicin-induced autophagic (LC3 accumulation) and apoptotic (caspase-3 activation and PARP cleavage) cell death. FKB+doxorubicin blocked gastric cancer cell xenografts in nude mice in vivo as compared to FKB/doxorubicin alone treatments. FKB and doxorubicin wielded synergistic anti-tumor effects in gastric cancer cells and is a promising therapeutic approach. [ABSTRACT FROM AUTHOR]

Abstract: The ability of flavonoid glycosides isolated from several plants to induce DNA breakage was examined using supercoiled plasmid pBR322 DNA by agarose gel electrophoresis in the presence of Cu(II). Among all the compounds, 1, 4, and 6 could cause significant breakages of supercoiled plasmid pBR322 DNA in the presence of Cu(II). Cu(I) was not shown to be an essential intermediate in the process of pBR322 DNA breakage by using the Cu(I)-specific sequestering reagent neocuproine. A decreased cell viability was enhanced in gastric carcinoma SCM-1 cells treating with lower concentrations of 1 and 6 when cotreated with increased concentrations of Cu(II), respectively. Treatments of SCM-1 cells with 500μM of 1 in the presence of 300 or 500μM of Cu(II) inhibited the Cu(II)-induced apoptosis. Compound 1 (500μM) could prevent cell death by inhibiting the 500μM Cu(II)-induced apoptosis and necrosis, but did not have any effect on the mitochondrial membrane potential changed by 500μM Cu(II). Both compounds 1 and 6 could inhibit the DNA breakages caused by while 1 also revealed inhibitory effect on xanthine oxidase with an IC50 value of 22.7±6.9μM. These results indicated that compound 1 with a higher concentration may probably mediate through the suppression of xanthine oxidase activity and reduce reactive oxygen species (ROS) induced by high concentration of Cu(II) (500μM) and prevent the following cell death. [Copyright &y& Elsevier]