Hepatocellular cell carcinoma (HCC) is one of the most commonly diagnosed cancers worldwide and in Taiwan. Chemoprevention of cancer with dietary bioactive compounds could potentially reverse, suppress, or prevent cancer progression. Licochalcone A (LicA) is a characteristic chalcone of licorice, which is the root of Glycyrrhiza inflate. It had been reported that LicA has anti-inflammatory, anti-microbial, and anti-tumor properties. However, the effects of LicA on the migration and invasion of human HCC cells have not yet been reported. In the present study, it was found that LicA inhibits the migratory and invasion ability of SK-Hep-1 and HA22T/VGH cells in a dose-dependent manner, as assessed by the cell migration and Matrigel cell invasion assay. Using casein zymography, Western blotting, reverse transcriptase polymerase chain reaction, and an immunofluorescence assay, it was found that LicA induces a dose-dependent inhibition of uPA activity and expression, as well as reduces mRNA levels in SK-Hep-1 and HA22T/VGH cells. LicA was also found to inhibit the expression of phosphor-JNK and phosphor-MKK4 in SK-Hep-1 cells. Furthermore, LicA significantly decreased uPA levels in SP600125-treated or si-MKK4-transfected cells alongside a marked reduction in cell migration and invasion, which supports the notion that an inhibition of MKK4/JNK results in anti-metastatic effects. Moreover, LicA inhibited the expression of nuclear NF-κB, as well as the binding ability of NF-κB to the uPA promoter. These findings further our understanding of the role of LicA in suppressing tumor metastasis and its underlying molecular mechanisms, as well as suggest that LicA may be a promising anti-metastatic agent.

Genetic polymorphism at G1790A of HIF-1alpha is an important factor for determining the susceptibility to hepatocellular carcinoma. The interaction effects of G1790A heterozygotes to tobacco and to alcohol consumption significantly increase the risk to develop hepatocellular carcinoma.

BackgroundPterostilbene (PTER) is a dimethylated analog of the phenolic phytoalexin, resveratrol, with higher anticancer activity in various tumors. Herein, the molecular mechanisms by which PTER exerts its anticancer effects against acute myeloid leukemia (AML) cells were investigated.Methodology and Principal FindingsResults showed that PTER suppressed cell proliferation in various AML cell lines. PTER-induced G0/G1-phase arrest occurred when expressions of cyclin D3 and cyclin-dependent kinase (CDK)2/6 were inhibited. PTER-induced cell apoptosis occurred through activation of caspases-8-9/-3, and a mitochondrial membrane permeabilization (MMP)-dependent pathway. Moreover, treatment of HL-60 cells with PTER induced sustained activation of extracellular signal-regulated kinase (ERK)1/2 and c-Jun N-terminal kinase (JNK)1/2, and inhibition of both MAPKs by their specific inhibitors significantly abolished the PTER-induced activation of caspases-8/-9/-3. Of note, PTER-induced cell growth inhibition was only partially reversed by the caspase-3-specific inhibitor, Z-DEVE-FMK, suggesting that this compound may also act through a caspase-independent pathway. Interestingly, we also found that PTER promoted disruption of lysosomal membrane permeabilization (LMP) and release of activated cathepsin B.ConclusionTaken together, our results suggest that PTER induced HL-60 cell death via MAPKs-mediated mitochondria apoptosis pathway and loss of LMP might be another cause for cell apoptosis induced by PTER.

BackgroundGlabridin, a prenylated isoflavonoid of G. glabra L. roots, has been associated with a wide range of biological properties such as regulation of energy metabolism, estrogenic, neuroprotective, anti-osteoporotic, and skin-whitening in previous studies. However, the effect of glabridin on tumor cells metastasis has not been clearly clarified. Here, the molecular mechanism by which glabridin anticancer effects in human promyelocytic leukemia cells was investigated.Methodology and Principal FindingsThe results showed that glabridin significantly inhibited cell proliferation of four AML cell lines (HL-60, MV4-11, U937, and THP-1). Furthermore, glabridin induced apoptosis of HL-60 cells through caspases-3, -8, and -9 activations and PARP cleavage in dose- and time-dependent manner. Moreover, western blot analysis also showed that glabridin increase phosphorylation of ERK1/2, p38 MAPK and JNK1/2 in dose- and time-dependent manner. Inhibition of p38 MAPK and JNK1/2 by specific inhibitors significantly abolished the glabridin-induced activation of the caspase-3, -8 and -9.ConclusionTaken together, our results suggest that glabridin induced HL-60 cell apoptosis through p38 MAPK and JNK1/2 pathways and could serve as a potential additional chemotherapeutic agent for treating AML.

Hispolon is an active phenolic compound of Phellinus igniarius, a mushroom that was recently shown to have antioxidant and anticancer activities in various solid tumors. Here, the molecular mechanisms by which hispolon exerts anticancer effects in acute myeloid leukemia (AML) cells was investigated. The results showed that hispolon suppressed cell proliferation in the various AML cell lines. Furthermore, hispolon effectively induced apoptosis of HL-60 AML cells through caspases-8, -9, and -3 activations and PARP cleavage. Moreover, treatment of HL-60 cells with hispolon induced sustained activation of JNK1/2, and inhibition of JNK by JNK1/2 inhibitor or JNK1/2-specific siRNA significantly abolished the hispolon-induced activation of the caspase-8/-9/-3. In vivo, hispolon significantly reduced tumor growth in mice with HL-60 tumor xenografts. In hispolon-treated tumors, activation of caspase-3 and a decrease in Ki67-positive cells were observed. Our results indicated that hispolon may have the potential to serve as a therapeutic tool to treat AML.

Nobiletin, a compound isolated from citrus fruits, is a polymethoxylated flavone derivative that was shown to have anti-inflammatory and anticancer activities in various solid tumors. The anticancer effect of nobiletin on nonsolid tumor remains unclear. Herein, the molecular mechanisms by which nobiletin exerts its anticancer effects on acute myeloid leukemia (AML) cells were investigated. The results showed that nobiletin suppressed cell proliferation in various types of AML cell lines. Moreover, nobiletin induced cell-cycle arrest of HL-60 AML cells at the G0/G1 phase by suppressing extracellular signal-regulated kinase (ERK) activity. Furthermore, nobiletin effectively induced apoptosis of HL-60 cells through caspase-8, caspase-9, and caspases-3 activation concomitantly with a marked induction of p38 mitogen-activated protein kinase (MAPK) activation, but without affecting expression levels of Bcl-2, Bax, or Bid. Taken together, our results suggest that nobiletin inhibited HL-60 cell proliferation through inducing cell-cycle arrest and apoptosis and could serve as a potential additional chemotherapeutic agent for treating AML.

BackgroundThe enhancer of zeste 2 (EZH2) gene encodes the histone methyltransferase that is the catalytic component of the polycomb repressive complex-2, which initiates epigenetic silencing of genes. The expression level of EZH2 in hepatocellular carcinoma (HCC) is highly correlated with tumor progression; however, it has not been determined if specific EZH2 genetic variants are associated with the risk of HCC. This study investigated the potential associations of EZH2 single-nucleotide polymorphisms with HCC susceptibility and its clinicopathologic characteristics.Methodology/Principal FindingsA total of 220 HCC patients and 552 cancer-free controls were analyzed for four EZH2 single-nucleotide polymorphisms (rs6950683, rs2302427, rs3757441, and rs41277434) using real-time PCR genotyping. After adjusting for other co-variants, the individuals carrying at least one C allele at EZH2 rs6950683 and rs3757441 had a 0.611-fold and a 0.660-fold lower risk of developing HCC than did wild-type (TT) carriers, respectively. The CCCA or CCTA haplotype among the four EZH2 sites (rs6950683, rs2302427, rs3757441, and rs41277434), respectively, was also associated with a reduced risk of HCC. Furthermore, HCC patients who carried at least one C allele at rs6950683 or rs3757441 had a higher lymph–node-metastasis risk but a lower liver-cirrhosis risk than did patients carrying the wild-type allele.ConclusionsThe rs6950683 and rs3757441 polymorphic genotypes of EZH2 might contribute to the prediction of susceptibility to and pathological development of HCC. This is the first study to provide insight into risk factors associated with EZH2 variants in carcinogenesis of HCC in Taiwan.

Timosaponin AIII (TAIII) is a steroidal saponin isolated from Anemarrhena asphodeloides that has been shown to inhibit cell growth and induce apoptosis in cancer. However, the effect of TAIII on acute myeloid leukemia (AML) remains unclear. Here, the molecular mechanism by which TAIII-induced apoptosis affects human AML cells was investigated. The results showed that TAIII significantly inhibited cell proliferation of four AML cell lines (MV4-11, U937, THP-1, and HL-60). Furthermore, TAIII induced apoptosis of HL-60 cells through caspase-3, caspase-8, and caspase-9 activations and PARP cleavage in a dose- and time-dependent manner. Moreover, Western blot analysis also showed that TAIII increased phosphorylation of JNK1/2 and p38 MAPK in a dose-dependent manner. Inhibition of JNK1/2 by specific inhibitors significantly abolished the TAIII-induced activation of the caspase-8. Taken together, our results suggest that TAIII induces HL-60 cell apoptosis through JNK1/2 pathways and could serve as a potential additional chemotherapeutic agent for treating AML.