Hsueh-Wei Chang

Diverse Tumorigenic Pathways in Ovarian Serous Carcinoma

This study was undertaken to analyze genetic alterations in 108 sporadic serous ovarian neoplasms to elucidate ovarian serous carcinogenesis. Our results demonstrate that K-ras mutations occur in approximately 50% of serous borderline tumors (SBTs), non-invasive micropapillary serous carcinomas (MPSCs), and invasive micropapillary serous carcinomas, which represent a morphological continuum of tumor progression. Moreover, progressive increase in the degree of allelic imbalance of chromosomes 1p, 5q, 8p, 18q, 22q, and Xp was observed comparing serous borderline tumors to noninvasive and invasive micropapillary serous carcinomas. In contrast, high-grade (conventional serous carcinoma) tumors contained wild-type K-ras in all 23 cases studied and a high frequency of allelic imbalance even in small (early) primary tumors similar to that found in advanced stage tumors. Based on these findings, we propose a dualistic model for ovarian serous carcinogenesis. One pathway involves a stepwise progression from SBT to noninvasive and then invasive MPSC. The other pathway is characterized by rapid progression from the ovarian surface epithelium or inclusion cysts to a conventional (high-grade) serous carcinoma.

Combinational polymorphisms of four DNA repair genes XRCC1, XRCC2, XRCC3, and XRCC4 and their association with oral cancer in Taiwan.

BACKGROUND Many single nucleotide polymorphisms (SNPs) have been found to be associated with oral cancer but the biological interactions through SNPs are seldom addressed. In this study, we focused on the joint effect for SNP combinations of four DNA repair genes, X-ray repair cross-complementing groups (XRCCs) 1-4, involved in major cancer-related pathways. METHODS Single nucleotide polymorphism genotyping was determined using by polymerase chain reaction-restriction fragment length polymorphism in this study (case = 103, control = 98). Different numbers of combinational SNPs with genotypes called the pseudo-haplotypes from these chromosome-wide genes were used to evaluate their joint effect on oral cancer risk. RESULTS Except for XRCC2 rs2040639-AG, none of these SNPs was found to individually contribute to oral cancer risk. However, for two combined SNPs, the proportion of subjects with oral cancer was significantly higher in the pseudo-haplotype with AG-CC genotypes in rs2040639-rs861539 (XRCC2-XRCC3) compared with those with non-AG-CC genotypes. Similarly, the pseudo-haplotype of rs2040639-rs861539-rs2075685 (XRCC2-XRCC3-XRCC4) and rs2040639-rs861539-rs2075685-rs1799782 (XRCCs 1-4) with specific genotype pattern (AG-CC-TG and CT-AG-CC-TG) among three and four combinational SNPs were significantly associated with oral cancer. After controlling for age, gender, smoking, drinking, and betel nut chewing, the estimated odds ratio of oral cancer were 2.45, 5.03, and 10.10 for two, three and four specific SNP combinations, respectively, comparing these specific pseudo-haplotypes to their corresponding non-pseudo-haplotypes. CONCLUSION We have identified the potential combined XRCCs 1-4 SNPs with genotypes that were associated with oral cancer risk and may have an impact on identification of a high-risk population.

Marine algal natural products with anti-oxidative, anti-inflammatory, and anti-cancer properties

For their various bioactivities, biomaterials derived from marine algae are important ingredients in many products, such as cosmetics and drugs for treating cancer and other diseases. This mini-review comprehensively compares the bioactivities and biological functions of biomaterials from red, green, brown, and blue-green algae. The anti-oxidative effects and bioactivities of several different crude extracts of algae have been evaluated both in vitro a nd in vivo. Natural products derived from marine algae protect cells by modulating the effects of oxidative stress. Because oxidative stress plays important roles in inflammatory reactions and in carcinogenesis, marine algal natural products have potential for use in anti-cancer and anti-inflammatory drugs.

Natural Products: Bioactivity, Biochemistry, and Biological Effects in Cancer and Disease Therapy

The drug discovery for chemoprevention and chemotherapy remains a challenge. Natural products-derived extracts and compounds are frequently reported to discover therapeutic agents for disease and cancer. The overall scenario of this special issue of The Scientific World Journal presents the recent advances in biological function of selected natural products for cancer and disease therapy in terms of crude extracts and components. Some studies describe the bioinformatics tool to help to investigate the field of natural products. The papers by S. Guleria et al. and C.-C. Lee et al. provide the essential oil and/or extracts of herb Zanthoxylum alatum and Zingiber officinale for its antioxidant and antimicrobial properties, respectively. O. O. Igbinosa et al. and C.-C. Lee et al. provide the animal experiments using extractsfrom Jatropha curcas (Linn) leaf and from supercritical carbon dioxide extracted ginger, respectively. Three studies (F. M. Al-Jasass and M. S. Al-Jasser, X.-W. Chen et al., and C.-Y. Lo et al.) focus on biological functions of the compounds from Saudi Arabia herbs, Chinese herb Huang Lian (Rhizoma coptidis), and from Alpinia galangal, respectively. Further, C.-Y. Yen et al. provide the toxicological study for cardiotoxin III in growth inhibition of oral cancer. C.-Y. Lin et al. provide a review article for the chemoprevention of cytochrome P450 in oral potentially malignant disorders (OPMDs) patients in terms of betel quid metabolism. S.-S. Liang et al. introduce the novel technique for online monitoring oxidative products and metabolites of nicotine based on tandem mass spectrometry. Some papers introduce the bioinformatics methods or resources to study or review the natural products-related studies. L. Wang et al. introduce the gene ontology (GO) network for the systems-theoretical analysis of human hepatocellular carcinoma. Y.-C. Lin et al. provide the database (TIPdb) for anticancer, antiplatelet, and antituberculosis phytochemicals from indigenous plants in Taiwan. Three papers (W.-H. Huang et al. and J.-Y. Tang et al.) provide the drug discovery for cancer and disease therapy in terms of RNA editing, alternative splicing, and long noncoding RNAs as well as the summary for their bioinformatics resources. Hsueh-Wei Chang Li-Yeh Chuang Sanjay Guleria Sammia Yasmin

Combinational Polymorphisms of Seven CXCL12-Related Genes Are Protective against Breast Cancer in Taiwan

Many single nucleotide polymorphisms (SNPs) have been found to be associated with breast cancer, but their SNP interactions are seldom addressed. In this study, we focused on the joint effect for SNP combinations of seven CXCL12-related genes involved in major cancer-related pathways. SNP genotyping was determined by PCR-restriction fragment length polymorphism (RFLP) in this study (case = 220, control = 334). Different numbers of combinational SNPs with genotypes called the SNP barcodes from different chromosomes were used to evaluate their joint effect on breast cancer risk. Except for vascular endothelial growth factor (VEGF) rs3025039-CT, none of these SNPs were found to individually contribute to breast cancer risk. However, for two combined SNPs, the proportion of subjects with breast cancer was significantly low in the SNP barcode with CC-GG genotypes in rs2228014-1801157 (CXCR4-CXCL12) compared to those with non-CC-GG genotypes. Similarly, the SNP barcode of rs12812942-rs2228014-rs3025039 (CD4-CXCR4-VEGF) and rs12812942-rs3136685-rs2228014-rs1801157 (CD4- CCR7-CXCR4-CXCL12) with specific genotype patterns (AT-CC-CC and AT-AG-CC-GG) among three and four combinational SNPs were significantly low in breast cancer occurrence. More SNP combinations larger than five SNPs were also addressed, and these showed similar effects. After controlling for age, and comparing their corresponding non-SNP barcodes, the estimated odds ratios for breast cancer ranged between 0.20 and 0.71 for specific SNP barcodes with two to seven SNPs. In conclusion, we have associated the potential combined CXCL12-related SNPs with genotypes that were protective against breast cancer, and that may contribute to identification of a low-risk population for the development of breast cancer.

4β-Hydroxywithanolide E from Physalis peruviana (golden berry) inhibits growth of human lung cancer cells through DNA damage, apoptosis and G2/M arrest

BackgroundThe crude extract of the fruit bearing plant, Physalis peruviana (golden berry), demonstrated anti-hepatoma and anti-inflammatory activities. However, the cellular mechanism involved in this process is still unknown.MethodsHerein, we isolated the main pure compound, 4β-Hydroxywithanolide (4βHWE) derived from golden berries, and investigated its antiproliferative effect on a human lung cancer cell line (H1299) using survival, cell cycle, and apoptosis analyses. An alkaline comet-nuclear extract (NE) assay was used to evaluate the DNA damage due to the drug.ResultsIt was shown that DNA damage was significantly induced by 1, 5, and 10 μg/mL 4βHWE for 2 h in a dose-dependent manner (p < 0.005). A trypan blue exclusion assay showed that the proliferation of cells was inhibited by 4βHWE in both dose- and time-dependent manners (p < 0.05 and 0.001 for 24 and 48 h, respectively). The half maximal inhibitory concentrations (IC50) of 4βHWE in H1299 cells for 24 and 48 h were 0.6 and 0.71 μg/mL, respectively, suggesting it could be a potential therapeutic agent against lung cancer. In a flow cytometric analysis, 4βHWE produced cell cycle perturbation in the form of sub-G1 accumulation and slight arrest at the G2/M phase with 1 μg/mL for 12 and 24 h, respectively. Using flow cytometric and annexin V/propidium iodide immunofluorescence double-staining techniques, these phenomena were proven to be apoptosis and complete G2/M arrest for H1299 cells treated with 5 μg/mL for 24 h.ConclusionsIn this study, we demonstrated that golden berry-derived 4βHWE is a potential DNA-damaging and chemotherapeutic agent against lung cancer.

Anti-proliferative effect of methanolic extract of Gracilaria tenuistipitata on oral cancer cells involves apoptosis, DNA damage, and oxidative stress

BackgroundMethanolic extracts of Gracilaria tenuistipitata (MEGT) were obtained from the edible red algae. Previously, we found that water extract of G. tenuistipitata was able to modulate oxidative stress-induced DNA damage and its related cellular responses.MethodsIn this study, the methanol extraction product MEGT was used to evaluate the cell growth inhibition in oral cancer cells and its possible mechanism was investigated.ResultsThe cell viability of MEGT treated Ca9-22 oral cancer cell line was significantly decreased in a dose–response manner (p < 0.05). The sub-G1 population and annexin V intensity of MEGT-treated Ca9-22 cancer cells were significantly increased in a dose–response manner (p < 0.0005 and p < 0.001, respectively). The γH2AX intensities of MEGT-treated Ca9-22 cancer cells were significantly increased in a dose–response manner (p < 0.05). The reactive oxygen species (ROS) and glutathione (GSH)-positive intensities of MEGT-treated Ca9-22 oral cancer cells were significantly increased and decreased, respectively, in a dose–response manner (p < 0.05). The DiOC2(3) intensity for mitochondrial membrane potential (MMP) of MEGT-treated Ca9-22 cancer cells was significantly decreased in a dose–response manner (p < 0.05).ConclusionsThese results indicated that MEGT had apoptosis-based cytotoxicity against oral cancer cells through the DNA damage, ROS induction, and mitochondrial depolarization. Therefore, MEGT derived from the edible algae may have potential therapeutic effects against oral squamous cell carcinoma (OSCC).

Goniothalamin Inhibits Growth of Human Lung Cancer Cells through DNA Damage, Apoptosis, and Reduced Migration Ability

We evaluated the possible anticancer performance of a natural compound, goniothalamin (GTN), against human lung cancer using as a non-small cell lung cancer (NSCLC) cell line, H1299, as the model system. Cellular proliferation was significantly inhibited by GTN. Using an improved alkaline comet-nuclear extract (comet-NE) assay, GTN was found to induce a significant increase in the tail DNA. Wound healing and zymography assays showed that GTN attenuated cell migration and caused a reduction in the activity level of two major migration-associated matrix metalloproteinases, MMP-2 and MMP-9. It can be concluded that the DNA-damaging effect of GTN against lung cancer cells leads to growth inhibition as well as a depression in migration ability. Therefore, GTN has potential as a chemotherapeutic agent against lung cancer.

Anonaine Induces DNA Damage and Inhibits Growth and Migration of Human Lung Carcinoma H1299 Cells

The anticancer effects of (-)-anonaine were investigated in this current study. (-)-Anonaine at concentration ranges of 50-200 μM exhibited significant inhibition to cell growth and migration activities on human lung cancer H1299 cells at 24 h, albeit cell cycle analyses showed that (-)-anonaine at the above concentration ranges did not cause any significant changes in cell-cycle distributions. Significant nuclear damages of H1299 cells were observed with 10-200 μM (-)-anonaine treatment in a comet assay, whereas higher concentrations (6 and 30 mM) of (-)-anonaine concentrations were required to cause DNA damages in an in vitro plasmid cleavage assay. In summary, our results demonstrated that (-)-anonaine exhibited dose-dependent antiproliferatory, antimigratory, and DNA-damaging effects on H1299 cells. We inferred that (-)-anonaine can cause cell-cycle arrest and DNA damage to hamper the physiological behavior of cancer cells at 72 h, and therefore, it can be useful as one of the potential herbal supplements for chemoprevention of human lung cancer.

Obtusilactone A and ())-sesamin induce apoptosis in human lung cancer cells by inhibiting mitochondrial Lon protease and activating DNA damage checkpoints

Several compounds from Cinnamomum kotoense show anticancer activities. However, the detailed mechanisms of most compounds from C. kotoense remain unknown. In this study, we investigated the anticancer activity of obtusilactone A (OA) and (−)‐sesamin in lung cancer. Our results show that human Lon is upregulated in non‐small‐cell lung cancer (NSCLC) cell lines, and downregulation of Lon triggers caspase‐3 mediated apoptosis. Through enzyme‐based screening, we identified two small‐molecule compounds, obtusilactone A (OA) and (−)‐sesamin from C. kotoense, as potent Lon protease inhibitors. Obtusilactone A and (−)‐sesamin interact with Ser855 and Lys898 residues in the active site of the Lon protease according to molecular docking analysis. Thus, we suggest that cancer cytotoxicity of the compounds is partly due to the inhibitory effects on Lon protease. In addition, the compounds are able to cause DNA double‐strand breaks and activate checkpoints. Treatment with OA and (−)‐sesamin induced p53‐independent DNA damage responses in NSCLC cells, including G1/S checkpoint activation and apoptosis, as evidenced by phosphorylation of checkpoint proteins (H2AX, Nbs1, and Chk2), caspase‐3 cleavage, and sub‐G1 accumulation. In conclusion, OA and (−)‐sesamin act as both inhibitors of human mitochondrial Lon protease and DNA damage agents to activate the DNA damage checkpoints as well induce apoptosis in NSCLC cells. These dual functions open a bright avenue to develop more selective chemotherapy agents to overcome chemoresistance and sensitize cancer cells to other chemotherapeutics. (Cancer Sci 2010; 101: 2612–2620)