Colorectal anticancer activities of polymethoxylated 3-naphthyl-5-phenylpyrazoline-carbothioamides.

To develop potent chemotherapeutic agents for treating colorectal cancers, polymethoxylated 3-naphthyl-5-phenylpyrazoline-carbothioamide derivatives were designed. Twenty-two novel derivatives were synthesized and their cytotoxicities were measured using a clonogenic long-term survival assay. Of these derivatives, 3-(1-hydroxynaphthalen-2-yl)-N-(3-methoxyphenyl)-5-(4-methoxyphenyl)-pyrazoline-1-carbothioamide (NPC 15) exhibited the best half-maximal cell growth inhibitory concentrations (196.35nM). To explain its cytotoxicity, further biological experiments were performed. Treatment with NPC 15 inhibited cell cycle progression and triggered apoptosis through the caspase-mediated pathway. Its inhibitory effects on several kinases participating in the cell cycle were investigated using an in vitro kinase assay. Its half-maximal inhibitory concentrations for aurora kinases A and B were 105.03µM and 8.53µM, respectively. Further analysis showed that NPC 15 decreased phosphorylation of aurora kinases A, B, and C and phosphorylation of histone H3, a substrate of aurora kinases A and B. Its molecular binding mode for aurora kinase B was elucidated using in silico docking. In summary, polymethoxylated 3-naphthyl-5-phenylpyrazoline-carbothioamides could be potent chemotherapeutic agents.

Euphorbia humifusa Willd exerts inhibition of breast cancer cell invasion and metastasis through inhibition of TNFα-induced MMP-9 expression.

BACKGROUND: Breast cancer is the most common type of malignancy in women worldwide. Euphorbia humifusa Willd (EuH) is a plant that is widely used as a traditional medicine. However, no systemic studies on the anti-cancer effects of EuH have been reported. The aim of this study is to evaluate the anti-metastatic effect of the EuH. METHODS: Ethyl acetate fraction was prepared from EuH methanol extracts (EA/EuH). Inhibitory effect of EA/EuH on cell migration was determined using an in vitro scratch-wound healing assay. The anti-invasive activity was determined by in vitro three-dimensional spheroid culture system and in vivo syngenic experimental lung metastasis experiment. Gene expression profiles were analyzed by using RT-PCR, real-time PCR, and luciferase reporter assay systems. RESULTS: Ethyl acetate fraction from the EuH extract (EA/EuH) inhibited the migration and invasive capabilities of highly metastatic MDA-MB-231 breast cancer cells and attenuated syngeneic lung metastasis of mouse 4 T1 breast cancer cells in vivo. Mechanistically, EA/EuH decreased tumor necrosis factor alpha (TNFα)-induced matrix metalloproteinase (MMP)-9 mRNA expression through the inhibition of NF-κB activity in MDA-MB-231 cells. CONCLUSION: EuH may be beneficial in the prevention of invasion and metastasis of early stage breast cancer and can be served as an anti-metastatic agent or adjuvant therapy against metastatic breast cancer.

Synthesis and biological evaluation of phenyl-1H-1,2,3-triazole derivatives as anti-inflammatory agents.

Rapid and efficient synthesis of a phenyl-1H-1,2,3-triazole library enabled cost-effective biological testing of a range of novel non-steroidal anti-inflammatory drugs with potential for improved drug efficacy and toxicity profiles. Anti-inflammatory activities of the phenyl-1H-1,2,3-triazole analogs synthesized in this report were assessed using the xylene-induced ear edema model in mice. At least four analogs, 2a, 2b, 2c, and 4a, showed more potent effects than the reference anti-inflammatory drug diclofenac at the same dose of 25 mg/kg. To explore relationships between the structural properties of phenyl-1H-1,2,3-triazole analogs and their anti-inflammatory activities in xylene-induced ear edema, comparative molecular field analysis was performed, and pharmacophores showing good anti-inflammatory activities were identified based on an analysis of contour maps obtained from comparative molecular field analysis. The anti-inflammatory effect on the molecular level was tested by the expression of tumor necrosis factor-alpha induced COX-2 using Western blots. Because the addition of the analog 2c caused the expression change of TNF-α induced COX-2, the molecular binding mode between 2c and COX-2 was elucidated using in silico docking.

Polyphenols bearing cinnamaldehyde scaffold showing cell growth inhibitory effects on the cisplatin-resistant A2780/Cis ovarian cancer cells.

Ovarian carcinoma remains the most lethal among gynecological cancers. Chemoresistance is a clinical problem that severely limits treatment success. To identify potent anticancer agents against the cisplatin-resistant human ovarian cancer cell line A2780/Cis, 26 polyphenols bearing a cinnamaldehyde scaffold were synthesized. Structural differences in their inhibitory effect on clonogenicity of A2780/Cis cells were elucidated using comparative molecular field analysis and comparative molecular similarity indices analysis. Structural conditions required for increased inhibitory activity can be derived based on the analysis of their contour maps. The two most active compounds (16 and 19) were selected and further characterized their biological activities. We found that compounds 16 and 19 trigger cell cycle arrest at the G2/M phase and apoptotic cell death in cisplatin-resistant A2780/Cis human ovarian cancer cells. The molecular mechanism of compound 16 was elucidated using in vitro aurora A kinase assay, and the binding mode between the compound 16 and aurora A kinase was interpreted using in silico docking experiments. The findings obtained here may help us develop novel plant-derived polyphenols used for potent chemotherapeutic agents. In conclusion, compounds 16 and 19 could be used as promising lead compounds for the development of novel anticancer therapies in the treatment of cisplatin-resistant ovarian cancers.

Plant-derived flavones as inhibitors of aurora B kinase and their quantitative structure-activity relationships.

Although several plant-derived flavones inhibit aurora B kinase (aurB), quantitative relationships between the structural properties of plant-derived flavones and their inhibitory effects on aurB remain unclear. In this report, these quantitative structure-activity relationships were obtained. For quercetagetin, found in the Eriocaulon species, showing the best IC50 value among the flavone derivatives tested in this report, further biological tests were performed using cell-based assays, including Western blot analysis, flow cytometry, and immunofluorescence microscopy. In vitro cellular experiments demonstrated that quercetagetin inhibits aurB. The molecular-binding mode between quercetagetin and aurB was elucidated using in silico docking. Quercetagetin binds to aurB, aurA, and aurC and prevents the active phosphorylation of all three aurora kinases. In addition, quercetagetin triggers mitotic arrest and caspase-mediated apoptosis. These observations suggest that quercetagetin is an aurora kinase inhibitor. Induction of mitosis-associated tumor cell death by quercetagetin is a promising strategy for developing novel chemotherapeutic anticancer agents.

Quantitative Relationships Between the Cytotoxicity of Flavonoids on the Human Breast Cancer Stem-Like Cells MCF7-SC and Their Structural Properties.

As some breast cancer-related deaths can be attributed to the metastasis of cancer stem cells, chemotherapeutic agents targeting breast cancer stem cells are of interest as a potential treatment. Flavonoids that exhibit cytotoxicity on breast cancer stem cells have rarely been observed. Thus, the objective of this study was to measure potential cytotoxic effects of 42 different flavonoids on the human breast cancer stem-like cell line, MCF7-SC. The relationship between flavonoid structural properties and cytotoxicity has not been reported previously; therefore, we determined quantitative structure-activity relationships using both comparative molecular field analysis and comparative molecular similarity analysis. Further biological experiments including Western blot analysis, flow cytometry, and immunofluorescence microscopy were also conducted on the most cytotoxic 8-chloroflavanone.

Targeting cancer cells via the reactive oxygen species-mediated unfolded protein response with a novel synthetic polyphenol conjugate.

PURPOSE: The selective killing of tumor cells is an important strategy for cancer therapeutics. The aim of this study was to develop a novel antitumor agent that is safe for normal cells with the ability to selectively target cancer cells. EXPERIMENTAL DESIGN: On the basis of quantitative structure-activity relationship, we synthesized a novel polyphenol conjugate (E)-3-(3,5-dimethoxyphenyl)-1-(2-methoxyphenyl)prop-2-en-1-one (DPP-23). We evaluated the effect of DPP-23 on proliferation, cell cycle, and apoptosis in various tumor cells. We also assessed molecular targets of DPP-23 using genome-wide expression profiling by DNA microarray and real-time PCR array systems. RESULTS: DPP-23 effectively inhibited the growth of cancer cells in vitro and in vivo (xenografts in Balb/c nude mice). At a molecular level, DPP-23 targeted the unfolded protein response (UPR) in the endoplasmic reticulum (ER) through the production of reactive oxygen species (ROS) in cancer cells, but not in normal cells, resulting in selective killing of tumor cells via caspase-dependent apoptosis. CONCLUSIONS: The selective generation of ROS in cancer cells could be an attractive strategy for the selective killing of cancer cells, while maintaining negligible cytotoxicity to normal cells. DPP-23 represents a promising novel therapeutic agent for the selective production of ROS in cancer cells.