Yeon Woo Song

Toxicity of Nano Molybdenum Trioxide toward Invasive Breast Cancer Cells

Current chemotherapy is limited by the nature of invasive cancer cells, which are similar to cancer stem cells. Nanomaterials provide a potential alternate mode of cancer therapy. This study investigated the cytotoxicity of molybdenum trioxide (MoO3) nanoplates toward invasive breast cancer iMCF-7 cells by analyzing morphological changes and performing Western blot and flow cytometry analyses. The findings suggested that MoO3 exposure induces apoptosis and generates reactive oxygen species (ROS) in iMCF-7 cells. This study revealed the potential utility of MoO3 for treating metastatic cancer cells, which might enable advancements in cancer therapy.

Sageone, a diterpene from Rosmarinus officinalis, synergizes with cisplatin cytotoxicity in SNU-1 human gastric cancer cells

BACKGROUND AND PURPOSE Chemotherapy resistance is a major obstacle for the effective treatment of cancers. Although several studies have described the anticancer properties of rosemary extract and its components, the detailed mechanisms of action are poorly understood. METHODS Activity-guided fractionation and repeated chromatographic separation of the n-hexane fraction of the aqueous methanol extract over silica gel, RP C18, and Sephadex LH-20 led to the isolation of three compounds. The structures of the compounds were determined using 1H, 13C, and two-dimensional nuclear magnetic resonance spectroscopy, mass spectroscopy, and infrared spectroscopy. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay was used to evaluate the cytotoxicity of these compounds. Cell cycle, apoptotic cell populations, and mitochondrial membrane potential were analyzed by flow cytometry. Western blot analysis was conducted to detect apoptosis-related proteins. RESULTS An abietane diterpenoid, sageone (1), an icetexane diterpenoid, (-)-barbatusol (2), and a monoterpene, (+)-verbenone (3), were identified. Of these compounds, sageone (1) showed cytotoxicity against SNU-1 cells with an IC50 of 9.45 ± 1.33 µM. Sageone reduced the expression of Akt dramatically, as opposed to cisplatin, which increased phosphorylated Akt. Sageone combined with a subtoxic dose of cisplatin had synergistic effects on apoptosis induction in SNU-1 cells, as confirmed by calculating the combination index. Co-treatment was significantly more effective than monotherapy at reducing cell viability and inducing apoptosis, as determined by analyzing DNA fragmentation. The combined treatment of sageone and cisplatin markedly reduced Akt expression and phosphorylation, accompanied by increases in cleaved caspase-3, -9 and PARP. CONCLUSION This is the first time compounds 1 and 2 have been isolated from R. officinalis. Sageone induced apoptosis in SNU-1 human gastric cancer cells and notably enhanced the cytotoxicity of cisplatin in SNU-1 cells, which are known to be resistant to cisplatin. These findings suggest that sageone represents a promising anticancer agent against gastric cancer that warrants further study.

Baicalein Inhibits Epithelial to Mesenchymal Transition via Downregulation of Cyr61 and LOXL-2 in MDA-MB231 Breast Cancer Cells.

Epithelial-mesenchymal transition (EMT) is a critical step in the acquisition of the migratory and invasive capabilities associated with metastatic competence. Cysteine-rich protein 61 (CCN1/Cyr61) has been implicated as an important mediator in the proliferation and metastasis of breast cancer. Hence, Cyr61 and associated pathways are attractive targets for therapeutic interventions directed against the EMT. In the present study, we report that baicalein significantly inhibits the expression of Cyr61 and migration and invasion of MDA-MB231 human breast cancer cells. Exposure to baicalein led to increased E-cadherin expression, possibly due to the ubiquitination of Snail and Slug, which was mediated by the Cyr61/Akt/glycogen synthase kinase 3β (GSK3β) pathway. Further analysis revealed that baicalein inhibited the expression of lysyl oxidase like-2 (LOXL-2), which is a functional collaborator of Snail and Slug, and subsequently attenuated the direct interaction between LOXL-2 and Snail or Slug, thereby enhancing GSK3β-dependent Snail and Slug degradation. Our findings provide new insights into the antimetastatic mechanism of baicalein and may contribute to its beneficial use in breast cancer therapies.

Camphor Induces Proliferative and Anti-senescence Activities in Human Primary Dermal Fibroblasts and Inhibits UV-Induced Wrinkle Formation in Mouse Skin.

Camphor ((1R)‐1,7,7‐trimethylbicyclo[2.2.1]heptan‐2‐one), a bicyclic monoterpene, is one of the major constituents of essential oils from various herbs such as rosemary, lavender, and sage. In this study, we investigated the beneficial effects of camphor as a botanical ingredient in cosmetics. Camphor induced the proliferation of human primary dermal fibroblasts in a dose‐dependent manner via the PI3K/AKT and ERK signaling pathways. Camphor attenuated the elevation of senescence associated with β‐galactosidase (SA‐β‐gal) activity. Elastase activity decreased, while the total amount of collagen increased, in a dose‐ and time‐dependent manner in human primary dermal fibroblasts treated with camphor. Camphor induced the expression of collagen IA, collagen IIIA, collagen IVA, and elastin in human primary dermal fibroblasts. In addition, posttreatment with 26 and 52 mM camphor for 2 weeks led to a significant reduction in the expression of MMP1 but increases in the expression of collagen IA, IIIA, and elastin in mouse skin exposed to UV for 4 weeks. These posttreatments also reduced the depths of the epidermis and subcutaneous fat layer in UV‐exposed mouse skin. Taken together, these findings suggest camphor to be a potent wound healing and antiwrinkle agent with considerable potential for use in cosmeceuticals. Copyright

Chemical Composition and Antiproliferative Activity of Supercritical Extract of Citrus grandis (L.) Osbeck Fruits from Korea

Abstract Constituents of supercritical CO2 extracts of peel and flesh from pummelo fruits (Citrus grandis Osbeck) were analyzed by gas chromatography-mass spectrometry (GC-MS). In total, 69 constituents were identified while 42 were common in both samples. The identified major constituents are 7-Methoxy-8- (2-oxo-3-methylbutyl) coumarin (11.4 %), (6E,8E,10E)-2,6,11,15-tetramethyl-2,6,8,10,14-hexadecapentaene (5.9 %) and γ-sitosterol (5.1 %) in peel and hexadecanoic acid (10.0 %), (E,E)-2,4-decadienal (6.3 %) and pentacosane (7.0 %) in flesh extracts. Antiproliferative activity, determined by cell viability assay and cellular morphology observation, revealed that 400 μg/ml concentration of peel extract possesses significant efficacy and potency for inhibition of human cervical carcinoma HeLa and gastric adenocarcinoma AGS cells.

Induction of apoptosis in anoikis-resistant breast cancer stem cells by supercritical CO2 extracts from Citrus hassaku Hort ex Tanaka

Anoikis (or cell-detachment-induced apoptosis) is a special form of apoptosis in which cells loose contact with other cells or the extracellular matrix. In the present study, we have found that the breast cancer stem cell line MCF-7-SC, isolated from MCF-7 breast cancer cells, shows characteristics of anoikis resistance. Treatment of supercritical CO2 extract from Citrus hassaku Hort ex Tanaka, locally known as Phalsak, reduced the expression of ATP-binding cassette sub-family G member 2 mRNA and induced apoptosis in MCF-7-SCs, as evidenced by an increase of apoptotic body formation, increased cell population in the sub-G1 phase, increase in the Bax/Bcl-2 ratio, proteolytic activation of caspase-9 and caspase-3, and the degradation of poly(ADP-ribose) polymerase (PARP) protein. The effects of supercritical CO2 extract from Phalsak on anoikis-resistant breast cancer stem cells suggest the use of this extract as a potential therapeutic agent for breast cancer stem cell treatment.

1H and 13C NMR characterization of 1,3,4-oxadiazole derivatives

Oxadiazoles are heterocyclic five‐membered rings containing an oxygen and two nitrogens. There are four oxadiazole isomers: 1,2,3‐oxadiazole, 1,2,4‐oxadiazole, 1,2,5‐oxadiazole, and 1,3,4‐oxadiazole (Figure 1). Among these, the 1,3,4‐oxadiazole skeleton has garnered considerable interest owing to its diverse biological properties including anti‐inflammatory, antimicrobial, anticonvulsant, antitubercular, antiviral, and anticancer activities. 1,3,4‐Oxadiazole is called oxybiazole. 4H‐chromen‐4‐one makes up flavone, which is a plant‐ derived secondary metabolite. Because the 4H‐chromen‐ 4‐one skeleton is known to exhibit anticancer effects, diverse derivatives have been reported. 3,5,4′‐Trihydroxy‐trans‐stilbene, resveratrol, is widely present in berries and grapes. Its analogues are known to show anticancer activities as well. As such, we designed 21 derivatives on the basis of 1,3,4‐oxadiazoles and 4H‐ chromen‐4‐one or 3,5,4′‐trimethoxy‐trans‐stilbene. Nuclear magnetic resonance (NMR) spectroscopy and high‐resolution mass spectrometry (HR/MS) were performed for the identification and characterization of the synthesized derivatives. Among the carbons in 15 derivatives containing 4H‐chromen‐4‐one, C‐2′ and C‐10′ do not show a difference by the existence or absence of 6′‐ methoxy group. C‐3′, C‐4′, C‐5′, C‐7′, and C‐9′ of derivatives without 6′‐methoxy group were more deshielded than those of derivatives with 6′‐methoxy group, and the chemical shifts of C‐8′ of the former were more shielded than those of the latter. Likewise, H‐5′ and H‐7′ of the former were more deshielded than those of the latter, and H‐ 8′ of the former was more shielded than those of the

Citrus unshiu leaf extract containing phytol as a major compound induces autophagic cell death in human gastric adenocarcinoma AGS cells

The pharmaceutical potential of the methanolic extract of Citrus unshiu leaves (MECL) was assessed through analysis of its inhibitory effect on cancer cells. The antiproliferative activities of the leaves were evaluated using several cancer cell lines and considerable cytotoxicity was observed in human gastric adenocarcinoma AGS cells. Inhibition of AGS cell viability was both time- and dose-dependent, and MECL induced non-apoptotic cell death. AGS cells treated with MECL increased the formation of acidic vesicular organelles and GFP-LC3 puncta. Pretreatment with an autophagy inhibitor, 3-methyladenine, inhibited MECL-induced cell death. These results indicated that the mechanism underlying the anticancer effects of MECL in AGS cells could be via the induction of autophagic cell death. The major compounds of MECL were identified as phytol, 4-ethenyl-2-methoxyphenol, hexadecanoic acid, 2,3-dihydro-3,5-dihydroxy-6-methyl-4H-pyran-4-one, and vitamin E using gas chromatography–mass spectrometry. These results indicate that C. unshiu leaves can be exploited for numerous pharmaceutical applications as a source of anticancer ingredients.

Synergistic effect of the novel benzochalcone derivative DK-78 and doxorubicin on MCF7-VN breast cancer stem cells

Several naturally occurring or synthesized forms of chalcone have been shown to possess multiple biological properties, including antitumor activities. A novel synthetic flavonoid, the benzochalcone derivative DK-78, was administered with the anticancer drug doxorubicin to two breast cancer cell lines (MCF7-VN and MDA-MB-231), and was evaluated for a synergistic cytotoxic effect. DK-78 reduced the expression of mesenchymal marker proteins and reduced cell migration and attachment. Sequential treatment with DK-78 and doxorubicin showed synergistic effects.

2,4‑Di‑tert‑butylphenol, a potential HDAC6 inhibitor, induces senescence and mitotic catastrophe in human gastric adenocarcinoma AGS cells

The natural product 2,4‑di‑tert‑butylphenol (DTBP) has a wide spectrum of biological functions, including anticancer activities, although the underlying mechanisms are poorly understood. Here, we found that DTBP induces senescence in human gastric adenocarcinoma AGS cells as evidenced by upregulation of p21 and Rb and increased β‑galactosidase activity. DTBP also induces mitotic catastrophe and generates multinucleated cells, which is accompanied by an increase in the proportion of polymerized tubulin, possibly caused by inhibition of HDAC6 enzyme activity. In silico docking analysis showed that DTBP docked at the entrance of the ligand-binding pocket of the HDAC6 enzyme. Accordingly, DTBP represents a promising lead structure for the development of HDAC6 inhibitors, with an improvement in specificity conferred by modification of the cap group. We propose for the first time that the underlying mechanism of the anticancer activity of DTBP is attributed to inhibition of HDAC6 activity.