Jeong Yong Moon

Mechanistic investigation on the toxicity of MgO nanoparticles toward cancer cells

Magnesium oxide nanoparticles (MgO NPs) are increasingly recognized for their applications in cancer therapy such as nano-cryosurgery and hyperthermia. The present study investigated the cytotoxic effects of magnesium oxide nanoparticles (MgO NPs) against normal lung fibroblast cells and different types of cancerous cells. MgO NPs exhibited a preferential ability to kill cancerous cells such as HeLa, AGS and SNU-16 cells. A detailed study has been undertaken to investigate the mechanism of cell death occurring in cancer cells (AGS cells) by the analysis of morphological changes, western blot analysis and flow cytometry measurements. Western blot analysis measurements suggested the role of apoptosis in cell death due to MgO exposure. MgO NPs enhanced ultrasound-induced lipid peroxidation in the liposomal membrane. Flow cytometry measurements using H2DCFDA showed that the toxicity of MgO NPs is attributed to the generation of reactive oxygen species, which further results in the induction of apoptosis in cancer cells. Our experimental results suggested the potential utility of MgO NPs in the treatment of cancer.

Quercetin induces mitochondrial mediated apoptosis and protective autophagy in human glioblastoma U373MG cells.

Quercetin is a dietary flavonoid with known antitumor effects against several types of cancers by promoting apoptotic cell death and inducing cell cycle arrest. However, U373MG malignant glioma cells expressing mutant p53 are resistant to a 24u2009h quercetin treatment. In this study, the anticancer effect of quercetin was reevaluated in U373MG cells, and quercetin was found to be significantly effective in inhibiting proliferation of U373MG cells in a concentration-dependent manner after 48 and 72u2009h of incubation. Quercetin induced U373MG cell death through apoptosis, as evidenced by the increased number of cells in the sub-G1 phase, the appearance of fragmented nuclei, decreased mitochondrial membrane potential, proteolytic activation of caspase-3 and caspase-7, an increase in caspase-3 and 9 activities, and degradation of poly(ADP-ribose) polymerase protein. Furthermore, quercetin activated JNK and increased the expression of p53, which translocated to the mitochondria and simultaneously led to the release of cytochrome c from mitochondria to the cytosol. We also found that quercetin induced autophagy. Pretreatment with chloroquine, an autophagy inhibitor, strongly augmented apoptosis in U373MG cells, indicating that quercetin induced protective autopagy in U373MG cells.

Comparative Antioxidant and Antiproliferative Activities of Red and White Pitayas and Their Correlation with Flavonoid and Polyphenol Content

Pitaya, commonly known as dragon fruit, has generated considerable consumer interest because of its attractive color and micronutrient content. The present study investigated the total polyphenol and flavonoid content, antioxidant activity against various free radicals, and antiproliferative effect on several cancer cell lines of extracts of flesh and peel of white and red pitayas, collected from Jeju Island, Korea. The total polyphenol and flavonoid contents of 80% methanol extracts of red pitaya peel (RPP) and white pitaya peel (WPP) were approximately 3- and 5-fold higher than those of red pitaya flesh (RPF) and white pitaya flesh (WPF), respectively. Overall, the total flavonoid and polyphenol contents of these extracts were RPP>WPP>RPF>WPF and WPP>RPP>RPF>WPF, respectively. In addition, a study involving nontargeted high-performance liquid chromatography coupled with a photodiode array and electrospray ionization mass spectrometry (HPLC-PDA-ESI-MS) of different pitaya extracts indicated the presence of phenolic, hydroxycinnamic acid derivatives, flavonol glycosides, betacyanin, and its derivatives with a few unknown compounds. Separately, peel extracts of both red and white pitayas showed higher 2,2-diphenyl-1-picrylhydrazyl, hydroxyl, and alkyl radical-scavenging activity than did the corresponding flesh extracts. Both peel extracts also showed stronger antiproliferative activity against AGS and MCF-7 cancer cells than either flesh extract. There was a direct correlation between the phenolic content and antioxidant effect, but no correlation observed between antioxidant activity and antiproliferative activity. These results suggest that the peel of white and red pitaya may be a valuable ingredient in foods and may also be useful in cosmetic, nutraceutical, and pharmaceutical applications.

Nobiletin Induces Apoptosis and Potentiates the Effects of the Anticancer Drug 5-Fluorouracil in p53-Mutated SNU-16 Human Gastric Cancer Cells

Nobiletin is a typical polymethoxyl flavone from citrus fruits that has anticancer properties, but the molecular mechanism of its inhibitory effects on the growth of p53-mutated SNU-16 human gastric cancer cells has not been explored. In this study, nobiletin was found to be effective at inhibiting the proliferation of SNU-16 cells than other flavonoids. Nobiletin induced the death of SNU-16 cells through apoptosis, as evidenced by the increased cell population in the sub-G1 phase, the appearance of fragmented nuclei, an increase in the Bax/Bcl-2 ratio, the proteolytic activation of caspase-9, an increase in caspase-3 activity, and the degradation of poly(ADP-ribose) polymerase (PARP) protein. We found that the combination of nobiletin plus the anticancer drug 5-fluorouracil (5-FU) reduced the viability of SNU-16 cells in a concentration-dependent manner and exhibited a synergistic anticancer effect (combination index = 0.38) when 5-FU was used at relatively low concentrations. The expression of p53 protein increased after treatment with 5-FU, but not nobiletin, whereas the expression of p21 WAF1/CIP1 protein increased after treatment with nobiletin, but not 5-FU. The cellular responses to nobiletin and 5-FU occurred through different pathways. The results of this study suggest the potential application of nobiletin to the enhancement of 5-FU efficiency in p53 mutant tumors.

Mechanism of 2′,3′-dimethoxyflavanone-induced apoptosis in breast cancer stem cells: Role of ubiquitination of caspase-8 and LC3

Accumulating evidence has displayed that targeting cancer stem cells (CSCs) is a very promising way for anti-cancer therapies. 2,3-Dimethoxyflavanone (2,3-DMF) showed the most potent toxicity of a group of 42 flavonoids tested in MCF-7-SC breast cancer stem cells. 2,3-DMF triggered intrinsic and extrinsic apoptosis by stimulating the cleavage of PARP and the activation of caspase-9, -8, and -3. Interestingly, 2,3-DMF induces a dramatic increase in the conversion of LC3, a well-known marker for autophagy. However, acidic vesicular organelles (AVOs), one of the autophagic flux markers were not detected. Co-treatment with chloroquine, the lysosomal inhibitor that blocks autophagic degradation did not show any change in the degree of LC3 conversion, implying that LC3 could play a role in the non-autophagic cell death of MCF-7-SC. We found that 2,3-DMF induces the ubiquitination of caspase-8, this resulted in an interaction between caspase-8 and LC3, which led to the aggregation and activation of caspase-8. Co-treating cells with 2,3-DMF and 3-methyladenine, an inhibitor of LC3 lipidation, reduced the activation of caspase-8. These findings provide novel insights into the anti-cancer effects of 2,3-DMF in breast cancer stem cells by revealing that it induced apoptosis in accompany with the activation of caspase-8 mediated by LC3 conversion.

Chemical Composition and Antiproliferative Activity of Supercritical Extract of Immature Citrus Peel in human cervical carcinoma HeLa cells

This study was performed to investigate the antiproliferative activities of supercritical extracts from phalsak(Citrus hassaku Hort ex Tanaka) and yeagam(Citrus iyo Hort. ex Tanaka) against human cervical carcinoma HeLa cells and the chemical compositions of the extracts. The anticancer properties of supercritical extracts were demonstrated using the MTT assay and Hoechst 33342 staining and the compositional analyses were conducted by using gas chromatography-mass spectrometry(GC-MS). The peel extracts of both species exhibited similar antiproliferative effect. The antiproliferative activity of the flesh extracts was not detected up to , whereas peel extracts of phalsak and yeagam reduced cell viability with 87.16% and 92.95% at , respectively. There was a dramatic increase of the apoptotic body formation in the cell treated with peel extracts while no apoptotic body formation detected in the cell treated with flesh extracts at 100, . By GC-MS analysis, 27 and 31 kinds of compounds identified in flesh and peel of phalsak, while 27 and 29 kinds of compounds were identified in flesh and peel of yeagam, respectively. 1,1,4,4-Tetramethyl-2-tetralone(20.86%), alloimperatorin(8.15%), limonene(11.23%), and auraptene(7.29%) were major in peel of phalsak, whereas limonene(22.19%), linalool(11.23%), and -sitosterol(9.12%) were major in peel of yeagam.

Induction of ER Stress-Mediated Apoptosis by the Major Component 5,7,4′-Trimethoxyflavone Isolated from Kaempferia parviflora Tea Infusion

Abstract Kaempferia parviflora (KP) is a famous medicinal plant from Thailand, and is a rich source of various kinds of methoxyflavones (MFs). Many kinds of food products such as tea, capsule, and liquor are manufactured from the rhizomes of KP. In this study, KP infusions were prepared with different brewing conditions, and the amounts of three major methoxylflavones, 5,7-dimethoxyflavone (DMF), 5,7,4′-trimethoxyflavone (TMF), and 3,5,7,3′,4′-pentamethoxyflavone (PMF), were analyzed. The antiproliferative activities of DMF, TMF, and PMF isolated from the brewed tea samples were evaluated. TMF was discovered to be significantly effective at inhibiting proliferation of SNU-16 human gastric cancer cells in a concentration dependent manner. TMF induced apoptosis, as evidenced by increments of sub-G1 phase, DNA fragmentation, annexin-V/PI staining, the Bax/Bcl-xL ratio, proteolytic activation of caspase-3,-7,-8, and degradation of poly (ADP-ribose) polymerase (PARP) protein. Furthermore, it was found that TMF induced apoptosis via ER stress, verified by an increase in the level of C/EBP homologous protein (CHOP), glucose regulated protein 78 (GRP78), inositol-requiring enzyme 1 α (IRE1α), activating transcription factor-4 (ATF-4), and the splice isoform of X-box-binding protein-1 (XBP-1) mRNA.