Anticancer activity of gomisin J from Schisandra chinensis fruit.

In attempting to identify effective anticancer drugs from natural products that are harmless to humans, we found that the gomisin J from Schisandra chinensis fruit has anticancer activity. Schisandra chinensis fruits are used in traditional herbal medicine and gomisin J is one of their chemical constituents. In the present study, we examined the anticancer activity of gomisin J in MCF7 and MDA-MB-231 breast cancer cell lines and in MCF10A normal cell line, in a time- and concentration-dependent manner. Our data revealed that gomisin J exerted a much stronger cytotoxic effect on MCF7 and MDA-MB-231 cancer cells than on MCF10A normal cells. Gomisin J suppressed the proliferation and decreased the viability of MCF7 and MDA-MB-231 cells at relatively low (<10 µg/ml) and high (>30 µg/ml) concentrations, respectively. Our data also revealed that gomisin J induced necroptosis, a programmed form of necrosis, as well as apoptosis. Notably, gomisin J predominantly induced necroptosis in MCF7 cells that are known to have high resistance to many pro-apoptotic anticancer drugs, while MDA-MB-231 exhibited a much lower level of necroptosis but instead a higher level of apoptosis. This data indicated the possibility that it may be used as a more effective anticancer drug, especially in apoptosis-resistant malignant cancer cells. In an extended study, gomisin J exhibited a strong cytotoxic effect on all tested various types of 13 cancer cell lines, indicating its potential to be used against a wide range of different types of cancer cells.

Inhibitory role of AMP­activated protein kinase in necroptosis of HCT116 colon cancer cells with p53 null mutation under nutrient starvation.

Simultaneous induction of other types of programmed cell death, alongside apoptosis, in cancer cells may be considered an attractive strategy for the development of more effective anticancer therapies. The present study aimed to investigate the role of AMP­activated protein kinase (AMPK) in nutrient/serum starvation­induced necroptosis, which is a programmed form of necrosis, in the presence or absence of p53. The present study detected higher cell proliferation and lower cell death rates in the HCT116 human colon cancer cell line containing a p53 null mutation (HCT116 p53­/­) compared with in HCT116 cells harboring wild­type p53 (HCT116 p53+/+), as determined using a cell viability assay. Notably, western blot analysis revealed a relatively lower level of necroptosis in HCT116 p53­/­ cells compared with in HCT116 p53+/+ cells. Investigating the mechanism, it was revealed that necroptosis may be induced in HCT116 p53+/+ cells by significantly increasing reactive oxygen species (ROS) and decreasing mitochondrial membrane potential (MMP), whereas little alterations were detected in HCT116 p53­/­ cells. Unexpectedly, a much lower level of ATP was detected in HCT116 p53­/­ cells compared with in HCT116 p53+/+ cells. Accordingly, AMPK phosphorylation on the Thr172 residue was markedly increased in HCT116 p53­/­ cells. Furthermore, western blot analysis and ROS measurements indicated that AMPK inhibition, using dorsomorphin dihydrochloride, accelerated necroptosis by increasing ROS generation in HCT116 p53­/­ cells. However, AMPK activation by AICAR did not suppress necroptosis in HCT116 p53+/+ cells. In conclusion, these data strongly suggested that AMPK activation may be enhanced in HCT116 p53­/­ cells under serum­depleted conditions via a drop in cellular ATP levels. In addition, activated AMPK may be at least partially responsible for the inhibition of necroptosis in HCT116 p53­/­ cells, but not in HCT116 p53+/+cells.

Anti-cancerous effect of cis-khellactone from Angelica amurensis through the induction of three programmed cell deaths.

Angelica amurensis has traditionally been used to treat various medical problems. In this report, we introduce cis-khellactone as a new anti-cancer agent, which was isolated from the chloroform soluble fraction of the rhizomes of Angelica amurensis. Its anti-cancerous effect was at first tested in MCF7 and MDA-MB-231 breast cell lines, in which MCF7 is well known to be resistant to many anti-cancer drugs; MCF10A normal breast cell line was used as a control. In vitro experiments showed that cis-khellactone suppressed cell growth and proliferation at a relatively low concentrations (<5 µg/ml) and decreased cell viability at high concentrations (>10 µg/ml) in both cancer cell lines in a time- and concentration-dependent manner. This anti-cancerous effect was also checked in additional 16 different types of normal and cancer cell lines. Cis-khellactone treatment significantly suppressed cell proliferation and enhanced cell death in all tested cancer cell lines. Furthermore, Western blot analysis showed that cis-khellactone induced three types of programmed cell death (PCD): apoptosis, autophagy-mediated cell death, and necrosis/necroptosis. Cis-khellactone concentration-dependently decreased cell viability by increasing the level of reactive oxygen species (ROS) and decreasing mitochondrial membrane potential (MMP), which are related to all three types of PCD. Mitochondrial fractionation data revealed that cis-khellactone induced the translocation of BAX and BAK into mitochondria as well as the overexpression of VDAC1, which probably accelerates MMP disruption and finally cell death. Importantly, our extended in vivo studies with xenograft model further confirmed these findings of anti-cancerous effects and showed no harmful effects in normal tissues, suggesting that there would be no side effects in humans.

Total Antioxidant Capacity from Dietary Supplement Decreases the Likelihood of Having Metabolic Syndrome in Korean Adults.

This study was conducted to estimate antioxidant vitamin intake and total antioxidant capacity (TAC) from diet and dietary supplements and to examine their association with metabolic syndrome (MetS) in Korean adults. Out of 6308 adults 19~64 years old from the 2010~2011 Korea National Health and Nutrition Examination Survey, 1847 adults were classified as dietary supplement users and the other 4461 adults were classified as non-users. Antioxidant intake and TAC from diet and dietary supplements were estimated using dietary intake data and linked with the antioxidant and TAC database for common Korean foods. The prevalence of MetS was lower in dietary supplement users (odds ratio (OR) = 0.82; 95% confidence interval (CI), 0.68-0.98) than that in non-users. Among dietary supplement users, a lower prevalence of MetS was observed in the highest tertile for vitamin A (OR = 0.72; 95% CI, 0.53-0.99) and vitamin E (OR = 0.74; 95% CI, 0.55- 0.99) intake than that in the lowest tertile among non-users. Subjects in the highest tertile of TAC among dietary supplement users showed a lower prevalence of MetS (OR = 0.72; 95% CI, 0.52-0.99) than non-users. The results imply that intake of vitamin A, vitamin E, and TAC from dietary supplements might have a protective effect on MetS among Korean adults.