Pterostilbene induces apoptosis and cell cycle arrest in human gastric carcinoma cells

Pterostilbene, an active constituent of blueberries, is known to possess anti-inflammatory activity and also induces apoptosis in various types of cancer cells. Here, the effects of pterostilbene on cell viability in human gastric carcinoma AGS cells were investigated. This study demonstrated that pterostilbene was able to inhibit cell proliferation and induce apoptosis in a concentration- and time-dependent manner. Pterostilbene-induced cell death was characterized with changes in nuclear morphology, DNA fragmentation, and cell morphology. The molecular mechanism of pterostilbene-induced apoptosis was also investigated. The results show the caspase-2, -3, -8, and -9 are all activated by pterostilbene, together with cleavage of the downstream caspase-3 target DNA fragmentation factor (DFF-45) and poly(ADP-riobse) polymerase. Moreover, the results indicate that the Bcl-family of proteins, the mitochondrial pathway, and activation of the caspase cascade are responsible for pterostilbene-induced apoptosis. Pterostilbene markedly enhanced the expression of growth arrest DNA damage-inducible gene 45 and 153 (GADD45 and GADD153) in a time-dependent manner. Flow cytometric analysis indicated that pterostilbene blocked cell cycle progression at G1 phase in a dose- and time-dependent manner. Pterostilbene increased the p53, p21, p27, and p16 proteins and decreased levels of cyclin A, cyclin E, cyclin-dependent kinase 2 (Cdk2), Cdk4, and Cdk6, but the expression of cyclin D1 was not affected. Over a 24 h exposure to pterostilbene, the degree of phosphorylation of Rb was decreased after 6 h. In summary, pterostilbene induced apoptosis in AGS cells through activating the caspase cascade via the mitochondrial and Fas/FasL pathway, GADD expression, and by modifying cell cycle progress and changes in several cycle-regulating proteins. The induction of apoptosis by pterostilbene may provide a pivotal mechanism of the antitumor effects and for treatment of human gastric cancer.     

Hispolon induces apoptosis and cell cycle arrest of human hepatocellular carcinoma Hep3B cells by modulating ERK phosphorylation

Hispolon is an active phenolic compound of Phellinus igniarius , a mushroom that has recently been shown to have antioxidant, anti-inflammatory, and anticancer activities. This study investigated the antiproliferative effect of hispolon on human hepatocellular carcinoma Hep3B cells by using the MTT assay, DNA fragmentation, DAPI (4,6-diamidino-2-phenylindole dihydrochloride) staining, and flow cytometric analyses. Hispolon inhibited cellular growth of Hep3B cells in a time-dependent and dose-dependent manner, through the induction of cell cycle arrest at S phase measured using flow cytometric analysis and apoptotic cell death, as demonstrated by DNA laddering. Hispolon-induced S-phase arrest was associated with a marked decrease in the protein expression of cyclins A and E and cyclin-dependent kinase (CDK) 2, with concomitant induction of p21waf1/Cip1 and p27Kip1. Exposure of Hep3B cells to hispolon resulted in apoptosis as evidenced by caspase activation, PARP cleavage, and DNA fragmentation. Hispolon treatment also activated JNK, p38 MAPK, and ERK expression. Inhibitors of ERK (PB98095), but not those of JNK (SP600125) and p38 MAPK (SB203580), suppressed hispolon-induced S-phase arrest and apoptosis in Hep3B cells. These findings establish a mechanistic link between the MAPK pathway and hispolon-induced cell cycle arrest and apoptosis in Hep3B cells.     

Resveratrol oligomers isolated from Carex species inhibit growth of human colon tumorigenic cells mediated by cell cycle arrest

Research has shown that members of the Carex genus produce biologically active stilbenoids including resveratrol oligomers. This is of great interest to the nutraceutical industry given that resveratrol, a constituent of grape and red wine, has attracted immense research attention due to its potential human health benefits. In the current study, five resveratrol oligomers (isolated from Carex folliculata and Carex gynandra ), along with resveratrol, were evaluated for antiproliferative effects against human colon cancer (HCT-116, HT-29, Caco-2) and normal human colon (CCD-18Co) cells. The resveratrol oligomers included one dimer, two trimers, and two tetramers: pallidol (1); α-viniferin (2) and trans-miyabenol C (3); and kobophenols A (4) and B (5), respectively. Although not cytotoxic, the resveratrol oligomers (1-5), as well as resveratrol, inhibited growth of the human colon cancer cells. Among the six stilbenoids, α-viniferin (2) was most active against the colon cancer cells with IC(50) values of 6-32 μM (>2-fold compared to normal colon cells). Moreover, α-viniferin (at 20 μM) did not induce apoptosis but arrested cell cycle (in the S-phase) for the colon cancer but not the normal colon cells. This study adds to the growing body of knowledge supporting the anticancer effects of resveratrol and its oligomers. Furthermore, Carex species should be investigated for their nutraceutical potential given that they produce biologically active stilbenoids such as α-viniferin.     

Growth inhibition and induction of apoptosis in NB4 promyelocytic leukemia cells by trypsin inhibitor from sweet potato storage roots

The objective of this study was to investigate the antiproliferative effect and the mechanism of trypsin inhibitor (TI) from sweet potato [Ipomoea batatas (L.) Lam. 'Tainong 57'] storage roots on NB4 promyelocytic leukemia cells. The results showed that TI inhibited cellular growth of NB4 promyelocytic leukemia cells in a time-dependent and dose-dependent manner, and treatment for 72 h induced a marked inhibition of cellular growth, showing an IC50 of 57.1 +/- 8.26 microg/mL. TI caused cell cycle arrest at the G1 phase as determined by flow cytometric analysis and apoptosis as shown by DNA laddering. TI-induced cell apoptosis involved p53, Bcl-2, Bax, and cytochrome c protein in NB4 cells. P53 and Bax proteins were accumulated, and antiapoptotic molecule Bcl-2 was decreased in the tested cells in a time-dependent manner during TI treatment. TI also induced a substantial release of cytochrome c from the mitochondria into the cytosol. Hence, TI induced apoptosis in NB4 cells through a mitochondria-dependent pathway, which was associated with the activation of caspase-3 and -8. These results demonstrated that TI induces NB4 cell apoptosis through the inhibition of cell growth and the activation of the pathway of caspase-3 and -8 cascades.     

Lucidenic acid B induces apoptosis in human leukemia cells via a mitochondria-mediated pathway

Ganoderma lucidum is known as a medicinal mushroom used in traditional Chinese medicine. In the present study, the effect of lucidenic acids (A, B, C, and N) isolated from a new G. lucidum (YK-02) on induction of cell apoptosis and the apoptotic pathway in HL-60 cells were investigated. The results demonstrated that lucidenic acids decreased cell population growth of HL-60 cells, assessed with the MTT assay. The cell cycle assay indicated that treatment of HL-60 cells with lucidenic acid A, C, and N caused cell cycle arrest in the G 1 phase. Lucidenic acid B (LAB) did not affect the cell cycle profile; however, it increased the number of early and late apoptotic cells but not necrotic cells. Treatment of HL-60 cells with LAB caused loss of mitochondria membrane potential. Moreover, the ratio of expression levels of pro- and antiapoptotic Bcl-2 family members was changed by LAB treatment. LAB-induced apoptosis involved release of mitochondria cytochrome c and subsequently induced the activation of caspase-9 and caspase-3, which were followed by cleavage of poly(ADP-ribose) polymerase (PARP). Pretreatment with a general caspase-9 inhibitor (Z-LEHD-FMK) and caspase-3 inhibitor (Z-DEVD-FMK) prevented LAB from inhibiting cell viability in HL-60 cells. Our finding may be critical to the chemopreventive potential of lucidenic acid B.     

Cyanidin and Malvidin from Oryza sativa cv. Heugjinjubyeo mediate cytotoxicity against human monocytic leukemia cells by arrest of G(2)/M phase and induction of apoptosis

Oryza sativa cv. Heugjinjubyeo (Gramineae), anthocyanin-pigmented rice, having dark purple grains, is known broadly as enriched rice with an improved taste. Two bioactive compounds were isolated from the 0.5% HCl-ethyl alcohol soluble fraction of the aleurone layer of O. sativa cv. Heugjinjubyeo through an activity-monitored fractionation and isolation method. From spectral analysis, the cytotoxic components were the anthocyanidins cyanidin (1) and malvidin (2) The 50% growth inhibitory concentrations (IC(50)) of cyanidin and malvidin on U937, human monocytic leukemia cells, were 60 and 40 microg/mL, respectively. These compounds showed cytotoxicity through the arrest of the G(2)/M phase of cell cycle and induction of apoptosis.     

Grape polyphenol resveratrol and the related molecule 4-hydroxystilbene induce growth inhibition, apoptosis, S-phase arrest, and upregulation of cyclins A, E, and B1 in human SK-Mel-28 melanoma cells

The effect of the naturally occurring polyphenol resveratrol (3,5,4'-trihydroxy-trans-stilbene; RES) on growth, cell cycle, and cyclins A, E, and B1 expression was investigated in the human SK-Mel-28 melanoma cell line. In addition, the structurally related compounds 4-hydroxy-trans-stilbene (4HST), piceatannol (3,5,3',4'-tetrahydroxy-trans-stilbene (PICE), and 4-trans-stilbenemethanol (4STMe) were also assayed in order to investigate the requirements of stilbenes to exert activity against melanoma cells. Both RES and 4HST inhibited cell growth in a dose- and time-dependent manner and upregulated the expression of cyclins A, E, and B1 with subsequent irreversible arrest of melanoma cells in the S-phase, concomitant with a decrease in G0/G1 and G2/M phases. In addition, potent apoptosis-mediated cell death was detected with the annexin V assay whereas no apoptosis was observed by flow cytometry, which encourages the assay of different methodologies to evaluate the effect of polyphenols on cell lines. The effect of PICE was not evaluated because of its instability in the reaction medium. No effect on cell cycle and cyclins expression was observed when 4STMe was assayed, which supported the critical requirement of the 4'-hydroxystyryl moiety to exert the above effects. In addition, this structural requirement also influenced the cellular uptake of stilbenes. The presence of two extra hydroxyl groups in RES increased its cytotoxicity whereas it diminished its efficiency to inhibit cell growth, upregulate cyclins expression, and arrest cell cycle in the S-phase with respect to 4HST. The present study suggests that the antimelanoma properties of dietary stilbenes, such as grape RES, cannot be ruled out, taking into account previous studies concerning the relationship between plasma and tissue concentrations and pharmacological activity of RES in animal models.     

Pyrrolidine dithiocarbamate inhibition of luteolin-induced apoptosis through up-regulated phosphorylation of Akt and caspase-9 in human leukemia HL-60 cells

Previously, we observed that luteolin effectively inhibited cell growth and induced apoptosis in HL-60 cells. In that study, we also explored the modulatory effects and molecular mechanisms of pyrrolidine dithiocarbamate (PDTC) on the cytotoxicity of luteolin to HL-60 cells. In this study, we found that PDTC was able to inhibit luteolin-induced cell apoptosis in a dose-dependent manner. When HL-60 cells were treated with PDTC for 0.5 h before 60 microM luteolin treatment, the DNA ladder disappeared. Moreover, flow cytometry showed that PDTC had dose dependently decreased the percentage of apoptotic HL-60 cells and had not interfered with luteolin's ability to change the mitochondrial membrane potential or its ability to trigger the release of cytochrome c to cytosol. Detection by Western blotting, however, did show that PDTC had interfered with luteolin's ability to cleave poly(ADP-ribose)polymerase and DNA fragmentation of factor-45. Three hours after the PDTC-pretreated HL-60 cells were treated with 60 microM luteolin, the product cleaved from Akt started to appear. Therefore, not only was PDTC able to stop the apoptosis of HL-60 cells treated with luteolin, it was also found to increase phosphorylation of Akt and caspase-9. These results suggest that in the luteolin-induced apoptotic pathway, phosphorylation of procaspase-9 by survival signals might play an important role in the ultimate fate of HL-60 cells.     

5-Hydroxy-3,6,7,8,3',4'-hexamethoxyflavone induces apoptosis through reactive oxygen species production, growth arrest and DNA damage-inducible gene 153 expression, and caspase activation in human leukemia cells

This study examined the growth inhibitory effects of structurally related polymethoxylated flavones in human cancer cells. Here, we report that 5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone (5-OH-HxMF) induces growth inhibition of human cancer cells and induction of apoptosis in HL-60 cells through modulation of mitochondrial functions regulated by reactive oxygen species (ROS). ROS generation occurs in the early stages of 5-OH-HxMF-induced apoptosis, preceding cytochrome c release, caspase activation, and DNA fragmentation. The changes occurred after single breaks in DNA were detected, suggesting that 5-OH-HxMF induced irreparable DNA damage, which in turn triggered the process of apoptosis. Up-regulation of Bax was found in 5-OH-HxMF-treated HL-60 cells. In addition, a caspase-independent pathway indicated by endonuclease G also contributed to apoptosis caused by 5-OH-HxMF. Antioxidants suppress 5-OH-HxMF-induced apoptosis. 5-OH-HxMF markedly enhanced growth arrest DNA damage-inducible gene 153 (GADD153) protein in a time-dependent manner. N-acetylcysteine (NAC) and catalase prevented up-regulation of GADD153 expression caused by 5-OH-HxMF. These findings suggest that 5-OH-HxMF creates an oxidative cellular environment that induces DNA damage and GADD153 gene activation, which in turn helps trigger apoptosis in HL-60 cells. Meanwhile, ROS were proven an important inducer in this apoptotic process. The C-5 hydroxyl on the ring of 5-OH-HxMF was found to be essential for the antiproliferative and apoptosis-inducing activity. Our study identified the novel mechanisms of 5-OH-HxMF-induced apoptosis and indicated that these results have significant applications as potential chemopreventive and chemotherapeutic agents.     

Naringenin and hesperetin induce growth arrest, apoptosis, and cytoplasmic fat deposit in human preadipocytes

Citrus flavonoids are reported to be promising bioactive compounds against hyperlipidemia and lipid biosynthesis. However, the mechanism of the lipid lowering effect by flavonoids remains unknown. The present study examines the effect of some flavanones on the adipocytic conversion of the human preadipocyte cell line, AML-I. Among four structure-related flavanones including naringenin, naringenin-7-rhamnoglucoside (naringin), hesperetin, and hesperetin-7-rhamnoglucoside (hesperidin), the aglycones such as naringenin and hesperetin exhibited the growth arrest of AML-I cells. When the cells were examined by Annexin V-FITC staining method, it was noticed that growth arrest was induced by apoptotic cell death. In the study of apoptosis-related protein in the naringenin-treated cells, anti-apoptotic proteins such as p-Akt, NF-kappaB, and Bcl-2 were decreased, and pro-apoptotic protein Bad was accumulated by Western blot analysis. Interestingly, exposure of AML-I cells to naringenin or hesperetin during short-term cultures increased cytoplasmic lipid droplets by Sudan Black B staining. Furthermore, expression of fatty acid synthase (FAS) and peroxisome proliferator activated receptor (PPAR)-gamma was enhanced in naringenin-treated cells. These data suggest that apoptosis by flavanones does not inhibit the adipocytic conversion of AML-I preadipocytes. The result also indicates that adipocyte may not be a direct target for the lipid-lowering activity of the flavanones.     

Selenocystine induces S-phase arrest and apoptosis in human breast adenocarcinoma MCF-7 cells by modulating ERK and Akt phosphorylation

Selenocystine (SeC) is a nutritionally available selenoamino acid with selective anticancer effects on a number of human cancer cell lines. The present study shows that SeC inhibited the proliferation of human breast adenocarcinoma MCF-7 cells in a time- and dose-dependent manner, through the induction of cell cycle arrest and apoptotic cell death. SeC-induced S-phase arrest was associated with a marked decrease in the protein expression of cyclins A, D1, and D3 and cyclin-dependent kinases (CDKs) 4 and 6, with concomitant induction of p21waf1/Cip1, p27Kip1, and p53. Exposure of MCF-7 cells to SeC resulted in apoptosis as evidenced by caspase activation, PARP cleavage, and DNA fragmentation. SeC treatment also triggered the activation of JNK, p38 MAPK, ERK, and Akt. Inhibitors of ERK (U0126) and Akt (LY294002), but not JNK (SP600125) and p38 MAPK (SB203580), suppressed SeC-induced S-phase arrest and apoptosis in MCF-7 cells. The findings establish a mechanistic link between the PI3K/Akt pathway, MAPK pathway, and SeC-induced cell cycle arrest and apoptosis in MCF-7 cells.     

Grape seed polyphenols protect cardiac cells from apoptosis via induction of endogenous antioxidant enzymes

Grape seed extract (GSE) has been reported to exert protective effects on various forms of cardiac disorders. The cardiovascular protective effects of GSE are believed to be ascribed to its antioxidative properties. A series of studies have demonstrated that polyphenols are instrumental for the antioxidative properties of GSE. This study was undertaken to investigate whether two major polyphenols isolated from GSE (catechin and proanthocyanidin B4) could increase the endogenous antioxidant enzymes in cardiomyocytes, and whether such increased cellular defenses could provide protection against oxidative cardiac cell injury. Incubation of cardiac H9C2 cells with micromolar concentrations of catechin or proanthocyanidin B4 resulted in a significant induction of cellular antioxidant enzymes in a concentration-dependent fashion. Furthermore, catechine or proanthocyanidin B4 pretreatment led to a marked reduction in xanthine oxidase (XO)/xanthine-induced intracellular reactive oxygen species (ROS) accumulation and cardiac cell apoptosis. These results indicated that grape seed polyphenols (GSP) could protect against cardiac cell apoptosis via the induction of endogenous antioxidant enzymes. This may be an important mechanism underlying the protective effects of GSE observed with various forms of cardiovascular disorders.     

Induction of apoptosis by the Lactuca indica L. in human leukemia cell line and its active components

Lactuca indica L. (Compositae family) is used as a folk medicine in anti-inflammatory, antibacterial, antidiabetic, and other medications in Asia. The objectives of this study were to evaluate the antiproliferative effect of ethanol extracts of Lactuca indica L. (EEL) on human leukemic HL-60 cell lines and its active components. The results showed that EEL exhibited strong cytotoxic effects against HL-60 cells; the IC50 value was 313 microg/mL. Flow cytometric analysis of the externalization of phosphatidylserine (PS) using the annexin V/PI method on EEL-treated HL-60 cells showed a concentration-dependent increase of apoptosis. Moreover, EEL could induce typical DNA fragmentation in a concentration- and time-dependent manner as determined by electrophoresis and TUNEL assays. The treatment of HL-60 cells with EEL induced significant accumulation of cells in the G0/G1 phase, indicating that EEL is a cell-cycle-dependent anticancer agent. Our results also indicate that EEL-induced apoptosis in HL-60 cells is associated with the loss of mitochondrial membrane potential (delta psi m). EEL contains 5% phenolic compounds, such as quercetin, caffeic acid, rutin, and chlorogenic acid. Among the four active phenolic compounds, quercetin was found to be the most effective in inhibition against cell viability and in alteration of mitochondrial function. Our results suggest that the induction of apoptosis by EEL might offer a pivotal mechanism for its chemopreventive action.     

Monascuspiloin induces apoptosis and autophagic cell death in human prostate cancer cells via the Akt and AMPK signaling pathways

Monascus pigments have been reported to possess anticancer effects in various cancer cells; however, the molecular mechanisms of their anticancer properties remain largely unknown. Monascuspiloin is an analogue of the Monascus pigment monascin, and its anticancer growth activity against human prostate cancer cells was evaluated using in vitro and in vivo models. Monascuspiloin effectively inhibits the growth of both androgen-dependent LNCaP and androgen-independent PC-3 human prostate cancer cells. Monascuspiloin preferentially induces apoptosis in LNCaP cells by attenuating the PI3K/Akt/mTOR pathway. In androgen-independent PC-3 cells, monascuspiloin induces G2/M arrest and autophagic cell death by an AMPK-dependent pathway. Induction of autophagy in PC-3 cells further sensitizes cells to apoptosis induced by monascuspiloin. Monascuspiloin inhibits tumor growth in nude mice bearing PC-3 xenografts through induction of apoptosis and autophagy. This study is the first to demonstrate that monascuspiloin has therapeutic potential for the treatment of both androgen-dependent and -independent human prostate cancers.     

Effect of black soybean extract on the suppression of the proliferation of human AGS gastric cancer cells via the induction of apoptosis

Black soybean is known to have a health-promoting effect because of its high content of polyphenolic compounds and antioxidant activities. The objective of the present study was to investigate the chemopreventive effects of black soybean extract against human AGS gastric cancer cells and its possible mechanism in inducing apoptosis. Black soybean extract was obtained by extracting black soybean with acidified aqueous acetone, and its phytochemical constituents, as determined by HPLC-DAD methods, were demonstrated to contain various phenolics. The black soybean extract inhibited AGS cell growth in a dose-dependent manner with an IC(50) of 3.69 mg/mL as measured by the MTT assay. This growth inhibition effect was further confirmed by the CFDA-SE assay. Flow cytometry analysis showed that black soybean extract dose-dependently induced apoptosis of AGS cells. Moreover, the involvement of black soybean extract in inducing apoptosis was confirmed by the expression of Bax, Bcl-2, caspase-3, and PARP. The results of the present study indicated that black soybean extract could be used as an apoptosis inducer in AGS cells and a natural chemopreventive agent in the treatment of human gastric cancer.     

Effects of capsaicin on induction of apoptosis and inhibition of adipogenesis in 3T3-L1 cells

Currently, at the beginning of the 21st century, obesity has become the leading metabolic disease in the world. It is a serious health problem in industrialized countries. Previous research has suggested that decreased preadipocyte differentiation and proliferation and decreased lipogenesis are mechanisms to reduce obesity. In the present study, the effects of capsaicin on the induction of apoptosis and inhibition of lipid accumulation in 3T3-L1 preadipocytes and adipocytes were investigated. The results demonstrated that capsaicin decreased cell population growth of 3T3-L1 preadipocytes, assessed with the MTT assay. Flow cytometric analysis of 3T3-L1 preadipocytes exposed to capsaicin showed that apoptotic cells increased in a time- and dose-dependent manner. Treatment with capsaicin decreased the number of normal cells and increased the number of early apoptotic and late apoptotic cells in a dose-dependent manner. The treatment of cells with capsaicin caused the loss of mitochondria membrane potential (delta psi m). The induction of apoptosis in 3T3-L1 preadipocytes by capsaicin was mediated through the activation of caspase-3, Bax, and Bak, and then through the cleavage of PARP and the down-regulation of Bcl-2. Moreover, capsaicin significantly decreased the amount of intracellular triglycerides and glycerol-3-phosphate dehydrogenase (GPDH) activity in 3T3-L1 adipocytes. Capsaicin also inhibited the expression of PPARgamma, C/EBPalpha, and leptin, but induced up-regulation of adiponectin at the protein level. These results demonstrate that capsaicin efficiently induces apoptosis and inhibits adipogenesis in 3T3-L1 preadipocytes and adipocytes.     

Induction of apoptosis by garcinol and curcumin through cytochrome c release and activation of caspases in human leukemia HL-60 cells

Garcinol, a polyisoprenylated benzophenone, was purified from Garcinia indica fruit rind. The effects of garcinol and curcumin on cell viability in human leukemia HL-60 cells were investigated. Garcinol and curcumin displayed strong growth inhibitory effects against human leukemia HL-60 cells, with estimated IC(50) values of 9.42 and 19.5 microM, respectively. Garcinol was able to induce apoptosis in a concentration- and time-dependent manner; however, curcumin was less effective. Treatment with garcinol caused induction of caspase-3/CPP32 activity in a dose- and time-dependent manner, but not caspase-1 activity, and induced the degradation of poly(ADP-ribose) polymerase (PARP). Pretreatment with caspase-3 inhibitor inhibited garcinol-induced DNA fragmentation. Treatment with garcinol (20 microM) caused a rapid loss of mitochondrial transmembrane potential, release of mitochondrial cytochrome c into cytosol, and subsequent induction of procaspase-9 processing. The cleavage of D4-GDI, an abundant hematopoietic cell GDP dissociation inhibitor for the Ras-related Rho family GTPases, occurred simultaneously with the activation of caspase-3 but preceded DNA fragmentation and the morphological changes associated with apoptotic cell death. Of these, Bcl-2, Bad, and Bax were studied. The level of expression of Bcl-2 slightly decreased, while the levels of Bad and Bax were dramatically increased in cells treated with garcinol. These results indicate that garcinol allows caspase-activated deoxyribonuclease to enter the nucleus and degrade chromosomal DNA and induces DFF-45 (DNA fragmentation factor) degradation. It is suggested that garcinol-induced apoptosis is triggered by the release of cytochrome c into the cytosol, procaspase-9 processing, activation of caspase-3 and caspase-2, degradation of PARP, and DNA fragmentation caused by the caspase-activated deoxyribonuclease through the digestion of DFF-45. The induction of apoptosis by garcinol may provide a pivotal mechanism for its cancer chemopreventive action.     

Protective effects of Chinese propolis and its component, chrysin, against neuronal cell death via inhibition of mitochondrial apoptosis pathway in SH-SY5Y cells

Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of neurodegenerative and ischemic disorders. The purpose of this study was to evaluate the effects of Chinese propolis and its constituents [chrysin, galangin, pinocembrin, caffeic acid, and caffeic acid phenethyl ester (CAPE)] against tunicamycin-induced neuronal cell death in SH-SY5Y cells. Both Chinese propolis and chrysin concentration-dependently inhibited such cell death, the tunicamycin-induced activation of caspase-3, and the effects of tunicamycin on mitochondria [release of cytochrome c into the cytosol and disruption of the mitochondrial membrane potential (DeltaPsim)]. Furthermore, Chinese propolis and chrysin each inhibited staurosporine-induced cell death. These findings indicate that the inhibitory effects of Chinese propolis against neuronal cell death induced by ER stress or staurosporine may be exerted primarily by chrysin. Moreover, the mechanism underlying the protective effects may, at least partly, involve inhibitions of caspase-3 activity and the mitochondrial apoptotic pathway.     

Curcuminoids-cellular uptake by human primary colon cancer cells as quantitated by a sensitive HPLC assay and its relation with the inhibition of proliferation and apoptosis

Curcumin, which is a bright orange-yellow pigment of turmeric with antioxidant properties, has been shown to produce a potent preventative action against several types of cancers in recent studies. It has also been reported to protect the development of colon tumor in animals being fed with carcinogen. In the colon cancer cells, curcumin was illustrated to inhibit cell proliferation and induce apoptosis. As an antioxidant, it acts as an anti-inflammatory as well as an antitumor agent. Curcumin has been detected to exist in nature in the form of curcuminoids, a mixture of curcumin, the major component, with two of its related demethoxy compounds (demethoxycurcumin and bisdemethoxycurcumin). In the present study, we have investigated the antiproliferation and induced apoptosis effects of curcuminoids on colon cancer, using the primary cancer cells isolated from Taiwanese colon cancer patients as the model for colorectal cancer. Results showed that curcuminoids inhibited cell proliferation and induced apoptosis of these human primary colon cancer cells. The effects were observed in a dose-dependent manner as dose increased from 12.5 to 100 microM. With the aim of furthering the fundamental understanding of the mechanisms underlying the antiproliferation and induced apoptosis effects of curcuminoids on these human colon cancer cells, we developed a sensitive, rapid, and reproducible assay method based on high-performance liquid chromatography (HPLC). This HPLC technique developed was found to successfully determine, in a quantitative manner, the cellular uptake of curcuminoids. The uptake of these curcuminoids by the colon cancer cells was shown to increase as the dose of curcuminoids was increased. The observations of inhibited proliferation and increased apoptosis in the colon cancer cells appeared to be associated with the cellular uptake of curcuminoids.     

Subamolide E from Cinnamomum subavenium induces sub-G1 cell-cycle arrest and caspase-dependent apoptosis and reduces the migration ability of human melanoma cells

The aim of this work was to investigate the anticancer cytotoxic effects of natural compound subamolide E on the human skin cancer melanoma A375.S2 cells. Subamolide E was isolated from Cinnamomum subavenium and demonstrated cytotoxicities in the cell-growth assay at concentration ranges from 0 to 100 μM at 24 h. Propidium iodide staining and flow cytometry analyses were used to evaluate cell-cycle distribution and found that subamolide E caused DNA damage in the sub-G1 phase with a dose-dependent manner after 24 h of treatment. According to the western blot result, subamolide-E-treated cells with the increase of caspase-dependent apoptotic proteins induced related pathway mechanisms. Subamolide E also showed antimigratory activities of A375.S2 cells on the wound-healing assay. Finally, subamolide E demonstrated minor cytotoxicities to normal human skin cells (keratinocytes, melanocytes, and fibroblasts); therefore, it is a potential chemotherapeutic agent against skin melanoma.