Displaying publications 21 - 40 of 40 in total

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  1. Differential cytotoxic activity of Quercetin on colonic cancer cells depends on ROS generation through COX-2 expression
    Raja SB, Rajendiran V, Kasinathan NK, P A, Venkatabalasubramanian S, Murali MR, et al.
    Food Chem Toxicol, 2017 Aug;106(Pt A):92-106.
    PMID: 28479391 DOI: 10.1016/j.fct.2017.05.006
    Quercetin is a bioactive compound with anti-inflammatory, antioxidant and anticancer properties. This study exemplifies the differential cytotoxic activity of Quercetin on two human colonic cancer cell lines, HT29 and HCT15. IC50 of Quercetin for HT29 and HCT15 cells were 42.5 μM and 77.4 μM, respectively. Activation of caspase-3, increased level of cytosolic cytochrome c, decreased levels of pAkt, pGSK-3β and cyclin D1 in 40 μM Quercetin treated HT29 cells alone. Though, nuclear translocation of NFkB was increased in 40 μM Quercetin treated HT29 and HCT15 cells, over expression of COX-2 was observed in 40 μM Quercetin treated HT29 cells, whereas, Quercetin treated HCT15 cells did not expressed COX-2. Increased generation of reactive oxygen species (ROS) was observed only in Quercetin treated HT29 cells, which is due to over expression of COX-2, as COX-2 silencing inhibited Quercetin induced apoptosis and ROS generation. Insilico analysis provided evidence that Quercetin could partially inhibit COX-2 enzyme by binding to subunit A which has peroxidase activity and serves as source of ROS. However, Quercetin showed minimal effect on normal intestinal epithelial cells i,e IEC-6. To conclude, differential sensitivity of two cancer cells, HT29 and HCT15, to Quercetin depends on COX-2 dependent ROS generation that induces apoptosis and inhibits cell survival.
    Matched MeSH terms: Colonic Neoplasms/metabolism
  2. In vitro and in vivo anti-colon cancer effects of Garcinia mangostana xanthones extract
    Aisha AF, Abu-Salah KM, Ismail Z, Majid AM
    BMC Complement Altern Med, 2012;12:104.
    PMID: 22818000
    BACKGROUND: Xanthones are a group of oxygen-containing heterocyclic compounds with remarkable pharmacological effects such as anti-cancer, antioxidant, anti-inflammatory, and antimicrobial activities.
    METHODS: A xanthones extract (81% α-mangostin and 16% γ-mangostin), was prepared by crystallization of a toluene extract of G. mangostana fruit rinds and was analyzed by LC-MS. Anti-colon cancer effect was investigated on HCT 116 human colorectal carcinoma cells including cytotoxicity, apoptosis, anti-tumorigenicity, and effect on cell signalling pathways. The in vivo anti-colon cancer activity was also investigated on subcutaneous tumors established in nude mice.
    RESULTS: The extract showed potent cytotoxicity (median inhibitory concentration 6.5 ± 1.0 μg/ml), due to induction of the mitochondrial pathway of apoptosis. Three key steps in tumor metastasis including the cell migration, cell invasion and clonogenicity, were also inhibited. The extract and α-mangostin up-regulate the MAPK/ERK, c-Myc/Max, and p53 cell signalling pathways. The xanthones extract, when fed to nude mice, caused significant growth inhibition of the subcutaneous tumor of HCT 116 colorectal carcinoma cells.
    CONCLUSIONS: Our data suggest new mechanisms of action of α-mangostin and the G. mangostana xanthones, and suggest the xanthones extract of as a potential anti-colon cancer candidate.
    Matched MeSH terms: Colonic Neoplasms/metabolism
  3. Fulltext Brewers' rice induces apoptosis in azoxymethane-induced colon carcinogenesis in rats via suppression of cell proliferation and the Wnt signaling pathway
    Tan BL, Esa NM, Rahman HS, Hamzah H, Karim R
    BMC Complement Altern Med, 2014;14:304.
    PMID: 25129221 DOI: 10.1186/1472-6882-14-304
    Brewers' rice is locally known as temukut, is a byproduct of the rice milling process, and consists of broken rice, rice bran, and rice germ. Unlike rice bran, the health benefit of brewers' rice has yet to be fully studied. Our present study aimed to identify the chemopreventive potential of brewers' rice with colonic tumor formation and to examine further the mechanistic action of brewers' rice during colon carcinogenesis.
    Matched MeSH terms: Colonic Neoplasms/metabolism
  4. Fulltext A Schiff base-derived copper (II) complex is a potent inducer of apoptosis in colon cancer cells by activating the intrinsic pathway
    Hajrezaie M, Paydar M, Moghadamtousi SZ, Hassandarvish P, Gwaram NS, Zahedifard M, et al.
    ScientificWorldJournal, 2014;2014:540463.
    PMID: 24737979 DOI: 10.1155/2014/540463
    Metal-based drugs with extensive clinical applications hold great promise for the development of cancer chemotherapeutic agents. In the last few decades, Schiff bases and their complexes have become well known for their extensive biological potential. In the present study, we examined the antiproliferative effect of a copper (II) complex on HT-29 colon cancer cells. The Cu(BrHAP)2 Schiff base compound demonstrated a potent antiproliferative effect in HT-29 cells, with an IC50 value of 2.87  μg/ml after 72 h of treatment. HT-29 cells treated with Cu (II) complexes underwent apoptosis death, as exhibited by a progressive elevation in the proportion of the G1 cell population. At a concentration of 6.25  μg/ml, the Cu(BrHAP)2 compound caused significant elevation in ROS production following perturbation of mitochondrial membrane potential and cytochrome c release, as assessed by the measurement of fluorescence intensity in stained cells. Furthermore, the activation of caspases 3/7 and 9 was part of the Cu (II) complex-induced apoptosis, which confirmed the involvement of mitochondrial-mediated apoptosis. Meanwhile, there was no significant activation of caspase-8. Taken together, these results imply that the Cu(BrHAP)2 compound is a potential candidate for further in vivo and clinical colon cancer studies to develop novel chemotherapeutic agents derived from metal-based agents.
    Matched MeSH terms: Colonic Neoplasms/metabolism*
  5. Resistance against apoptosis by the cellular prion protein is dependent on its glycosylation status in oral HSC-2 and colon LS 174T cancer cells
    Yap YH, Say YH
    Cancer Lett, 2011 Jul 1;306(1):111-9.
    PMID: 21439722 DOI: 10.1016/j.canlet.2011.02.040
    Most studies have focused on the role of the cellular prion protein (PrP(C)) in neurodegenerative diseases, whereas the function of this ubiquitous protein outside the nervous system remains elusive. Therefore, the anti-apoptotic property of PrP(C) in oral squamous cell carcinoma (HSC-2) and colon adenocarcinoma (LS 174T) was evaluated in this study, by stable shRNA knockdown and overexpression, respectively. PrP(C) confers resistance against oxidative stress-apoptosis as indicated by MTT assay, Annexin V-FITC/PI and DCFH-DA staining, but this property is abolished upon N-glycosylation inhibition by tunicamycin. Our results indicate that the inhibition of glycosylation in cancer cells overexpressing PrP(C) could represent a potential therapeutic target.
    Matched MeSH terms: Colonic Neoplasms/metabolism*
  6. Fulltext Events associated with apoptotic effect of p-Coumaric acid in HCT-15 colon cancer cells
    Jaganathan SK, Supriyanto E, Mandal M
    World J Gastroenterol, 2013 Nov 21;19(43):7726-34.
    PMID: 24282361 DOI: 10.3748/wjg.v19.i43.7726
    AIM: To investigate the events associated with the apoptotic effect of p-Coumaric acid, one of the phenolic components of honey, in human colorectal carcinoma (HCT-15) cells.

    METHODS: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tertazolium-bromide assay was performed to determine the antiproliferative effect of p-Coumaric acid against colon cancer cells. Colony forming assay was conducted to quantify the colony inhibition in HCT 15 and HT 29 colon cancer cells after p-Coumaric acid treatment. Propidium Iodide staining of the HCT 15 cells using flow cytometry was done to study the changes in the cell cycle of treated cells. Identification of apoptosis was done using scanning electron microscope and photomicrograph evaluation of HCT 15 cells after exposing to p-Coumaric acid. Levels of reactive oxygen species (ROS) of HCT 15 cells exposed to p-Coumaric acid was evaluated using 2', 7'-dichlorfluorescein-diacetate. Mitochondrial membrane potential of HCT-15 was assessed using rhodamine-123 with the help of flow cytometry. Lipid layer breaks associated with p-Coumaric acid treatment was quantified using the dye merocyanine 540. Apoptosis was confirmed and quantified using flow cytometric analysis of HCT 15 cells subjected to p-Coumaric acid treatment after staining with YO-PRO-1.

    RESULTS: Antiproliferative test showed p-Coumaric acid has an inhibitory effect on HCT 15 and HT 29 cells with an IC₅₀ (concentration for 50% inhibition) value of 1400 and 1600 μmol/L respectively. Colony forming assay revealed the time-dependent inhibition of HCT 15 and HT 29 cells subjected to p-Coumaric acid treatment. Propidium iodide staining of treated HCT 15 cells showed increasing accumulation of apoptotic cells (37.45 ± 1.98 vs 1.07 ± 1.01) at sub-G1 phase of the cell cycle after p-Coumaric acid treatment. HCT-15 cells observed with photomicrograph and scanning electron microscope showed the signs of apoptosis like blebbing and shrinkage after p-Coumaric acid exposure. Evaluation of the lipid layer showed increasing lipid layer breaks was associated with the growth inhibition of p-Coumaric acid. A fall in mitochondrial membrane potential and increasing ROS generation was observed in the p-Coumaric acid treated cells. Further apoptosis evaluated by YO-PRO-1 staining also showed the time-dependent increase of apoptotic cells after treatment.

    CONCLUSION: These results depicted that p-Coumaric acid inhibited the growth of colon cancer cells by inducing apoptosis through ROS-mitochondrial pathway.

    Matched MeSH terms: Colonic Neoplasms/metabolism
  7. Suppression of β-catenin and cyclooxygenase-2 expression and cell proliferation in azoxymethane-induced colonic cancer in rats by rice bran phytic acid (PA)
    Saad N, Esa NM, Ithnin H
    Asian Pac J Cancer Prev, 2013;14(5):3093-9.
    PMID: 23803085
    BACKGROUND: Phytic acid (PA) is a polyphosphorylated carbohydrate that can be found in high amounts in most cereals, legumes, nut oil, seeds and soy beans. It has been suggested to play a significant role in inhibition of colorectal cancer. This study was conducted to investigate expression changes of β-catenin and cyclooxygenase-2 (COX-2) and cell proliferation in the adenoma-carcinoma sequence after treatment with rice bran PA by immunocytochemistry.

    MATERIALS AND METHODS: Seventy-two male Sprague-Dawley rats were divided into 6 equal groups with 12 rats in each group. For cancer induction two intraperitoneal injections of azoxymethane (AOM) were given at 15 mg/kg bodyweight over a 2-weeks period. During the post initiation phase, two different concentrations of PA, 0.2% (w/v) and 0.5% (w/v) were administered in the diet.

    RESULTS: Results of β-catenin, COX-2 expressions and cell proliferation of Ki-67 showed a significant contribution in colonic cancer progression. For β-catenin and COX-2 expression, there was a significant difference between groups at p<0.05. With Ki-67, there was a statistically significant lowering the proliferating index as compared to AOM alone (p<0.05). A significant positive correlation (p=0.01) was noted between COX-2 expression and proliferation. Total β-catenin also demonstrated a significant positive linear relationship with total COX-2 (p=0.044).

    CONCLUSIONS: This study indicated potential value of PA extracted from rice bran in reducing colonic cancer risk in rats.

    Matched MeSH terms: Colonic Neoplasms/metabolism
  8. Fulltext Cycloart-24-ene-26-ol-3-one, a New Cycloartane Isolated from Leaves of Aglaia exima Triggers Tumour Necrosis Factor-Receptor 1-Mediated Caspase-Dependent Apoptosis in Colon Cancer Cell Line
    Leong KH, Looi CY, Loong XM, Cheah FK, Supratman U, Litaudon M, et al.
    PLoS One, 2016;11(4):e0152652.
    PMID: 27070314 DOI: 10.1371/journal.pone.0152652
    Plants in the Meliaceae family are known to possess interesting biological activities, such as antimalaral, antihypertensive and antitumour activities. Previously, our group reported the plant-derived compound cycloart-24-ene-26-ol-3-one isolated from the hexane extracts of Aglaia exima leaves, which shows cytotoxicity towards various cancer cell lines, in particular, colon cancer cell lines. In this report, we further demonstrate that cycloart-24-ene-26-ol-3-one, from here forth known as cycloartane, reduces the viability of the colon cancer cell lines HT-29 and CaCO-2 in a dose- and time-dependent manner. Further elucidation of the compound's mechanism showed that it binds to tumour necrosis factor-receptor 1 (TNF-R1) leading to the initiation of caspase-8 and, through the activation of Bid, in the activation of caspase-9. This activity causes a reduction in mitochondrial membrane potential (MMP) and the release of cytochrome-C. The activation of caspase-8 and -9 both act to commit the cancer cells to apoptosis through downstream caspase-3/7 activation, PARP cleavage and the lack of NFkB translocation into the nucleus. A molecular docking study showed that the cycloartane binds to the receptor through a hydrophobic interaction with cysteine-96 and hydrogen bonds with lysine-75 and -132. The results show that further development of the cycloartane as an anti-cancer drug is worthwhile.
    Matched MeSH terms: Colonic Neoplasms/metabolism
  9. Inducing G2/M Cell Cycle Arrest and Apoptosis through Generation Reactive Oxygen Species (ROS)-Mediated Mitochondria Pathway in HT-29 Cells by Dentatin (DEN) and Dentatin Incorporated in Hydroxypropyl-β-Cyclodextrin (DEN-HPβCD)
    Ashwaq AS, Al-Qubaisi MS, Rasedee A, Abdul AB, Taufiq-Yap YH, Yeap SK
    Int J Mol Sci, 2016 Oct 18;17(10).
    PMID: 27763535
    Dentatin (DEN), purified from the roots of Clausena excavata Burm f., has poor aqueous solubility that reduces its therapeutic application. The aim of this study was to assess the effects of DEN-HPβCD (hydroxypropyl-β-cyclodextrin) complex as an anticancer agent in HT29 cancer cell line and compare with a crystal DEN in dimethyl sulfoxide (DMSO). The exposure of the cancer cells to DEN or DEN-HPβCD complex leads to cell growth inhibition as determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. To analyze the mechanism, in which DEN or DEN-HPβCD complex causes the death in human colon HT29 cancer cells, was evaluated by the enzyme-linked immunosorbent assay (ELIZA)-based assays for caspase-3, 8, 9, and reactive oxygen species (ROS). The findings showed that an anti-proliferative effect of DEN or DEN-HPβCD complex were via cell cycle arrest at the G2/M phase and eventually induced apoptosis through both mitochondrial and extrinsic pathways. The down-regulation of poly(ADP-ribose) polymerase (PARP) which leaded to apoptosis upon treatment, was investigated by Western-blotting. Hence, complexation between DEN and HPβCD did not diminish or eliminate the effective properties of DEN as anticancer agent. Therefore, it would be possible to resolve the conventional and current issues associated with the development and commercialization of antineoplastic agents in the future.
    Matched MeSH terms: Colonic Neoplasms/metabolism
  10. 6-Shogaol inhibits breast and colon cancer cell proliferation through activation of peroxisomal proliferator activated receptor γ (PPARγ)
    Tan BS, Kang O, Mai CW, Tiong KH, Khoo AS, Pichika MR, et al.
    Cancer Lett, 2013 Aug 9;336(1):127-39.
    PMID: 23612072 DOI: 10.1016/j.canlet.2013.04.014
    6-Shogaol has been shown to possess many antitumor properties including inhibition of cancer cell growth, inhibition of cancer metastasis, induction of apoptosis in cancer cells and induction of cancer cell differentiation. Despite its prominent antitumor effects, the direct molecular target of 6-shogaol has remained elusive. To identify the direct targets of 6-shogaol, a comprehensive antitumor profile of 6-shogaol (NSC752389) was tested in the NCI-60 cell line in an in vitro screen. The results show that 6-shogaol is COMPARE negative suggesting that it functions via a mechanism of action distinct from existing classes of therapeutic agents. Further analysis using microarray gene profiling and Connectivity Map analysis showed that MCF-7 cells treated with 6-shogaol display gene expression signatures characteristic of peroxisome proliferator activated receptor γ (PPARγ) agonists, suggesting that 6-shogaol may activate the PPARγ signaling pathway for its antitumor effects. Indeed, treatment of MCF-7 and HT29 cells with 6-shogaol induced PPARγ transcriptional activity, suppressed NFκB activity, and induced apoptosis in breast and colon cancer cells in a PPARγ-dependent manner. Furthermore, 6-shogaol is capable of binding to PPARγ with a binding affinity comparable to 15-delta prostaglandin J2, a natural ligand for PPARγ. Together, our findings suggest that the antitumor effects of 6-shogaol are mediated through activation of PPARγ and imply that activation of PPARγ might be beneficial for breast and colon cancer treatment.
    Matched MeSH terms: Colonic Neoplasms/metabolism*
  11. Phosphanegold(I) thiolates, Ph3PAu[SC(OR)=NC 6H 4Me-4] for R = Me, Et and iPr, induce apoptosis, cell cycle arrest and inhibit cell invasion of HT-29 colon cancer cells through modulation of the nuclear factor-κB activation pathway and ubiquitination
    Ooi KK, Yeo CI, Ang KP, Akim AM, Cheah YK, Halim SN, et al.
    J Biol Inorg Chem, 2015 Jul;20(5):855-73.
    PMID: 26003312 DOI: 10.1007/s00775-015-1271-5
    The phosphanegold(I) carbonimidothioates, Ph3PAu{SC(OR)=NC6H4Me-4} for R = Me (1), Et (2) and iPr (3), feature linear P-Au-S coordination geometries and exhibit potent in vitro cytotoxicity against HT-29 colon cancer cells in both monolayer and multi-cellular spheroid models (e.g., IC50 = 11.9 ± 0.4 and 20.3 ± 0.3 μM for 2, respectively). Both intrinsic and extrinsic pathways of apoptosis are demonstrated by human apoptosis PCR array analysis, caspase activities, DNA fragmentation and cell apoptotic assays. Compounds 1-3 induce an extrinsic pathway that leads to down-regulation of NFκB. Compound 2 also exhibits an extrinsic apoptotic pathway involving the activation of both p53 and p73, whereas 3 activates p53 only. Lys48- and Lys63-linked polyubiquitination are also promoted by 1-3. Each of cytotoxic Ph3PAu{SC(OR)=NC6H4Me-4}, for R = Me (1), Et (2) and iPr (3), induce an intrinsic apoptotic pathway as well as an extrinsic pathway leading to down-regulation of NFκB. Lys48- and Lys63-linked polyubiquitination are promoted by 1-3 and these are able to inhibit cell invasion and to suppress the activity of TrxR.
    Matched MeSH terms: Colonic Neoplasms/metabolism
  12. γ-Synuclein confers both pro-invasive and doxorubicin-mediated pro-apoptotic properties to the colon adenocarcinoma LS 174T cell line
    Goh KW, Say YH
    Tumour Biol., 2015 Sep;36(10):7947-60.
    PMID: 25956278 DOI: 10.1007/s13277-015-3455-6
    γ-synuclein, a neuronal protein of the synuclein family, is involved in carcinogenesis. To investigate its role in colorectal cancer carcinogenesis, we overexpressed γ-synuclein in LS 174T colon adenocarcinoma cell line (termed LS 174T-γsyn). When compared with untransfected/mock transfectants, LS 174T-γsyn had higher mobility in scratch wound assay, tend to scatter more in cell-scattering assay, and had enhanced lamellipodia and filopodia formation in cell-spreading assay. Enhanced adhesion of LS 174T-γsyn to fibronectin and collagen and significantly higher proliferation rate showed that γ-synuclein was able to increase extracellular matrix interaction and promoted proliferation of LS 174T. Higher invasiveness of LS 174T-γsyn was evidenced by enhanced invasion to the bottom of the basement membrane in Boyden chamber assay. However, LS 174T-γsyn were significantly more vulnerable to doxorubicin, vincristine and hydrogen peroxide insults, via apoptotic cell death. LS 174T-γsyn also had reduced anchorage-independent growth as shown by reduced colony formation and reduced anoikis resistance. We found that overexpression of γ-synuclein confers both pro-invasive and doxorubicin-mediated pro-apoptotic properties to LS 174T, where the former was mediated through enhanced cyclic adenosine monophosphate response element binding protein (CREB) phosphorylation, while the latter involved hepatocyte growth factor (HGF) downregulation and subsequent downstream signalling pathways possibly involving extracellular signal-regulated kinases (ERK)1/2, p38α, c-Jun N-terminal kinase (JNK) pan and Signal Transducers and Activators of Transcription (STATs). This unexpected contrasting finding as compared to other similar studies on colon cancer cell lines might be correlated with the degree of tumour advancement from which the cell lines were derived from.
    Matched MeSH terms: Colonic Neoplasms/metabolism
  13. Fulltext Apoptotic effect of novel Schiff based CdCl₂(C₁₄H₂₁N₃O₂) complex is mediated via activation of the mitochondrial pathway in colon cancer cells
    Hajrezaie M, Paydar M, Looi CY, Moghadamtousi SZ, Hassandarvish P, Salga MS, et al.
    Sci Rep, 2015 Mar 13;5:9097.
    PMID: 25764970 DOI: 10.1038/srep09097
    The development of metal-based agents has had a tremendous role in the present progress in cancer chemotherapy. One well-known example of metal-based agents is Schiff based metal complexes, which hold great promise for cancer therapy. Based on the potential of Schiff based complexes for the induction of apoptosis, this study aimed to examine the cytotoxic and apoptotic activity of a CdCl2(C14H21N3O2) complex on HT-29 cells. The complex exerted a potent suppressive effect on HT-29 cells with an IC50 value of 2.57 ± 0.39 after 72 h of treatment. The collapse of the mitochondrial membrane potential and the elevated release of cytochrome c from the mitochondria to the cytosol indicate the involvement of the intrinsic pathway in the induction of apoptosis. The role of the mitochondria-dependent apoptotic pathway was further proved by the significant activation of the initiator caspase-9 and the executioner caspases-3 and -7. In addition, the activation of caspase-8, which is associated with the suppression of NF-κB translocation to the nucleus, also revealed the involvement of the extrinsic pathway in the induced apoptosis. The results suggest that the CdCl2(C14H21N3O2) complex is able to induce the apoptosis of colon cancer cells and is a potential candidate for future cancer studies.
    Matched MeSH terms: Colonic Neoplasms/metabolism
  14. Fulltext Inhibitory effect of Curcuma purpurascens BI. rhizome on HT-29 colon cancer cells through mitochondrial-dependent apoptosis pathway
    Rouhollahi E, Zorofchian Moghadamtousi S, Paydar M, Fadaeinasab M, Zahedifard M, Hajrezaie M, et al.
    BMC Complement Altern Med, 2015;15:15.
    PMID: 25652758 DOI: 10.1186/s12906-015-0534-6
    BACKGROUND: Curcuma purpurascens BI. (Zingiberaceae) commonly known as 'Koneng Tinggang' and 'Temu Tis' is a Javanese medicinal plant which has been used for numerous ailments and diseases in rural Javanese communities. In the present study, the apoptogenic activity of dichloromethane extract of Curcuma purpurascens BI. rhizome (DECPR) was investigated against HT-29 human colon cancer cells.
    METHODS: Acute toxicity study of DECPR was performed in Sprague-Dawley rats. Compounds of DECPR were analyzed by the gas chromatography-mass spectrometry-time of flight (GC-MS-TOF) analysis. Cytotoxic effect of DECPR on HT-29 cells was analyzed by MTT and lactate dehydrogenase (LDH) assays. Effects of DECPR on reactive oxygen species (ROS) formation and mitochondrial-initiated events were investigated using a high content screening system. The activities of the caspases were also measured using a fluorometric assay. The quantitative PCR analysis was carried out to examine the gene expression of Bax, Bcl-2 and Bcl-xl proteins.
    RESULTS: The in vivo acute toxicity study of DECPR on rats showed the safety of this extract at the highest dose of 5 g/kg. The GC-MS-TOF analysis of DECPR detected turmerone as the major compound in dichloromethane extract. IC50 value of DECPR towards HT-29 cells after 24 h treatment was found to be 7.79 ± 0.54 μg/mL. In addition, DECPR induced LDH release and ROS generation in HT-29 cells through a mechanism involving nuclear fragmentation and cytoskeletal rearrangement. The mitochondrial-initiated events, including collapse in mitochondrial membrane potential and cytochrome c leakage was also triggered by DECPR treatment. Initiator caspase-9 and executioner caspase-3 was dose-dependently activated by DECPR. The quantitative PCR analysis on the mRNA expression of Bcl-2 family of proteins showed a significant up-regulation of Bax associated with down-regulation in Bcl-2 and Bcl-xl mRNA expression.
    CONCLUSIONS: The findings presented in the current study showed that DECP suppressed the proliferation of HT-29 colon cancer cells and triggered the induction of apoptosis through mitochondrial-dependent pathway.
    Matched MeSH terms: Colonic Neoplasms/metabolism
  15. Fulltext 1-(2,6-dihydroxy-4-methoxyphenyl)-2-(4-hydroxyphenyl) ethanone-induced cell cycle arrest in G₁/G₀ in HT-29 cells human colon adenocarcinoma cells
    Lay MM, Karsani SA, Malek SN
    Int J Mol Sci, 2014 Jan 02;15(1):468-83.
    PMID: 24451128 DOI: 10.3390/ijms15010468
    1-(2,6-Dihydroxy-4-methoxyphenyl)-2-(4-hydroxyphenyl) ethanone (DMHE) was isolated from the ethyl acetate fraction of Phaleria macrocarpa (Scheff.) Boerl fruits and the structure confirmed by GC-MS (gas chromatography-mass spectrometry) and NMR (nuclear magnetic resonance) analysis. This compound was tested on the HT-29 human colon adenocarcinoma cell line using MTT (method of transcriptional and translational) cell proliferation assay. The results of MTT assay showed that DMHE exhibited good cytotoxic effect on HT-29 cells in a dose- and time-dependent manner but no cytotoxic effect on the MRC-5 cell line after 72 h incubation. Morphological features of apoptotic cells upon treatment by DMHE, e.g., cell shrinkage and membrane blebbing, were examined by an inverted and phase microscope. Other features, such as chromatin condension and nuclear fragmentation were studied using acridine orange and propidium iodide staining under the fluorescence microscope. Future evidence of apoptosis/necrosis was provided by result fromannexin V-FITC/PI (fluorescein-isothiocyanate/propidium iodide) staining revealed the percentage of early apoptotic, late apoptotic, necrotic and live cells in a dose- and time-dependent manner using flow cytometry. Cell cycle analysis showed G0/G1 arrest in a time-dependent manner. A western blot analysis indicated that cell death might be associated with the up-regulation of the pro-apoptotic proteins Bax PUMA. However, the anit-apotptic proteins Bcl-2, Bcl-xL, and Mcl-1 were also found to increase in a time-dependent manner. The expression of the pro-apoptotic protein Bak was not observed.
    Matched MeSH terms: Colonic Neoplasms/metabolism
  16. pH dependent poly[2-(methacryloyloxyethyl)trimetylammonium chloride-co-methacrylic acid]hydrogels for enhanced targeted delivery of 5-fluorouracil in colon cancer cells
    Mishra RK, Ramasamy K, Ahmad NA, Eshak Z, Majeed AB
    J Mater Sci Mater Med, 2014 Apr;25(4):999-1012.
    PMID: 24398912 DOI: 10.1007/s10856-013-5132-x
    Stimuli responsive hydrogels have shown enormous potential as a carrier for targeted drug delivery. In this study we have developed novel pH responsive hydrogels for the delivery of 5-fluorouracil (5-FU) in order to alleviate its antitumor activity while reducing its toxicity. We used 2-(methacryloyloxyethyl) trimetylammonium chloride a positively charged monomer and methacrylic acid for fabricating the pH responsive hydrogels. The released 5-FU from all except hydrogel (GEL-5) remained biologically active against human colon cancer cell lines [HT29 (IC50 = 110-190 μg ml(-1)) and HCT116 (IC50 = 210-390 μg ml(-1))] but not human skin fibroblast cells [BJ (CRL2522); IC50 ≥ 1000 μg ml(-1)]. This implies that the copolymer hydrogels (1-4) were able to release 5-FU effectively to colon cancer cells but not normal human skin fibroblast cells. This is probably due to the shorter doubling time that results in reduced pH in colon cancer cells when compared to fibroblast cells. These pH sensitive hydrogels showed well defined cell apoptosis in HCT116 cells through series of events such as chromatin condensation, membrane blebbing, and formation of apoptotic bodies. No cell killing was observed in the case of blank hydrogels. The results showed the potential of these stimuli responsive polymer hydrogels as a carrier for colon cancer delivery.
    Matched MeSH terms: Colonic Neoplasms/metabolism
  17. Fulltext Flavokawain C Inhibits Cell Cycle and Promotes Apoptosis, Associated with Endoplasmic Reticulum Stress and Regulation of MAPKs and Akt Signaling Pathways in HCT 116 Human Colon Carcinoma Cells
    Phang CW, Karsani SA, Sethi G, Abd Malek SN
    PLoS One, 2016;11(2):e0148775.
    PMID: 26859847 DOI: 10.1371/journal.pone.0148775
    Flavokawain C (FKC) is a naturally occurring chalcone which can be found in Kava (Piper methysticum Forst) root. The present study evaluated the effect of FKC on the growth of various human cancer cell lines and the underlying associated mechanisms. FKC showed higher cytotoxic activity against HCT 116 cells in a time- and dose-dependent manner in comparison to other cell lines (MCF-7, HT-29, A549 and CaSki), with minimal toxicity on normal human colon cells. The apoptosis-inducing capability of FKC on HCT 116 cells was evidenced by cell shrinkage, chromatin condensation, DNA fragmentation and increased phosphatidylserine externalization. FKC was found to disrupt mitochondrial membrane potential, resulting in the release of Smac/DIABLO, AIF and cytochrome c into the cytoplasm. Our results also revealed that FKC induced intrinsic and extrinsic apoptosis via upregulation of the levels of pro-apoptotic proteins (Bak) and death receptors (DR5), while downregulation of the levels of anti-apoptotic proteins (XIAP, cIAP-1, c-FlipL, Bcl-xL and survivin), resulting in the activation of caspase-3, -8 and -9 and cleavage of poly(ADP-ribose) polymerase (PARP). FKC was also found to cause endoplasmic reticulum (ER) stress, as suggested by the elevation of GADD153 protein after FKC treatment. After the cells were exposed to FKC (60μM) over 18hrs, there was a substantial increase in the phosphorylation of ERK 1/2. The expression of phosphorylated Akt was also reduced. FKC also caused cell cycle arrest in the S phase in HCT 116 cells in a time- and dose-dependent manner and with accumulation of cells in the sub-G1 phase. This was accompanied by the downregulation of cyclin-dependent kinases (CDK2 and CDK4), consistent with the upregulation of CDK inhibitors (p21Cip1 and p27Kip1), and hypophosphorylation of Rb.
    Matched MeSH terms: Colonic Neoplasms/metabolism
  18. Oral 5-fluorouracil colon-specific delivery through in vivo pellet coating for colon cancer and aberrant crypt foci treatment
    Bose A, Elyagoby A, Wong TW
    Int J Pharm, 2014 Jul 1;468(1-2):178-86.
    PMID: 24709212 DOI: 10.1016/j.ijpharm.2014.04.006
    In situ coating of 5-fluorouracil pellets by ethylcellulose and pectin powder mixture (8:3 weight ratio) in capsule at simulated gastrointestinal media provides colon-specific drug release in vitro. This study probes into pharmacodynamic and pharmacokinetic profiles of intra-capsular pellets coated in vivo in rats with reference to their site-specific drug release outcomes. The pellets were prepared by extrusion-spheronization technique. In vitro drug content, drug release, in vivo pharmacokinetics, local colonic drug content, tumor, aberrant crypt foci, systemic hematology and clinical chemistry profiles of coated and uncoated pellets were examined against unprocessed drug. In vivo pellet coating led to reduced drug bioavailability and enhanced drug accumulation at colon (179.13 μg 5-FU/g rat colon content vs 4.66 μg/g of conventional in vitro film-coated pellets at 15 mg/kg dose). The in vivo coated pellets reduced tumor number and size, through reforming tubular epithelium with basement membrane and restricting expression of cancer from adenoma to adenocarcinoma. Unlike uncoated pellets and unprocessed drug, the coated pellets eliminated aberrant crypt foci which represented a putative preneoplastic lesion in colon cancer. They did not inflict additional systemic toxicity. In vivo pellet coating to orally target 5-fluorouracil delivery at cancerous colon is a feasible therapeutic treatment approach.
    Matched MeSH terms: Colonic Neoplasms/metabolism
  19. Annona muricata leaves induce G₁ cell cycle arrest and apoptosis through mitochondria-mediated pathway in human HCT-116 and HT-29 colon cancer cells
    Zorofchian Moghadamtousi S, Karimian H, Rouhollahi E, Paydar M, Fadaeinasab M, Abdul Kadir H
    J Ethnopharmacol, 2014 Oct 28;156:277-89.
    PMID: 25195082 DOI: 10.1016/j.jep.2014.08.011
    ETHNOPHARMACOLOGICAL RELEVANCE: Annona muricata known as "the cancer killer" has been widely used in the traditional medicine for the treatment of cancer and tumors. The purpose of this study is to investigate the anticancer properties of ethyl acetate extract of Annona muricata leaves (EEAM) on HT-29 and HCT-116 colon cancer cells and the underlying mechanisms.
    MATERIALS AND METHODS: The effect of EEAM on the cell proliferation of HT-29 and HCT-116 cells was analyzed by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium) assay. High content screening system (HCS) was applied to investigate the cell membrane permeability, mitochondrial membrane potential (MMP), nuclear condensation and cytochrome c translocation from mitochondria to cytosol. Reactive oxygen species (ROS) formation, lactate dehydrogenase (LDH) release and activation of caspase-3/7, -8 and -9 were measured while treatment. Flow cytometric analysis was used to determine the cell cycle distribution and phosphatidylserine externalization. The protein expression of Bax and Bcl-2 was determined using immunofluorescence analysis. In addition, the potential of EEAM to suppress the migration and invasion of colon cancer cells was also examined.
    RESULTS: EEAM exerted significant cytotoxic effects on HCT-116 and HT-29 cells as determined by MTT and LDH assays. After 24 h treatment, EEAM exhibited the IC₅₀ value of 11.43 ± 1.87 µg/ml and 8.98 ± 1.24 µg/ml against HT-29 and HCT-116 cells, respectively. Flow cytometric analysis demonstrated the cell cycle arrest at G1 phase and phosphatidylserine externalization confirming the induction of apoptosis. EEAM treatment caused excessive accumulation of ROS followed by disruption of MMP, cytochrome c leakage and activation of the initiator and executioner caspases in both colon cancer cells. Immunofluorescence analysis depicted the up-regulation of Bax and down-regulation of Bcl-2 proteins while treated with EEAM. Furthermore, EEAM conspicuously blocked the migration and invasion of HT-29 and HCT-116 cells.
    CONCLUSIONS: These findings provide a scientific basis for the use of A. muricata leaves in the treatment of cancer, although further in vivo studies are still required.
    Matched MeSH terms: Colonic Neoplasms/metabolism
  20. Fulltext Brewers' rice modulates oxidative stress in azoxymethane-mediated colon carcinogenesis in rats
    Tan BL, Norhaizan ME, Huynh K, Yeap SK, Hazilawati H, Roselina K
    World J Gastroenterol, 2015 Aug 7;21(29):8826-35.
    PMID: 26269672 DOI: 10.3748/wjg.v21.i29.8826
    To investigate the mechanistic action of brewers' rice in regulating the Wnt/nuclear factor-kappa B (NF-κB)/Nrf2-signaling pathways during colon carcinogenesis in male Sprague-Dawley rats.
    Matched MeSH terms: Colonic Neoplasms/metabolism
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