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  1. Fulltext Synthesis, characterization and apoptotic activity of quinazolinone Schiff base derivatives toward MCF-7 cells via intrinsic and extrinsic apoptosis pathways
    Zahedifard M, Faraj FL, Paydar M, Yeng Looi C, Hajrezaei M, Hasanpourghadi M, et al.
    Sci Rep, 2015 Jun 25;5:11544.
    PMID: 26108872 DOI: 10.1038/srep11544
    The current study investigated the cytotoxic effect of 3-(5-chloro-2-hydroxybenzylideneamino)-2-(5-chloro-2-hydroxyphenyl)-2,3-dihydroquinazolin-41(H)-one (A) and 3-(5-nitro-2-hydroxybenzylideneamino)-2-(5-nitro-2-hydroxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (B) on MCF-7, MDA-MB-231, MCF-10A and WRL-68 cells. The mechanism involved in apoptosis was assessed to evaluate the possible pathways induced by compound A and B. MTT assay results using A and B showed significant inhibition of MCF-7 cell viability, with IC50 values of 3. 27 ± 0.171 and 4.36 ± 0.219 μg/mL, respectively, after a 72 hour treatment period. Compound A and B did not demonstrate significant cytotoxic effects towards MDA-MB-231, WRL-68 and MCF-10A cells. Acute toxicity tests also revealed an absence of toxic effects on mice. Fluorescent microscopic studies confirmed distinct morphological changes (membrane blebbing and chromosome condensation) corresponding to typical apoptotic features in treated MCF-7 cells. Using Cellomics High Content Screening (HCS), we found that compound A and B could trigger the release of cytochrome c from mitochondria to the cytosol. The release of cytochrome c activated the expression of caspases-9 and then stimulated downstream executioner caspase-3/7. In addition, caspase-8 showed remarkable activity, followed by inhibition of NF-κB activation in A-and B-treated MCF-7 cells. The results indicated that A and B could induce apoptosis via a mechanism that involves either extrinsic or intrinsic pathways.
    Matched MeSH terms: Apoptosis/drug effects
  2. Elephantopus scaber induces apoptosis through ROS-dependent mitochondrial signaling pathway in HCT116 human colorectal carcinoma cells
    Chan CK, Supriady H, Goh BH, Kadir HA
    J Ethnopharmacol, 2015 Jun 20;168:291-304.
    PMID: 25861953 DOI: 10.1016/j.jep.2015.03.072
    Elephantopus scaber also known as Elephant's foot (Asteraceae family) has a plethora of traditional applications including dysuria, diarrhea, dysentery, leukemia and cancer. This study aimed to investigate the apoptosis inducing effects of E. scaber and the underlying mechanisms in HCT116 colorectal cell line.
    Matched MeSH terms: Apoptosis/drug effects
  3. Modulation of the Nitrergic Pathway via Activation of PPAR-γ Contributes to the Neuroprotective Effect of Pioglitazone Against Streptozotocin-Induced Memory Dysfunction
    Prakash A, Kumar A, Ming LC, Mani V, Majeed AB
    J Mol Neurosci, 2015 Jul;56(3):739-50.
    PMID: 25854775 DOI: 10.1007/s12031-015-0508-7
    Alzheimer's disease (AD) is a neurodegenerative disease characterized by impaired memory function and oxidative damage. NO is a major signaling molecule produced in the central nervous system to modulate neurological activity through modulating nitric oxide synthase. Recently, PPAR-γ agonists have shown neuroprotective effects in neurodegenerative disorders. However, there have been only a few studies identifying mechanisms through which cognitive benefits may be exerted. The present study was designed to investigate the possible nitric oxide mechanism in the protective effect of pioglitazone against streptozotocin (STZ)-induced memory dysfunction. Wistar rats were intracerebroventricularly (ICV) injected with STZ. Then rats were treated with pioglitazone, NO modulators [L-arginine and nitro-L-arginine methyl ester (L-NAME)] for 21 days. Behavioral alterations were assessed in between the study period. Animals were sacrificed immediately after behavioral session, and mito-oxidative parameters, TNF-α, IL-6, and caspase-3 activity were measured. STZ-treated rats showed a memory deficit and significantly increased in mito-oxidative damage and inflammatory mediators and apoptosis in the hippocampus. Chronic treatment of pioglitazone significantly improved memory retention and attenuated mito-oxidative damage parameters, inflammatory markers, and apoptosis in STZ-treated rats. However, L-arginine pretreatment with lower dose of pioglitazone has not produced any protective effect as compared to per se. Furthermore, pretreatment of L-NAME significantly potentiated its protective effect, which indicates the involvement of nitric oxide for activation of PPAR-γ action. These results demonstrate that pioglitazone offers protection against STZ-induced memory dysfunction possibly due to its antioxidant, anti-inflammatory, and anti-apoptotic action mediating nitric oxide pathways and, therefore, could have a therapeutic potential in AD.
    Matched MeSH terms: Apoptosis/drug effects
  4. 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: Apoptosis/drug effects*
  5. Fulltext (6E,10E) Isopolycerasoidol and (6E,10E) Isopolycerasoidol Methyl Ester, Prenylated Benzopyran Derivatives from Pseuduvaria monticola Induce Mitochondrial-Mediated Apoptosis in Human Breast Adenocarcinoma Cells
    Taha H, Looi CY, Arya A, Wong WF, Yap LF, Hasanpourghadi M, et al.
    PLoS One, 2015;10(5):e0126126.
    PMID: 25946039 DOI: 10.1371/journal.pone.0126126
    Phytochemicals from Pseuduvaria species have been reported to display a wide range of biological activities. In the present study, a known benzopyran derivative, (6E,10E) isopolycerasoidol (1), and a new benzopyran derivative, (6E,10E) isopolycerasoidol methyl ester (2), were isolated from a methanol extract of Pseuduvaria monticola leaves. The structures of the isolated compounds were elucidated by spectroscopic methods including 1D and 2D NMR, IR, UV, and LCMS-QTOF, and by comparison with previously published data. The anti-proliferative and cytotoxic effects of these compounds on human breast cancer cell-lines (MCF-7 and MDA-MB-231) and a human normal breast epithelial cell line (MCF-10A) were investigated. MTT results revealed both (1) and (2) were efficient in reducing cell viability of breast cancer cells. Flow cytometry analysis demonstrated that (1) and (2) induced cell death via apoptosis, as demonstrated by an increase in phosphotidylserine exposure. Both compounds elevated ROS production, leading to reduced mitochondrial membrane potential and increased plasma membrane permeability in breast cancer cells. These effects occurred concomitantly with a dose-dependent activation of caspase 3/7 and 9, a down-regulation of the anti-apoptotic gene BCL2 and the accumulation of p38 MAPK in the nucleus. Taken together, our data demonstrate that (1) and (2) induce intrinsic mitochondrial-mediated apoptosis in human breast cancer cells, which provides the first pharmacological evidence for their future development as anticancer agents.
    Matched MeSH terms: Apoptosis/drug effects
  6. 2-Methoxy-1,4-naphthoquinone (MNQ) induces apoptosis of A549 lung adenocarcinoma cells via oxidation-triggered JNK and p38 MAPK signaling pathways
    Ong JY, Yong PV, Lim YM, Ho AS
    Life Sci, 2015 Aug 15;135:158-64.
    PMID: 25896662 DOI: 10.1016/j.lfs.2015.03.019
    The compound 2-methoxy-1,4-naphthoquinone (MNQ) was previously shown to be cytotoxic against several cancer cell lines, but its mode of action is poorly understood. In this study, we aimed to explore the molecular mechanism of MNQ-induced cytotoxicity of A549 lung adenocarcinoma cells.
    Matched MeSH terms: Apoptosis/drug effects*
  7. SIRT1 inhibition in pancreatic cancer models: contrasting effects in vitro and in vivo
    Oon CE, Strell C, Yeong KY, Östman A, Prakash J
    Eur J Pharmacol, 2015 Jun 15;757:59-67.
    PMID: 25843411 DOI: 10.1016/j.ejphar.2015.03.064
    Gemcitabine remains the standard treatment for pancreatic cancer, although most patients acquire resistance to the therapy. Up-regulated in pancreatic cancer, SIRT1 is involved in tumorigenesis and drug resistance. However the mechanism through which SIRT1 regulates drug sensitivity in cancer cells is mainly unknown. We hypothesise that inhibiting SIRT1 activity may increase sensitivity of pancreatic cancer cells to gemcitabine treatment through the regulation of apototic cell death, cell cycle, epithelial-mesenschymal-transition (EMT) and senescence. We demonstrate that gemcitabine or 6-Chloro-2,3,4,9-tetrahydro-1 H-Carbazole-1-carboxamide (EX527) SIRT1 inhibitor reduces PANC-1 cell proliferation in vitro. EX527 enhanced sensitivity of PANC-1 cells to gemcitabine treatment through increased apoptosis. However, EX527 displayed no beneficial effect either as a monotreatment or in combination with gemcitabine in the modulation of cell cycle progression. Combination treatment did not reverse the two phenomena known to affect drug sensitivity, namely EMT and senescence, which are both induced by gemcitabine. Unexpectedly, EX527 promoted PANC-1 xenograft tumour growth in SCID mice compared to control group. Dual tX527 and gemcitabine displayed no synergistic effect compared to gemcitabine alone. The study reveals that SIRT1 is involved in chemoresistance and that inhibiting SIRT1 activity with EX527 sensitised PANC-1 cells to gemcitabine treatment in vitro. Sensitisation of cells is shown to be mainly through induction of micronuclei formation as a result of DNA damage and apoptosis in vitro. However, the absence of positive combinatorial effects in vivo indicates possible effects on cells of the tumor microenvironment and suggests caution regarding the clinical relevance of tissue culture findings with EX527.
    Matched MeSH terms: Apoptosis/drug effects
  8. Fulltext In vivo antitumor and antimetastatic effects of flavokawain B in 4T1 breast cancer cell-challenged mice
    Abu N, Mohamed NE, Yeap SK, Lim KL, Akhtar MN, Zulfadli AJ, et al.
    Drug Des Devel Ther, 2015;9:1401-17.
    PMID: 25834398 DOI: 10.2147/DDDT.S67976
    Flavokawain B (FKB) is a naturally occurring chalcone that can be isolated through the root extracts of the kava-kava plant (Piper methysticum). It can also be synthesized chemically to increase the yield. This compound is a promising candidate as a biological agent, as it is reported to be involved in a wide range of biological activities. Furthermore, FKB was reported to have antitumorigenic effects in several cancer cell lines in vitro. However, the in vivo antitumor effects of FKB have not been reported on yet. Breast cancer is one of the major causes of cancer-related deaths in the world today. Any potential treatment should not only impede the growth of the tumor, but also modulate the immune system efficiently and inhibit the formation of secondary tumors. As presented in our study, FKB induced apoptosis in 4T1 tumors in vivo, as evidenced by the terminal deoxynucleotidyl transferase dUTP nick end labeling and hematoxylin and eosin staining of the tumor. FKB also regulated the immune system by increasing both helper and cytolytic T-cell and natural killer cell populations. In addition, FKB also enhanced the levels of interleukin 2 and interferon gamma but suppressed interleukin 1B. Apart from that, FKB was also found to inhibit metastasis, as evaluated by clonogenic assay, bone marrow smearing assay, real-time polymerase chain reaction, Western blot, and proteome profiler analysis. All in all, FKB may serve as a promising anticancer agent, especially in treating breast cancer.
    Matched MeSH terms: Apoptosis/drug effects
  9. Synthesis of Apoptotic New Quinazolinone-Based Compound and Identification of its Underlying Mitochondrial Signalling Pathway in Breast Cancer Cells
    Zahedifard M, Faraj FL, Paydar M, Looi CY, Hasandarvish P, Hajrezaie M, et al.
    Curr Pharm Des, 2015;21(23):3417-26.
    PMID: 25808938
    The anti-carcinogenic effect of the new quinazolinone compound, named MMD, was tested on MCF-7 human breast cancer cell line. The synthesis of quinazolinone-based compounds attracted strong attention over the past few decades as an alternative mean to produce analogues of natural products. Quinazolinone compounds sharing the main principal core structures are currently introduced in the clinical trials and pharmaceutical markets as anti-cancer agents. Thus, it is of high clinical interest to identify a new drug that could be used to control the growth and expansion of cancer cells. Quinazolinone is a metabolite derivative resulting from the conjugation of 2-aminobenzoyhydrazide and 5-methoxy-2- hydroxybenzaldehyde based on condensation reactions. In the present study, we analysed the influence of MMD on breast cancer adenoma cell morphology, cell cycle arrest, DNA fragmentation, cytochrome c release and caspases activity. MCF-7 is a type of cell line representing the breast cancer adenoma cells that can be expanded and differentiated in culture. Using different in vitro strategies and specific antibodies, we demonstrate a novel role for MMD in the inhibition of cell proliferation and initiation of the programmed cell death. MMD was found to increase cytochrome c release from the mitochondria to the cytosol and this effect was enhanced over time with effective IC50 value of 5.85 ± 0.71 μg/mL detected in a 72-hours treatment. Additionally, MMD induced cell cycle arrest at G0/G1 phase and caused DNA fragmentation with obvious activation of caspase-9 and caspases-3/7. Our results demonstrate a novel role of MMD as an anti-proliferative agent and imply the involvement of mitochondrial intrinsic pathway in the observed apoptosis.
    Matched MeSH terms: Apoptosis/drug effects*
  10. Fulltext Basic fibroblast growth factor modulates cell cycle of human umbilical cord-derived mesenchymal stem cells
    Ramasamy R, Tong CK, Yip WK, Vellasamy S, Tan BC, Seow HF
    Cell Prolif, 2012 Apr;45(2):132-9.
    PMID: 22309282 DOI: 10.1111/j.1365-2184.2012.00808.x
    BACKGROUND: Mesenchymal stem cells (MSC) have great potential in regenerative medicine, immunotherapy and gene therapy due to their unique properties of self-renewal, high plasticity, immune modulation and ease for genetic modification. However, production of MSC at sufficient clinical scale remains an issue as in vitro generation of MSC inadequately fulfils the demand with respect to patients.

    OBJECTIVES: This study has aimed to establish optimum conditions to generate and characterize MSC from human umbilical cord (UC-MSC).

    MATERIALS AND METHODS: To optimize MSC population growth, basic fibroblast growth factor (bFGF) was utilized in culture media. Effects of bFGF on expansion kinetics, cell cycle, survival of UC-MSC, cytokine secretion, expression of early stem-cell markers and immunomodulation were investigated.

    RESULTS: bFGF supplementation profoundly enhanced UC-MSC proliferation by reducing population doubling time without altering immunophenotype and immunomodulatory function of UC-MSC. However, cell cycle studies revealed that bFGF drove the cells into the cell cycle, as a higher proportion of cells resided in S phase and progressed into M phase. Consistent with this, bFGF was shown to promote expression of cyclin D proteins and their relevant kinases to drive UC-MSC to transverse cell cycle check points, thus, committing the cells to DNA synthesis. Furthermore, supplementation with bFGF changed the cytokine profiles of the cells and reduced their apoptotic level.

    CONCLUSION: Our study showed that bFGF supplementation of UC-MSC culture enhanced the cells' growth kinetics without compromising their nature.

    Matched MeSH terms: Apoptosis/drug effects
  11. Fulltext Tocotrienols promote apoptosis in human breast cancer cells by inducing poly(ADP-ribose) polymerase cleavage and inhibiting nuclear factor kappa-B activity
    Loganathan R, Selvaduray KR, Nesaretnam K, Radhakrishnan AK
    Cell Prolif, 2013 Apr;46(2):203-13.
    PMID: 23510475 DOI: 10.1111/cpr.12014
    OBJECTIVES: Tocotrienols and tocopherols are members of the vitamin E family, with similar structures; however, only tocotrienols have been reported to achieve potent anti-cancer effects. The study described here has evaluated anti-cancer activity of vitamin E to elucidate mechanisms of cell death, using human breast cancer cells.

    MATERIALS AND METHODS: Anti-cancer activity of a tocotrienol-rich fraction (TRF) and a tocotrienol-enriched fraction (TEF) isolated from palm oil, as well as pure vitamin E analogues (α-tocopherol, α-, δ- and γ-tocotrienols) were studied using highly aggressive triple negative MDA-MB-231 cells and oestrogen-dependent MCF-7 cells, both of human breast cancer cell lines. Cell population growth was evaluated using a Coulter particle counter. Cell death mechanism, poly(ADP-ribose) polymerase cleavage and levels of NF-κB were determined using commercial ELISA kits.

    RESULTS: Tocotrienols exerted potent anti-proliferative effects on both types of cell by inducing apoptosis, the underlying mechanism of cell death being ascertained using respective IC50 concentrations of all test compounds. There was marked induction of apoptosis in both cell lines by tocotrienols compared to treatment with Paclitaxel, which was used as positive control. This activity was found to be associated with cleavage of poly(ADP-ribose) polymerase (a DNA repair protein), demonstrating involvement of the apoptotic cell death signalling pathway. Tocotrienols also inhibited expression of nuclear factor kappa-B (NF-κB), which in turn can increase sensitivity of cancer cells to apoptosis.

    CONCLUSION: Tocotrienols induced anti-proliferative and apoptotic effects in association with DNA fragmentation, poly(ADP-ribose) polymerase cleavage and NF-κB inhibition in the two human breast cancer cell lines.

    Matched MeSH terms: Apoptosis*
  12. Fulltext Induction of apoptosis in MCF-7 cells by the hemagglutinin-neuraminidase glycoprotein of Newcastle disease virus Malaysian strain AF2240
    Ghrici M, El Zowalaty M, Omar AR, Ideris A
    Oncol Rep, 2013 Sep;30(3):1035-44.
    PMID: 23807159 DOI: 10.3892/or.2013.2573
    Newcastle disease virus (NDV) exerts its naturally occurring oncolysis possibly through the induction of apoptosis. We hypothesized that the binding of the virus to the cell via the hemagglutinin-neuraminidase (HN) glycoprotein may be sufficient to not only induce apoptosis but to induce a higher apoptosis level than the parental NDV AF2240 virus. NDV AF2240 induction of apoptosis in MCF-7 human breast cancer cells was analyzed and quantified. In addition, the complete HN gene of NDV strain AF2240 was amplified, sequenced and cloned into the pDisplay eukaryotic expression vector. HN gene expression was first detected at the cell surface membrane of the transfected MCF-7 cells. HN induction of apoptosis in transfected MCF-7 cells was analyzed and quantified. The expression of the HN gene alone was able to induce apoptosis in MCF-7 cells but it was a less potent apoptosis inducer compared to the parental NDV AF2240 strain. In conclusion, the NDV AF2240 strain is a more suitable antitumor candidate agent than its recombinant HN gene unless the latter is further improved by additional modifications.
    Matched MeSH terms: Apoptosis*
  13. D-pinitol mitigates tumor growth by modulating interleukins and hormones and induces apoptosis in rat breast carcinogenesis through inhibition of NF-κB
    Rengarajan T, Nandakumar N, Rajendran P, Ganesh MK, Balasubramanian MP, Nishigaki I
    J Physiol Biochem, 2015 Jun;71(2):191-204.
    PMID: 25827943 DOI: 10.1007/s13105-015-0397-9
    Breast cancer is the most prevalent malignant neoplasm in the world, and chemoprevention through dietary intervention strategy is an emerging option to reduce the incidence. D-pinitol (DP), a major component of soya bean, possesses attractive biological actions. We have investigated whether D-pinitol have an effect on tumor growth in vivo against 7,12-dimethylbenz(a)anthracene (DMBA)-initiated rat mammary carcinogenesis and investigated its mechanism of action. Tumors were induced in Sprague-Dawley (SD) rats by a gastric dose of 20 mg/kg DMBA, and after 13 weeks of induction period, the rats were orally administered with D-pinitol for 45 days. At the end of the assay, animals in carcinogen control group prompted a tumor incidence of 100 % and developed a tumor volume of 8.35 ± 0.56, which was significantly reduced to 5.74 ± 0.32 for the animals treated with D-pinitol. The D-pinitol treatment not only decreased the tumor volume but also further examination revealed that tumors from animals that received D-pinitol reduced nuclear factor kappa B (NF-κB) activation which in turn results in modulation of its downstreaming p53 and proteins of caspase-3 family. Bcl-2 expression and caspase-3 activation were also decreased after D-pinitol supplementation leading to induction of apoptosis and finally cell death. Furthermore, the status of the inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-2, IL-6, and tumor markers, lipid profile, and hormones was also significantly declined up on D-pinitol administration. Thus, it reveals the collective involvement of the above-mentioned parameters along with NF-κB signaling through which D-pinitol induces apoptosis and subsequently suppresses breast cancer during DMBA-induced rat breast carcinogenesis.
    Matched MeSH terms: Apoptosis/drug effects
  14. Fulltext The synergism of Clinacanthus nutans Lindau extracts with gemcitabine: downregulation of anti-apoptotic markers in squamous pancreatic ductal adenocarcinoma
    Hii LW, Lim SE, Leong CO, Chin SY, Tan NP, Lai KS, et al.
    BMC Complement Altern Med, 2019 Sep 14;19(1):257.
    PMID: 31521140 DOI: 10.1186/s12906-019-2663-9
    BACKGROUND: Clinacanthus nutans extracts have been consumed by the cancer patients with the hope that the extracts can kill cancers more effectively than conventional chemotherapies. Our previous study reported its anti-inflammatory effects were caused by inhibiting Toll-like Receptor-4 (TLR-4) activation. However, we are unsure of its anticancer effect, and its interaction with existing chemotherapy.

    METHODS: We investigated the anti-proliferative efficacy of polar leaf extracts (LP), non-polar leaf extracts (LN), polar stem extract (SP) and non-polar stem extracts (SN) in human breast, colorectal, lung, endometrial, nasopharyngeal, and pancreatic cancer cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT assay. The most potent extracts was tested along with gemcitabine using our established drug combination analysis. The effect of the combinatory treatment in apoptosis were quantified using enzyme-linked immunosorbent assay (ELISA), Annexin V assay, antibody array and immunoblotting. Statistical significance was analysed using one-way analysis of variance (ANOVA) and post hoc Dunnett's test. A p-value of less than 0.05 (p 

    Matched MeSH terms: Apoptosis/drug effects*
  15. Mucoadhesive guargum hydrogel inter-connected chitosan-g-polycaprolactone micelles for rifampicin delivery
    Yuan X, Amarnath Praphakar R, Munusamy MA, Alarfaj AA, Suresh Kumar S, Rajan M
    Carbohydr Polym, 2019 Feb 15;206:1-10.
    PMID: 30553301 DOI: 10.1016/j.carbpol.2018.10.098
    Natural polymer guar gum has one of the highest viscosities in water solution and hence, these are significantly used in pharmaceutical applications. Guar gum inter-connected micelles as a new carrier has been developed for poor water soluble rifampicin drug. The hydrogel inter-connected micelle core was formulated as a hydrophilic inner and hydrophobic outer core by using guar gum/chitosan/polycaprolactone and the carrier interaction with rifampicin was confirmed by FT-IR. The morphological observations were carried out through TEM, SEM and AFM analysis. The encapsulation efficiency and in-vitro drug release behavior of prepared hydrogel based micelle system was analyzed by UV-vis spectrometry. The anti-bacterial activity against K. pneumoniae and S. aureus was studied by observing their ruptured surface by SEM. The cytotoxicity study reveals that the pure polymeric system has no toxic effect whereas drug loaded ones showed superior activity against THP-1 cells. From the cell apoptosis analyses, the apoptosis was carried out in a time dependent manner. The cell uptake behavior was also observed in THP-1 cells which indicate that the hydrogel based micelle system is an excellent material for the mucoadhesive on intracellular alveolar macrophage treatment.
    Matched MeSH terms: Apoptosis/drug effects
  16. Suppressing growth, migration, and invasion of human hepatocellular carcinoma HepG2 cells by Catharanthus roseus‑silver nanoparticles
    Azhar NA, Ghozali SZ, Abu Bakar SA, Lim V, Ahmad NH
    Toxicol In Vitro, 2020 Sep;67:104910.
    PMID: 32526345 DOI: 10.1016/j.tiv.2020.104910
    Application of silver nanoparticles serves as a new approach in cancer treatment due to its unique features. Biosynthesis of silver nanoparticles using plant is advantageous since they are easily accessible, nontoxic and produce quicker reaction compared to other methods. To evaluate the cytotoxicity, mechanism of cell death and DNA damage of biosynthesized Catharanthus roseus-silver nanoparticles on human liver cancer (HepG2) cells. The antiproliferative activity of Catharanthus roseus‑silver nanoparticles was measured using MTT assay. The cytotoxic effects were further evaluated by measuring nitric oxide and reactive oxygen species (ROS). The mechanism of cell death was determined by annexin-FITC/propidium iodide, mitochondrial membrane potential (MMP) and cell cycle assays. The assessment of DNA damage was evaluated using Comet assay method. The uptake of the nanoparticles were evaluated by Transmission Electron Microscopy (TEM). Catharanthus roseus‑silver nanoparticles has inhibited the proliferation of HepG2 cells in a time-dependent manner with a median IC50 value of 3.871 ± 0.18 μg/mL. The concentration of nitrite and ROS were significantly higher than control. The cell death was due to apoptosis associated with MMP loss, cell cycle arrest, and extensive DNA damage. TEM analysis indicated the presence of free nanoparticles and endosomes containing the nanoparticles. The findings show that Catharanthus roseus‑silver nanoparticles have produced cytotoxic effects on HepG2 cells and thus may have a potential to be used as an anticancer treatment, particularly for hepatocellular carcinoma.
    Matched MeSH terms: Apoptosis/drug effects
  17. Protective effects of atorvastatin on high glucose-induced oxidative stress and mitochondrial apoptotic signaling pathways in cultured chondrocytes
    Hosseinzadeh A, Bahrampour Juybari K, Kamarul T, Sharifi AM
    J Physiol Biochem, 2019 Jun;75(2):153-162.
    PMID: 30796627 DOI: 10.1007/s13105-019-00666-8
    The high glucose concentration is able to disturb chondrocyte homeostasis and contribute to OA pathogenesis. This study was designed to investigate the protective effects of atorvastatin (ATO) on high glucose (HG)-mediated oxidative stress and mitochondrial apoptosis in C28I2 human chondrocytes. The protective effect of ATO (0.01 and 0.1 μM) on HG (75 mM)-induced oxidative stress and apoptosis was evaluated in C28I2 cells. The effects of ATO on HG-induced intracellular ROS production and lipid peroxidation were detected and the protein expression levels of Bax, Bcl-2, caspase-3, total and phosphorylated JNK and P38 MAPKs were analyzed by Western blotting. The mRNA expression levels of antioxidant enzymes including heme oxygenase-1, NAD(P)H quinine oxidoreductase, glutathione S-transferase-P1, catalase, superoxide dismutase-1, glutathione peroxidase-1, -3, -4 were evaluated by reverse transcription-polymerase chain reaction. Pretreatment with ATO remarkably increased the gene expression levels of antioxidant enzymes and reduced HG-induced elevation of ROS, lipid peroxidation, Bax/Bcl-2 ratio, caspase-3 activation, and JNK and P38 phosphorylation. Atorvastatin could considerably reduce HG-induced oxidative stress and mitochondrial apoptosis through increasing the expression of antioxidant enzymes. Atorvastatin may be considered as a promising agent to prevent high glucose-induced cartilage degradation in OA patients.
    Matched MeSH terms: Apoptosis/drug effects*
  18. Fulltext Changing survival, memory cell compartment, and T-helper balance of lymphocytes between severe and mild asthma
    Abdulamir AS, Hafidh RR, Abubakar F, Abbas KA
    BMC Immunol, 2008;9:73.
    PMID: 19087256 DOI: 10.1186/1471-2172-9-73
    BACKGROUND: Asthma is a complicated network of inflammatory reactions. It is classified into mild, moderate, and severe persistent asthma. The success of asthma therapy relies much on understanding the underlying mechanisms of inflammation at each stage of asthma severity. The aim of this study was to explore the differences in apoptotic potential, CD4/CD8 ratio, memory compartment, and T- helper (Th) 1 and 2 profile of peripheral blood lymphocytes (PBL) in patients with mild intermittent asthma and severe persistent asthma during exacerbation periods.
    RESULTS: Four research lines were investigated and compared among mild asthmatics, severe asthmatics, and healthy groups by applying immunocytochemical staining of PBL. Antiapoptotic and proapoptotic proteins with Bcl-2/Bax ratio, CD4, CD8 markers with CD4+/CD8+ ratio, CD45RO+, CD45RA+ markers with memory/naive ratio (CD45RO+/CD45RA+). Th2/Th1 cytokines balance represented by IL-4/IFN-gamma ratio was measured by enzyme-linked immunosorbent assay (ELISA) for in vitro PBL cytokine synthesis. It was found that Bcl-2/Bax ratio was higher in severe than in mild asthmatics which in turn was higher than in healthy group. And memory/naive ratio of PBL was higher in severe than in mild asthmatics. Moreover, memory cells, CD45RO+ and CD45RO+/CD45RA+ ratio were correlated directly with Bcl-2/Bax, in severe and mild asthma patients. In contrast, CD4+/CD8+ ratio was not changed significantly among healthy group, mild and severe asthmatics. However, CD8+ cells were correlated directly with memory cells, CD45RO+, in severe asthmatics only. Interestingly, the dominant profile of cytokines appeared to change from T helper 2 (Th2) in mild asthmatics to T helper 1 (Th1) in severe asthmatics where the lowest in vitro IL-4/IFN-gamma ratio and highest IFN-gamma were found.
    CONCLUSION: It was concluded that the underlying mechanisms of inflammation might vary greatly with asthma stage of severity. Mild intermittent asthma is mainly Th2 allergen-oriented reaction during exacerbations with good level of apoptosis making the inflammation as self-limiting, while in severe persistent asthma, the inflammatory reaction mediated mainly by Th1 cytokines with progressive loss of apoptosis leading to longer exacerbations, largely expanded memory cells, CD45RO+, leading to persistent baseline inflammation.
    Matched MeSH terms: Apoptosis/immunology
  19. Garlic flavonoids alleviate H2 O2 induced oxidative damage in L02 cells and induced apoptosis in HepG2 cells by Bcl-2/Caspase pathway
    Gao X, Yanan J, Santhanam RK, Wang Y, Lu Y, Zhang M, et al.
    J Food Sci, 2021 Feb;86(2):366-375.
    PMID: 33448034 DOI: 10.1111/1750-3841.15599
    Liver damage is a common liver disorder, which could induce liver cancer. Oral antioxidant is one of the effective treatments to prevent and alleviate liver damage. In this study, three flavonoids namely myricetin, isoquercitrin, and isorhamnetin were isolated and identified from Laba garlic. The isolated compounds were investigated on the protective effects against H2 O2 -induced oxidative damages in hepatic L02 cells and apoptosis inducing mechanism in hepatic cancer cells HepG2 by using MTT assay, flow cytometry and western blotting analysis. Myricetin, isoquercitrin, and isorhamnetin showed proliferation inhibition on HepG2 cells with IC50 value of 44.32 ± 0.213 µM, 49.68 ± 0.192 µM, and 54.32 ± 0.176 µM, respectively. While they showed low toxicity on normal cell lines L02. They could significantly alleviate the oxidative damage towards L02 cells (P < 0.05), via inhibiting the morphological changes in mitochondria and upholding the integrity of mitochondrial structure and function. The fluorescence intensity of L02 cells pre-treated with myricetin, isoquercitrin, and isorhamnetin (100 µM) was 89.23 ± 1.26%, 89.35 ± 1.43% and 88.97 ± 0.79%, respectively. Moreover, the flavonoids could induce apoptosis in HepG2 cells via Bcl-2/Caspase pathways, where it could up-regulate the expression of Bax and down-regulate the expression of Bcl-2, Bcl-xL, pro-Caspase-3, and pro-Caspase-9 proteins in a dose dependent manner. Overall, the results suggested that the flavonoids from Laba garlic might be a promising candidate for the treatment of various liver disorders. PRACTICAL APPLICATION: Flavonoids from Laba garlic showed selective toxicity towards HepG2 cells in comparison to L02 cells via regulating Bcl-2/caspase pathway. Additionally, the isolated flavonoids expressively barred the oxidative damage induced by H2 O2 in L02 cells. These results suggested that the flavonoids from laba garlic could be a promising agent towards the development of functional foods.
    Matched MeSH terms: Apoptosis/drug effects*
  20. Synergistic Growth Inhibition by Afatinib and Trametinib in Preclinical Oral Squamous Cell Carcinoma Models
    Yee PS, Zainal NS, Gan CP, Lee BKB, Mun KS, Abraham MT, et al.
    Target Oncol, 2019 04;14(2):223-235.
    PMID: 30806895 DOI: 10.1007/s11523-019-00626-8
    BACKGROUND: Given that aberrant activation of epidermal growth factor receptor family receptors (ErbB) is a common event in oral squamous cell carcinoma, and that high expression of these receptor proteins is often associated with poor prognosis, this rationalizes the approach of targeting ErbB signaling pathways to improve the survival of patients with oral squamous cell carcinoma. However, monotherapy with the ErbB blocker afatinib has shown limited survival benefits.

    OBJECTIVES: This study was performed to identify mechanisms of afatinib resistance and to explore potential afatinib-based combination treatments with other targeted inhibitors in oral squamous cell carcinoma.

    METHODS: We determined the anti-proliferative effects of afatinib on a panel of oral squamous cell carcinoma cell lines using a crystal violet-growth inhibition assay, click-iT 5-ethynyl-2'-deoxyuridine staining, and cell-cycle analysis. Biochemical assays were performed to study the underlying mechanism of drug treatment as a single agent or in combination with the MEK inhibitor trametinib. We further evaluated and compared the anti-tumor effects of single agent and combined treatment by using oral squamous cell carcinoma xenograft models.

    RESULTS: In this study, we showed that afatinib inhibited oral squamous cell carcinoma cell proliferation via cell-cycle arrest at the G0/G1 phase, and inhibited tumor growth in xenograft mouse models. Interestingly, we demonstrated reactivation of the mitogen-activated protein kinase (ERK1/2) pathway in vitro, which possibly reduced the effects of ErbB inhibition. Concomitant treatment of oral squamous cell carcinoma cells with afatinib and trametinib synergized the anti-tumor effects in oral squamous cell carcinoma-bearing mouse models.

    CONCLUSIONS: Our findings provide insight into the molecular mechanism of resistance to afatinib and support further clinical evaluation into the combination of afatinib and MEK inhibition in the treatment of oral squamous cell carcinoma.

    Matched MeSH terms: Apoptosis/drug effects
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