Displaying publications 1 - 20 of 1084 in total

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  1. Zainuddin A, Chua KH, Tan JK, Jaafar F, Makpol S
    J Physiol Biochem, 2017 Feb;73(1):59-65.
    PMID: 27743340 DOI: 10.1007/s13105-016-0524-2
    Human diploid fibroblasts (HDFs) proliferation in culture has been used as a model of aging at the cellular level. Growth arrest is one of the most important mechanisms responsible for replicative senescence. Recent researches have been focusing on the function of vitamin E in modulating cellular signaling and gene expression. Therefore, the aim of this study was to elucidate the effect of palm γ-tocotrienol (vitamin E) in modulating cellular aging through p16INK4a pathway in HDF cells. Primary culture of senescent HDFs was incubated with 70 μM of palm γ-tocotrienol for 24 hours. Silencing of p16INK4a was carried out by siRNA transfection. RNA was extracted from the different treatment groups and gene expression analysis was carried out by real-time reverse transcription polymerase chain reaction. Proteins that were regulated by p16INK4a were determined by western blot technique. The finding of this study showed that p16INK4a mRNA was overexpressed in senescent HDFs, and hypophosphorylated-pRb and cyclin D1 protein expressions were increased (p cell cycle regulation during cellular aging. In conclusion, senescent HDFs showed change in biological process specifically in cell cycle regulation with elevated expression of genes and proteins which may contribute to cell cycle arrest. Palm γ-tocotrienol may delay cellular senescence of HDFs by regulating cell cycle through downregulation of p16INK4a and hypophosphorylated-pRb and cyclin D1 protein expressions.
    Matched MeSH terms: Cell Proliferation
  2. Yusof KM, Makpol S, Jamal R, Harun R, Mokhtar N, Ngah WZ
    Molecules, 2015 Jun 03;20(6):10280-97.
    PMID: 26046324 DOI: 10.3390/molecules200610280
    Numerous bioactive compounds have cytotoxic properties towards cancer cells. However, most studies have used single compounds when bioactives may target different pathways and exert greater cytotoxic effects when used in combination. Therefore, the objective of this study was to determine the anti-proliferative effect of γ-tocotrienol (γ-T3) and 6-gingerol (6G) in combination by evaluating apoptosis and active caspase-3 in HT-29 and SW837 colorectal cancer cells. MTS assays were performed to determine the anti-proliferative and cytotoxicity effect of γ-T3 (0-150 µg/mL) and 6G (0-300 µg/mL) on the cells. The half maximal inhibitory concentration (IC50) value of 6G+ γ-T3 for HT-29 was 105 + 67 µg/mL and for SW837 it was 70 + 20 µg/mL. Apoptosis, active caspase-3 and annexin V FITC assays were performed after 24 h of treatment using flow cytometry. These bioactives in combination showed synergistic effect on HT-29 (CI: 0.89 ± 0.02,) and SW837 (CI: 0.79 ± 0.10) apoptosis was increased by 21.2% in HT-29 and 55.4% in SW837 (p < 0.05) after 24 h treatment, while normal hepatic WRL-68 cells were unaffected. Increased apoptosis by the combined treatments was also observed morphologically, with effects like cell shrinkage and pyknosis. In conclusion, although further studies need to be done, γ-T3 and 6G when used in combination act synergistically increasing cytotoxicity and apoptosis in cancer cells.
    Matched MeSH terms: Cell Proliferation/drug effects
  3. 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: Cell Proliferation/drug effects
  4. Dahham SS, Tabana Y, Asif M, Ahmed M, Babu D, Hassan LE, et al.
    Int J Mol Sci, 2021 Sep 29;22(19).
    PMID: 34638895 DOI: 10.3390/ijms221910550
    Beta-Caryophyllene (BCP), a naturally occurring sesquiterpene abundantly found in cloves, hops, and cannabis, is the active candidate of a relatively new group of vascular-inhibiting compounds that aim to block existing tumor blood vessels. Previously, we have reported the anti-cancer properties of BCP by utilizing a series of in-vitro anti-tumor-related assays using human colorectal carcinoma cells. The present study aimed to investigate the effects of BCP on in-vitro, ex-vivo, and in-vivo models of anti-angiogenic assays and evaluate its anti-cancer activity in xenograft tumor (both ectopic and orthotopic) mice models of human colorectal cancer. Computational structural analysis and an apoptosis antibody array were also performed to understand the molecular players underlying this effect. BCP exhibited strong anti-angiogenic activity by blocking the migration of endothelial cells, tube-like network formation, suppression of vascular endothelial growth factor (VEGF) secretion from human umbilical vein endothelial cells and sprouting of rat aorta microvessels. BCP has a probable binding at Site#0 on the surface of VEGFR2. Moreover, BCP significantly deformed the vascularization architecture compared to the negative control in a chick embryo chorioallantoic membrane assay. BCP showed a remarkable reduction in tumor size and fluorescence molecular tomography signal intensity in all the mice treated with BCP, in a dose-dependent relationship, in ectopic and orthotopic tumor xenograft models, respectively. The histological analysis of the tumor from BCP-treated mice revealed a clear reduction of the density of vascularization. In addition, BCP induced apoptosis through downregulation of HSP60, HTRA, survivin, and XIAP, along with the upregulation of p21 expressions. These results suggest that BCP acts at multiple stages of angiogenesis and could be used as a promising therapeutic candidate to halt the growth of colorectal tumor cells.
    Matched MeSH terms: Cell Proliferation/drug effects
  5. Ibrahim MY, Hashim NM, Mohan S, Abdulla MA, Kamalidehghan B, Ghaderian M, et al.
    Drug Des Devel Ther, 2014;8:1629-47.
    PMID: 25302018 DOI: 10.2147/DDDT.S66105
    Cratoxylum arborescens is an equatorial plant belonging to the family Guttiferae. In the current study, α-Mangostin (AM) was isolated and its cell death mechanism was studied. HCS was undertaken to detect the nuclear condensation, mitochondrial membrane potential, cell permeability, and the release of cytochrome c. An investigation for reactive oxygen species formation was conducted using fluorescent analysis. To determine the mechanism of cell death, human apoptosis proteome profiler assay was conducted. In addition, using immunofluorescence and immunoblotting, the levels of Bcl-2-associated X protein (Bax) and B-cell lymphoma (Bcl)-2 proteins were also tested. Caspaces such as 3/7, 8, and 9 were assessed during treatment. Using HCS and Western blot, the contribution of nuclear factor kappa-B (NF-κB) was investigated. AM had showed a selective cytotoxicity toward the cancer cells with no toxicity toward the normal cells even at 30 μg/mL, thereby indicating that AM has the attributes to induce cell death in tumor cells. The treatment of MCF-7 cells with AM prompted apoptosis with cell death-transducing signals. This regulated the mitochondrial membrane potential by down-regulation of Bcl-2 and up-regulation of Bax, thereby causing the release of cytochrome c from the mitochondria into the cytosol. The liberation of cytochrome c activated caspace-9, which, in turn, activated the downstream executioner caspace-3/7 with the cleaved poly (ADP-ribose) polymerase protein, thereby leading to apoptotic alterations. Increase of caspace 8 had showed the involvement of an extrinsic pathway. This type of apoptosis was suggested to occur through both extrinsic and intrinsic pathways and prevention of translocation of NF-κB from the cytoplasm to the nucleus. Our results revealed AM prompt apoptosis of MCF-7 cells through NF-κB, Bax/Bcl-2 and heat shock protein 70 modulation with the contribution of caspaces. Moreover, ingestion of AM at (30 and 60 mg/kg) significantly reduced tumor size in an animal model of breast cancer. Our results suggest that AM is a potentially useful agent for the treatment of breast cancer.
    Matched MeSH terms: Cell Proliferation/drug effects
  6. Jafarlou M, Baradaran B, Shanehbandi D, Saedi TA, Jafarlou V, Ismail P, et al.
    Cell Mol Biol (Noisy-le-grand), 2016 May 30;62(6):44-9.
    PMID: 27262801
    Acute myeloid leukemia (AML) is one of the most frequent types of leukemia which mostly affects adult people. Resistance to therapeutic drugs is considered as a major clinical concern resulting in a weaker response to chemotherapy, disease relapse and decreased survival rate. Survivin, a member of Inhibitor of Apoptosis Proteins (IAPs), is associated with drug resistance and inhibition of apoptotic mechanisms in numerous hematological malignancies. In the present study, we examined the combined effect of etoposide and siRNA-mediated silencing of survivin on U-937 acute myeloid leukemia cells. The AML cells were transfected with survivin specific siRNA and gene knockdown was confirmed by quantitative real time PCR and western blotting. Subsequently, U-937 cells were assessed for response to etoposide treatment and apoptosis rate was measured with flowcytometery. The cytotoxic effects in siRNA-etoposide group were measured and compared to etoposide single therapy group. Survivin siRNA effectively knocked down the mRNA and protein levels of survivin, which led to lower cell proliferation and enhanced apoptosis. Furthermore, combined treatment of etoposide and survivin siRNA synergistically increased the cell toxic effects of etoposide and its ability to induce apoptosis.
    Matched MeSH terms: Cell Proliferation/drug effects
  7. Yu F, Bracken CP, Pillman KA, Lawrence DM, Goodall GJ, Callen DF, et al.
    PLoS One, 2015;10(6):e0129190.
    PMID: 26061048 DOI: 10.1371/journal.pone.0129190
    p53 is a master tumour repressor that participates in vast regulatory networks, including feedback loops involving microRNAs (miRNAs) that regulate p53 and that themselves are direct p53 transcriptional targets. We show here that a group of polycistronic miRNA-like non-coding RNAs derived from small nucleolar RNAs (sno-miRNAs) are transcriptionally repressed by p53 through their host gene, SNHG1. The most abundant of these, sno-miR-28, directly targets the p53-stabilizing gene, TAF9B. Collectively, p53, SNHG1, sno-miR-28 and TAF9B form a regulatory loop which affects p53 stability and downstream p53-regulated pathways. In addition, SNHG1, SNORD28 and sno-miR-28 are all significantly upregulated in breast tumours and the overexpression of sno-miR-28 promotes breast epithelial cell proliferation. This research has broadened our knowledge of the crosstalk between small non-coding RNA pathways and roles of sno-miRNAs in p53 regulation.
    Matched MeSH terms: Cell Proliferation
  8. Chowchaikong N, Nilwarangkoon S, Laphookhieo S, Tanunyutthawongse C, Watanapokasin R
    Int J Oncol, 2018 Jun;52(6):2031-2040.
    PMID: 29620273 DOI: 10.3892/ijo.2018.4353
    Colorectal cancer, which is the third most common type of cancer diagnosed in both men and women, is the leading cause of cancer-related deaths worldwide. Cowanin is a pure compound extracted from Garcinia cowa Roxb., a tree species present in Thailand, Malaysia and Myanmar. The crude extract has been demonstrated to have antitumor activity, inflammation induction, antibacterial activity, anti-inflammatory activity and antimalarial activity. In the present study, the effects of cowanin on apoptosis induction and on the apoptosis-related and mitogen-activated protein kinase (MAPK) pathways were investigated in the LoVo human colorectal cancer cell line. The cytotoxicity of cowanin in LoVo cells was determined by MTT assay. Hoechst 33342 and JC‑1 staining were used to determine nuclear morphological changes and mitochondrial membrane potential, respectively. The expression levels of BCL2 apoptosis regulator (Bcl‑2) family, MAPK and AKT serine/threonine kinase 1 (Akt) pathway proteins following cowanin treatment were determined by western blot analysis. The results demonstrated that cowanin inhibited cell proliferation and induced cell death via the apoptosis pathway. Cowanin treatment increased BCL2 associated X (Bax) and decreased Bcl‑2 expression. In addition, cowanin activated caspase‑9, -7 and poly-ADP-ribose-polymerase expression. Furthermore, cowanin decreased the levels of phosphorylated extracellular signal-regulated kinase (p‑ERK), p‑Akt, p‑3‑phosphoinositide‑dependent protein kinase‑1, while it increased p‑p38 expression, thus resulting in the induction of apoptosis. In conclusion, cowanin inhibited cell proliferation and induced apoptosis of LoVo cells via the MAPK and Akt signaling pathways. Notably, inhibition of p38 by using a p38 inhibitor (SB203580) prevented the cowanin-induced apoptosis in LoVo cells. These results suggested that cowanin may be a potential candidate for the treatment of colorectal cancer and provided important information on the molecular mechanisms underlying its antitumor activity.
    Matched MeSH terms: Cell Proliferation/drug effects
  9. Gao Y, Zhang W, Liu C, Li G
    Sci Rep, 2019 12 11;9(1):18844.
    PMID: 31827114 DOI: 10.1038/s41598-019-54289-6
    Resistance to tamoxifen is a major clinical challenge. Research in recent years has identified epigenetic changes as mediated by dysregulated miRNAs that can possibly play a role in resistance to tamoxifen in breast cancer patients expressing estrogen receptor (ER). We report here elevated levels of EMT markers (vimentin and ZEB1/2) and reduced levels of EMT-regulating miR-200 (miR-200b and miR-200c) in ER-positive breast cancer cells, MCF-7, that were resistant to tamoxifen, in contrast with the naïve parental MCF-7 cells that were sensitive to tamoxifen. Further, we established regulation of c-MYB by miR-200 in our experimental model. C-MYB was up-regulated in tamoxifen resistant cells and its silencing significantly decreased resistance to tamoxifen and the EMT markers. Forced over-expression of miR-200b/c reduced c-MYB whereas reduced expression of miR-200b/c resulted in increased c-MYB We further confirmed the results in other ER-positive breast cancer cells T47D cells where forced over-expression of c-MYB resulted in induction of EMT and significantly increased resistance to tamoxifen. Thus, we identify a novel mechanism of tamoxifen resistance in breast tumor microenvironment that involves miR-200-MYB signaling.
    Matched MeSH terms: Cell Proliferation
  10. Manvati S, Mangalhara KC, Kalaiarasan P, Chopra R, Agarwal G, Kumar R, et al.
    Cancer Cell Int, 2019;19:230.
    PMID: 31516387 DOI: 10.1186/s12935-019-0933-8
    Background: Despite several reports describing the dual role of miR-145 as an oncogene and a tumor suppressor in cancer, not much has been resolved and understood.

    Method: In this study, the potential targets of miR-145 were identified bio-informatically using different target prediction tools. The identified target genes were validated in vitro by dual luciferase assay. Wound healing and soft agar colony assay assessed cell proliferation and migration. miR-145 expression level was measured quantitatively by RT-PCR at different stages of breast tumor. Western blot was used to verify the role of miR-145 in EMT transition using key marker proteins.

    Result: Wound healing and soft agar colony assays, using miR-145 over-expressing stably transfected MCF7 cells, unraveled its role as a pro-proliferation candidate in cancerous cells. The association between miR-145 over-expression and differential methylation patterns in representative target genes (DR5, BCL2, TP53, RNF8, TIP60, CHK2, and DCR2) supported the inference drawn. These in vitro observations were validated in a representative set of nodal positive tumors of stage 3 and 4 depicting higher miR-145 expression as compared to early stages. Further, the role of miR-145 in epithelial-mesenchymal (EMT) transition found support through the observation of two key markers, Vimentin and ALDL, where a positive correlation with Vimentin protein and a negative correlation with ALDL mRNA expression were observed.

    Conclusion: Our results demonstrate miR-145 as a pro-cancerous candidate, evident from the phenotypes of aggressive cellular proliferation, epithelial to mesenchymal transition, hypermethylation of CpG sites in DDR and apoptotic genes and upregulation of miR-145 in later stages of tumor tissues.

    Matched MeSH terms: Cell Proliferation
  11. Lai SL, Wong PF, Lim TK, Lin Q, Mustafa MR
    Phytomedicine, 2015 Jan 15;22(1):203-12.
    PMID: 25636890 DOI: 10.1016/j.phymed.2014.11.016
    Panduratin A (PA), a cyclohexanyl chalcone from Boesenbergia rotunda (L.) Mansf. was shown to possess anti-angiogenic effects in our previous study. In the present study, the molecular targets and anti-angiogenic mechanisms of PA on human umbilical vein endothelial cells (HUVECs) were identified using an iTRAQ-based quantitative proteomics approach. A total of 263 proteins were found to be differentially regulated in response to treatment with PA. Ingenuity Pathway Analysis revealed that cellular growth and proliferation, protein synthesis, RNA post-transcriptional modification, cellular assembly and organization and cell-to-cell signaling and interaction were the most significantly deregulated molecular and cellular functions in PA-treated HUVECs. PA inhibited the expressions of ARPC2 and CTNND1 that are associated with the formation of actin cytoskeleton, focal adhesion and cellular protrusions. In addition, PA down-regulated CD63, GRB-2, ICAM-2 and STAB-1 that are implicated in adhesion, migration and tube formation of endothelial cells. The differential expressions of three targets, namely, ARPC2, CDK4, and GRB-2 were validated by western blot analyses. Furthermore, PA inhibited G1-S progression, and resulted in G0/G1 arrest in HUVECs. The blockage in cell cycle progression was accompanied with the suppression of mTOR signaling. Treatment of HUVECs with PA resulted in decreased phosphorylation of ribosomal S6 and 4EBP1 proteins, the two downstream effectors of mTOR signaling. We further showed that PA is able to inhibit mTOR signaling induced by VEGF, a potent inducer of angiogenesis. Taken together, by integrating quantitative proteomic approach, we identified protein targets in which PA mediates its anti-angiogenic effects. The present study thus provides mechanistic evidence to the previously reported multifaceted anti-angiogenic effects of PA. Our study further identified mTOR signaling as an important target of PA, and therefore highlights the potential of PA for therapeutic intervention against angiogenesis-related pathogenesis, particularly, metastatic malignancy.
    Matched MeSH terms: Cell Proliferation/drug effects
  12. Aisha AF, Abu-Salah KM, Ismail Z, Majid AM
    Molecules, 2012;17(3):2939-54.
    PMID: 22402764 DOI: 10.3390/molecules17032939
    Despite the progress in colon cancer treatment, relapse is still a major obstacle. Hence, new drugs or drug combinations are required in the battle against colon cancer. α-Mangostin and betulinic acid (BA) are cytotoxic compounds that work by inducing the mitochondrial apoptosis pathway, and cisplatin is one of the most potent broad spectrum anti-tumor agents. This study aims to investigate the enhancement of BA cytotoxicity by α-mangostin, and the cytoprotection effect of α-mangostin and BA on cisplatin-induced cytotoxicity on HCT 116 human colorectal carcinoma cells. Cytotoxicity was investigated by the XTT cell proliferation test, and the apoptotic effects were investigated on early and late markers including caspases-3/7, mitochondrial membrane potential, cytoplasmic shrinkage, and chromatin condensation. The effect of α-mangostin on four signalling pathways was also investigated by the luciferase assay. α-Mangostin and BA were more cytotoxic to the colon cancer cells than to the normal colonic cells, and both compounds showed a cytoprotective effect against cisplatin-induced cytotoxicity. On the other hand, α-mangostin enhanced the cytotoxic and apoptotic effects of BA. Combination therapy hits multiple targets, which may improve the overall response to the treatment, and may reduce the likelihood of developing drug resistance by the tumor cells. Therefore, α-mangostin and BA may provide a novel combination for the treatment of colorectal carcinoma. The cytoprotective effect of the compounds against cisplatin-induced cytotoxicity may find applications as chemopreventive agents against carcinogens, irradiation and oxidative stress, or to neutralize cisplatin side effects.
    Matched MeSH terms: Cell Proliferation/drug effects
  13. Chin LF, Kong SM, Seng HL, Tiong YL, Neo KE, Maah MJ, et al.
    J Biol Inorg Chem, 2012 Oct;17(7):1093-105.
    PMID: 22825726 DOI: 10.1007/s00775-012-0923-y
    Two ternary Zn(II) complexes, with 1,10-phenanthroline (phen) as the main ligand and a carboxylate-containing ligand [dipicolinate (dipico) or L-threoninate (L-Thr)] as the subsidiary ligand, were prepared and characterized by elemental analysis, Fourier transform IR, UV, and fluorescence spectroscopy, X-ray diffraction, molar conductivity, and electrospray ionization mass spectrometry. X-ray structure analysis shows that both [Zn(phen)(dipico)(H(2)O)]·H(2)O (1) and [Zn(phen)(L-Thr)(H(2)O)Cl]·2H(2)O (2) have octahedral geometry about the Zn(II) atom. Both complexes can inhibit topoisomerase I, and have better anticancer activity than cisplatin against nasopharyngeal cancer cell lines, HK1 and HONE-1, with concentrations causing 50 % inhibition of cell proliferation (IC(50)) in the low micromolar range. Complex 2 has the highest therapeutic index for HK1. Both Zn(II) complexes can induce cell death by apoptosis. Changing the subsidiary ligand in the Zn(II) complexes affects the UV-fluorescence spectral properties of the coordinated phen ligand, the binding affinity for some DNA sequences, nucleobase sequence-selective binding, the phase at which cell cycle progression was arrested for treated cancer cells, and their therapeutic index.
    Matched MeSH terms: Cell Proliferation/drug effects
  14. Fan JY, Dama G, Liu YL, Guo WY, Lin JT
    Mol Biol (Mosk), 2023;57(4):668-670.
    PMID: 37528786
    In an in vitro culture system, primary hepatocytes usually display a low proliferation capacity, accompanied with a decrease of viability and a loss of hepatocyte-specific functions. Previous studies have demonstrated that the combination introductions of certain hepatocyte-specific transcription factors are able to convert fibroblasts into functional hepatocyte-like cells. However, such combinational usage of transcription factors in primary hepatocytes culture has not yet sufficiently studied. The forkhead box protein A3 (FoxA3) and hepatocyte nuclear factor 4α (Hnf4α) are liver-enriched transcription factors that play vital roles in the differentiation, and maintenance of hepatocytes. Thus, we simultaneously overexpressed the two genes, Foxa3 and Hnf4α, in rat hepatocytes and observed that the combinational augmentation of these two transcription factors have enhanced the proliferation and stabilized the hepatocyte-specific functions of primary hepatocytes over a long-term culture period.
    Matched MeSH terms: Cell Proliferation/genetics
  15. Manandhar B, Paudel KR, Clarence DD, De Rubis G, Madheswaran T, Panneerselvam J, et al.
    Naunyn Schmiedebergs Arch Pharmacol, 2024 Jan;397(1):343-356.
    PMID: 37439806 DOI: 10.1007/s00210-023-02603-5
    Lung cancer is the second most prevalent type of cancer and is responsible for the highest number of cancer-related deaths worldwide. Non-small-cell lung cancer (NSCLC) makes up the majority of lung cancer cases. Zerumbone (ZER) is natural compound commonly found in the roots of Zingiber zerumbet which has recently demonstrated anti-cancer activity in both in vitro and in vivo studies. Despite their medical benefits, ZER has low aqueous solubility, poor GI absorption and oral bioavailability that hinders its effectiveness. Liquid crystalline nanoparticles (LCNs) are novel drug delivery carrier that have tuneable characteristics to enhance and ease the delivery of bioactive compounds. This study aimed to formulate ZER-loaded LCNs and investigate their effectiveness against NSCLC in vitro using A549 lung cancer cells. ZER-LCNs, prepared in the study, inhibited the proliferation and migration of A549 cells. These inhibitory effects were superior to the effects of ZER alone at a concentration 10 times lower than that of free ZER, demonstrating a potent anti-cancer activity of ZER-LCNs. The underlying mechanisms of the anti-cancer effects by ZER-LCNs were associated with the transcriptional regulation of tumor suppressor genes P53 and PTEN, and metastasis-associated gene KRT18. The protein array data showed downregulation of several proliferation associated proteins such as AXL, HER1, PGRN, and BIRC5 and metastasis-associated proteins such as DKK1, CAPG, CTSS, CTSB, CTSD, and PLAU. This study provides evidence of potential for increasing the potency and effectiveness of ZER with LCN formulation and developing ZER-LCNs as a treatment strategy for mitigation and treatment of NSCLC.
    Matched MeSH terms: Cell Proliferation
  16. Foong JN, Selvarajah GT, Rasedee A, Rahman HS, How CW, Beh CY, et al.
    Biomed Res Int, 2018;2018:8691569.
    PMID: 30410940 DOI: 10.1155/2018/8691569
    Canine mammary gland tumor (CMT) is the most common tumor in intact female dog. Zerumbone (ZER) has promising anticancer properties, but plagued with poor water solubility, poor absorption, bioavailability, and delivery to target tissues. To solubilize, ZER was loaded into nanostructured lipid carrier (NLC) to produce ZER-loaded NLC (ZER-NLC). The objectives of this study were to determine the antiproliferative effect and the mode of cell death induced by ZER-NLC and ZER on a canine mammary gland tumor (CMT) adenocarcinoma primary cell line. There was no significant difference (p>0.05) between ZER-NLC and ZER treatments in the inhibition of CMT cell proliferation; thus, the loading of ZER into NLC did not compromise the cytotoxic effect of ZER. Microscopically, ZER-NLC- and ZER-treated CMT cells showed apoptotic cell morphology. ZER-NLC and ZER treatments significantly downregulated the antiapoptotic Bcl-2 and upregulated the proapoptotic Bax gene expressions in CMT cells. Both ZER-NLC and ZER-treated CMT cells showed significant (p<0.0001) increases in caspase-8, -9, and -3/7 protein activities. In conclusion, ZER-NLC induced CMT cell death via regulation of Bcl-2 and Bax gene expressions and caspase activations, indicating the involvement of both the intrinsic and extrinsic pathways of apoptosis. This study provided evidences for the potential of ZER-NLC as an anticanine mammary gland adenocarcinoma chemotherapy.
    Matched MeSH terms: Cell Proliferation
  17. Zainal NS, Gan CP, Lau BF, Yee PS, Tiong KH, Abdul Rahman ZA, et al.
    Phytomedicine, 2018 Jan 15;39:33-41.
    PMID: 29433681 DOI: 10.1016/j.phymed.2017.12.011
    BACKGROUND: The CXCR4-RhoA and PI3K-mTOR signaling pathways play crucial roles in the dissemination and tumorigenesis of oral squamous cell carcinoma (OSCC). Activation of these pathways have made them promising molecular targets in the treatment of OSCC. Zerumbone, a bioactive monocyclic sesquiterpene isolated from the rhizomes of tropical ginger, Zingiber zerumbet (L.) Roscoe ex Sm. has displayed promising anticancer properties with the ability to modulate multiple molecular targets involved in carcinogenesis. While the anticancer activities of zerumbone have been well explored across different types of cancer, the molecular mechanism of action of zerumbone in OSCC remains largely unknown.

    PURPOSE: Here, we investigated whether OSCC cells were sensitive towards zerumbone treatment and further determined the molecular pathways involved in the mechanism of action.

    METHODS: Cytotoxicity, anti-proliferative, anti-migratory and anti-invasive effects of zerumbone were tested on a panel of OSCC cell lines. The mechanism of action of zerumbone was investigated by analysing the effects on the CXCR4-RhoA and PI3K-mTOR pathways by western blotting.

    RESULTS: Our panel of OSCC cells was broadly sensitive towards zerumbone with IC50 values of less than 5 µM whereas normal keratinocyte cells were less responsive with IC50 values of more than 25 µM. Representative OSCC cells revealed that zerumbone inhibited OSCC proliferation and induced cell cycle arrest and apoptosis. In addition, zerumbone treatment inhibited migration and invasion of OSCC cells, with concurrent suppression of endogenous CXCR4 protein expression in a time and dose-dependent manner. RhoA-pull down assay showed reduction in the expression of RhoA-GTP, suggesting the inactivation of RhoA by zerumbone. In association with this, zerumbone also inhibited the PI3K-mTOR pathway through the inactivation of Akt and S6 proteins.

    CONCLUSION: We provide evidence that zerumbone could inhibit the activation of CXCR4-RhoA and PI3K-mTOR signaling pathways leading to the reduced cell viability of OSCC cells. Our results suggest that zerumbone is a promising phytoagent for development of new therapeutics for OSCC treatment.

    Matched MeSH terms: Cell Proliferation/drug effects
  18. Abdelwahab SI, Abdul AB, Mohan S, Taha MM, Syam S, Ibrahim MY, et al.
    Leuk. Res., 2011 Feb;35(2):268-71.
    PMID: 20708800 DOI: 10.1016/j.leukres.2010.07.025
    Zerumbone (ZER) is a potential anticancer natural compound, isolated from Zingiber zerumbet Smith. In this investigation, the anticancer properties of ZER were evaluated on cancer cells of T-acute lymphoblastic leukemia, CEM-ss. The results showed that ZER has cytotoxic effect against CEM-ss cells with an IC(50) of 8.4 ± 1.9 μg/ml (coefficient of variation < 30%). Comparatively, 5-fluorouracil (positive control), imposed an inhibitory effect on CEM-ss cells with an IC(50) of 1.94 ± 0.06 μg/ml. Scanning electron microscopy (SEM) results revealed abnormalities such as membrane blebbing, holes and cytoplasmic extrusions, all of which are characteristics of apoptosis. In addition, ZER has increased the number of TUNEL-positive stain and the cellular level of caspase-3, the hallmarks of apoptosis, on treated CEM-ss cells. It could be concluded that, ZER was able to produce apoptosis on T-acute lymphoblastic leukemia, CEM-ss. The current findings suggest that ZER might be helpful for improving the usefulness of anticancer agents in the therapy of leukemia.
    Matched MeSH terms: Cell Proliferation/drug effects
  19. E M Eid E, S Alanazi A, Koosha S, A Alrasheedy A, Azam F, M Taban I, et al.
    Molecules, 2019 Jul 13;24(14).
    PMID: 31337024 DOI: 10.3390/molecules24142554
    Cell-penetrating peptides (CPPs) are highly promising tools to deliver therapeutic molecules into tumours. αVβ3 integrins are cell-matrix adhesion receptors, and are considered as an attractive target for anticancer therapies owing to their roles in the process of metastasis and angiogenesis. Therefore, this study aims to assess the effect of co-administration of zerumbone (ZER) and ZERencapsulated in hydroxypropyl-β-cyclodextrin with TP5-iRGD peptide towards cell cytotoxicity, apoptosis induction, and proliferation of normal and cancerous breast cells utilizing in vitro assays, as well as to study the molecular docking of ZER in complex with TP5-iRGD peptide. Cell viability assay findings indicated that ZER and ZERencapsulated in hydroxypropyl-β-cyclodextrin (ZER-HPβCD) inhibited the growth of estrogen receptor positivebreast cancer cells (ER+ MCF-7) at 72 h treatment with an inhibitory concentration (IC)50 of 7.51 ± 0.2 and 5.08 ± 0.2 µg/mL, respectively, and inhibited the growth of triple negative breast cancer cells (MDA-MB-231) with an IC50 of 14.96 ± 1.52 µg/mL and 12.18 ± 0.7 µg/mL, respectively. On the other hand, TP5-iRGD peptide showed no significant cytotoxicity on both cancer and normal cells. Interestingly, co-administration of TP5-iRGD peptide in MCF-7 cells reduced the IC50 of ZER from 7.51 ± 0.2 µg/mL to 3.13 ± 0.7 µg/mL and reduced the IC50 of ZER-HPβCD from 5.08 ± 0.2 µg/mL to 0.49 ± 0.004 µg/mL, indicating that the co-administration enhances the potency and increases the efficacy of ZER and ZER-HPβCD compounds. Acridine orange (AO)/propidium iodide (PI) staining under fluorescence microscopy showed evidence of early apoptosis after 72 h from the co-administration of ZER or ZER-HPβCD with TP5-iRGD peptide in MCF-7 breast cancer cells. The findings of the computational modelling experiment provide novel insights into the ZER interaction with integrin αvβ3 in the presence of TP5-iRGD, and this could explain why ZER has better antitumor activities when co-administered with TP5-iRGD peptide.
    Matched MeSH terms: Cell Proliferation/drug effects
  20. Velaithan V, Okuda KS, Ng MF, Samat N, Leong SW, Faudzi SM, et al.
    Invest New Drugs, 2017 04;35(2):166-179.
    PMID: 28058624 DOI: 10.1007/s10637-016-0423-y
    Zebrafish represents a powerful in vivo model for phenotype-based drug discovery to identify clinically relevant small molecules. By utilizing this model, we evaluated natural product derived compounds that could potentially modulate Notch signaling that is important in both zebrafish embryogenesis and pathogenic in human cancers. A total of 234 compounds were screened using zebrafish embryos and 3 were identified to be conferring phenotypic alterations similar to embryos treated with known Notch inhibitors. Subsequent secondary screens using HEK293T cells overexpressing truncated Notch1 (HEK293TΔE) identified 2 compounds, EDD3 and 3H4MB, to be potential Notch antagonists. Both compounds reduced protein expression of NOTCH1, Notch intracellular domain (NICD) and hairy and enhancer of split-1 (HES1) in HEK293TΔE and downregulated Notch target genes. Importantly, EDD3 treatment of human oral cancer cell lines demonstrated reduction of Notch target proteins and genes. EDD3 also inhibited proliferation and induced G0/G1 cell cycle arrest of ORL-150 cells through inducing p27KIP1. Our data demonstrates the utility of the zebrafish phenotypic screen and identifying EDD3 as a promising Notch antagonist for further development as a novel therapeutic agent.
    Matched MeSH terms: Cell Proliferation/drug effects
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