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  1. Non-steroid receptor-mediated antiproliferative activity of styrylpyrone derivative in human breast cancer cell lines
    Pihie AH, Stanslas J, Din LB
    Anticancer Res, 1998 May-Jun;18(3A):1739-43.
    PMID: 9673398
    The antiproliferative activity of a styrylpyrone derivative (SPD) plant extract, was studied in three different human breast cancer cell lines in culture, and was compared with tamoxifen. The number of living cells was evaluated by Methylene Blue staining technique. SPD showed strong antiproliferative activity in estrogen receptor (ER) and progestin receptor (PgR) positive MCF-7 cells (EC50 = 6.30 x 10(-7) M) and receptor-negative MDA-MB-231 (EC50 = 5.62 x 10(-7) M), but it partially inhibited the high progestin receptor positive T47D cells (EC50 = 1.58 x 10(-6) M). Whereas tamoxifen, a nonsteroidal antiestrogen exhibited strong inhibition on MCF-7 cells (EC50 = 1.41 x 10(-6) M) and partial inhibition on T47D cells (EC50 = 2.5 x 10(-6) M), but did not affect the MDA-MB-231 cells in the concentration range 0.1 nM-1 microM (EC50 = 5.01 microM). At the same concentration range SPD and tamoxifen did not inhibit the proliferation of normal human liver cell line CCL 13 and normal bovine kidney MDBK; whereas adriamycin, a common chemotherapy drug for the treatment of advance cancer, caused 95% inhibition at 10(-6) M. Competitive binding studies showed SPD had no ability to inhibit the binding of [3H]estradiol and [3H]progesterone to ER and PgR, respectively but, tamoxifen exhibited affinity for ER. Therefore, it can be concluded that the antiproliferative activity of SPD was selective towards breast cancer cell lines and not mediated by ER or PgR.
  2. Fulltext Chemical composition, antioxidant, and antibacterial activity of essential oils from Etlingera sayapensis A.D. Poulsen & Ibrahim
    Mahdavi B, Yaacob WA, Din LB
    Asian Pac J Trop Med, 2017 Aug;10(8):819-826.
    PMID: 28942832 DOI: 10.1016/j.apjtm.2017.08.006
    OBJECTIVE: To report the chemical composition and bioactivity (including antioxidant and antimicrobial activity) of essential oils from the rhizomes, stems, and leaves of Etlingera sayapensis (E. sayapensis) A.D. Poulsen & Ibrahim for the first time.

    METHODS: First, the essential oils were obtained using a Clevenger-type apparatus. Then, the essential oils compositions were identified by chromatography methods including GC-FID and GC-MS. For the next step, DPPH radical scavenging activity (RSA), β-carotene bleaching (BCB), and ferrous ion chelating ability (FIC) were chosen to evaluate the essential oils antioxidant activity. Finally, disc diffusion assay and minimum inhibitory concentration method (MIC) was applied to investigate antimicrobial activity of the rhizomes and leaves oils of E. sayapensis against 18 microorganisms.

    RESULTS: All of the oils contained oxygenated monoterpenes (leaves: 74.18%, stems: 75.60%, and rhizome: 54.61%), The essential oil obtained from leaves contained high amount of carvone (21.38%), cis-carveol (13.49%); The rhizomes oil was rich in linalool formate (25.47%), eugenol (11.84%); and the stems oil was dominated by α-terpineol (39.86%), linalool formate (30.55%). The leaves oil represented the highest ability in all of the antioxidant activity tests. For antimicrobial activity, the rhizome oil presented more active when compared to leaves oil against Bacillus subtilis, Bacillus thuringiensis, Staphylococcus aureus, methicillin resistant Staphylococcus aureus (MRSA), Aeromonas hydrophila, Escherichia coli, Enterobacter aerogenes, Proteus mirabilis, Shigella sonnei, Serratia marcescens, Vibrio parahaemolyticus, Candida albicans, and Candida parapsilosis.

    CONCLUSIONS: The most components of the essential oils belong to oxygenated monoterpenes. Linalool formate, carvone, and α-terpineol are found as the most abundant compounds in the oils of the different parts of E. sayapensis. The rhizomes oil can prevent the growth of wide spectrum microorganisms; however, the oils are not highly potent in antioxidant assays.

  3. Altholactone, a novel styryl-lactone induces apoptosis via oxidative stress in human HL-60 leukemia cells
    Inayat-Hussain SH, Osman AB, Din LB, Taniguchi N
    Toxicol Lett, 2002 May 28;131(3):153-9.
    PMID: 11992734
    Plant styryl-lactone derivatives isolated from Goniothalamus sp. are potential compounds for cancer chemotherapy. In this study, we have examined the mechanisms of apoptosis induced by altholactone, a stryl-lactone isolated from the Malaysian plant G. malayanus on human HL-60 promyelocytic leukemia cells. Flow cytometric analysis of the externalization of phosphatidylserine (PS) using the annexin V/PI method on altholactone treated HL-60 cells showed a concentration-dependent increase of apoptosis from concentrations ranging from 10.8 (2.5 microg/ml) to 172.4 microM (40 microg/ml). Pre-treatment with the antioxidant N-acetylcysteine (1 mM) completely abrogated apoptosis induced by altholactone, suggesting for the involvement of oxidative stress. Further flow cytometric assessment of the level of intracellular peroxides using the fluorescent probe 2',7'-dichlorofluorescein diacetate (DCFH-DA) confirmed that altholactone induced an increase in cellular oxidative stress in HL-60 cells which was suppressed by N-acetylcysteine. In summary, our results demonstrate for the first time that altholactone induced apoptosis in HL-60 cells occurs via oxidative stress.
  4. Fulltext Acuminatol and other antioxidative resveratrol oligomers from the stem bark of Shorea acuminata
    Muhammad N, Din LB, Sahidin I, Hashim SF, Ibrahim N, Zakaria Z, et al.
    Molecules, 2012 Jul 30;17(8):9043-55.
    PMID: 22847143 DOI: 10.3390/molecules17089043
    A new resveratrol dimer, acuminatol (1), was isolated along with five known compounds from the acetone extract of the stem bark of Shorea acuminata. Their structures and stereochemistry were determined by spectroscopic methods, which included the extensive use of 2D NMR techniques. All isolated compounds were evaluated for their antioxidant activity using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity (RSA) and the β-carotene-linoleic acid (BCLA) assays, and compared with those of the standards of ascorbic acid (AscA) and butylated hydroxytoluene (BHT). All compounds tested exhibited good to moderate antioxidant activity in the DPPH assay (IC₅₀s 0.84 to 10.06 mM) and displayed strong inhibition of β-carotene oxidation (IC₅₀s 0.10 to 0.22 mM). The isolated compounds were evaluated on the Vero cell line and were found to be non-cytotoxic with LC₅₀ values between 161 to 830 µM.
  5. Fulltext Goniothalamin induces coronary artery smooth muscle cells apoptosis: the p53-dependent caspase-2 activation pathway
    Chan KM, Rajab NF, Siegel D, Din LB, Ross D, Inayat-Hussain SH
    Toxicol. Sci., 2010 Aug;116(2):533-48.
    PMID: 20498002 DOI: 10.1093/toxsci/kfq151
    Goniothalamin (GN), a styryl-lactone isolated from Goniothalamus andersonii, has been demonstrated to possess antirestenostic properties by inducing apoptosis on coronary artery smooth muscle cells (CASMCs). In this study, the molecular mechanisms of GN-induced CASMCs apoptosis were further elucidated. Apoptosis assessment based on the externalization of phosphatidylserine demonstrated that GN induces CASMCs apoptosis in a concentration-dependent manner. The GN-induced DNA damage occurred with concomitant elevation of p53 as early as 2 h, demonstrating an upstream signal for apoptosis. However, the p53 elevation in GN-treated CASMCs was independent of NAD(P)H: quinone oxidoreductase 1 and Mdm-2 expression. An increase in hydrogen peroxide and reduction in free thiols confirmed the role for oxidative stress in GN treatment. Pretreatment with the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (z-VAD-FMK) that significantly abrogated GN-induced CASMCs apoptosis suggested the involvement of caspase(s). The role of apical caspase-2, -8, and -9 was then investigated, and sequential activation of caspase-2 and -9 but not caspase-8 leading to downstream caspase-3 cleavage was observed in GN-treated CASMCs. Reduction of ATP level and decrease in oxygen consumption further confirmed the role of mitochondria in GN-induced apoptosis in CASMCs. The mitochondrial release of cytochrome c was seen without mitochondrial membrane potential loss and was independent of cardiolipin. These data provide insight into the mechanisms of GN-induced apoptosis, which may have important implications in the development of drug-eluting stents.
  6. Dichlorinated pulvinic acid derivative from a Malaysian Scleroderma sp
    van der Sar SA, Blunt JW, Cole AL, Din LB, Munro MH
    J Nat Prod, 2005 Dec;68(12):1799-801.
    PMID: 16378381
    A new dichlorinated pulvinic acid derivative, methyl-3',5'-dichloro-4,4'-di-O-methylatromentate, was isolated from the fruiting body of a Scleroderma sp. The structure was determined using spectroscopic methods, and an X-ray analysis was carried out for confirmation of the structure. Compound was found to display moderate antimicrobial activity against Bacillus subtilis.
  7. Loss of mitochondrial transmembrane potential and caspase-9 activation during apoptosis induced by the novel styryl-lactone goniothalamin in HL-60 leukemia cells
    Inayat-Hussain SH, Annuar BO, Din LB, Ali AM, Ross D
    Toxicol In Vitro, 2003 Aug;17(4):433-9.
    PMID: 12849726
    Styryl-lactones such as goniothalamin represent a new class of compounds with potential anti-cancer properties. In this study, we investigated the mechanisms of goniothalamin (GTN), a plant styryl-lactone induced apoptosis in human promyelocytic leukemia HL-60 cells. This plant extract resulted in apoptosis in HL-60 cells as assessed by the externalisation of phosphatidylserine. Using the mitochondrial membrane dye (DIOC(6)) in conjunction with flow cytometry, we found that GTN treated HL-60 cells demonstrated a loss of mitochondrial transmembrane potential (Deltapsi(m)). Further immunoblotting on these cells showed activation of initiator caspase-9 and the executioner caspases-3 and -7. Pretreatment with the pharmacological caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone (Z-VAD.FMK) abrogated apoptosis as assessed by all of the apoptotic features in this study. In summary, our results demonstrate that goniothalamin-induced apoptosis occurs via the mitochondrial pathway in a caspase dependent manner.
  8. Goniothalamin induces apoptosis in vascular smooth muscle cells
    Chan KM, Rajab NF, Ishak MH, Ali AM, Yusoff K, Din LB, et al.
    Chem Biol Interact, 2006 Feb 1;159(2):129-40.
    PMID: 16297902
    Restenosis represents a major impediment to the success of coronary angioplasty. Abnormal proliferation of vascular smooth muscle cells (VSMCs) has been shown to be an important process in the pathogenesis of restenosis. A number of agents, particularly rapamycin and paclitaxel, have been shown to impact on this process. This study was carried out to determine the mechanisms of cytotoxicity of goniothalamin (GN) on VSMCs. Results from MTT cytotoxicity assay showed that the IC(50) for GN was 4.4 microg/ml (22 microM), which was lower compared to the clinically used rapamycin (IC(50) of 25 microg/ml [27.346 microM]). This was achieved primarily via apoptosis where up to 25.83 +/- 0.44% of apoptotic cells were detected after 72 h treatment with GN. In addition, GN demonstrated similar effects as rapamycin in inhibiting VSMCs proliferation using bromodeoxyuridine (BrdU) cell proliferation assay after 72 h treatment at IC(50) concentration (p > 0.05). In order to understand the mechanisms of GN, DNA damage detection using comet assay was determined at 2h post-treatment with GN. Our results showed that there was a concentration-dependent increase in DNA damage in VSMCs prior to cytotoxicity. Moreover, GN effects were comparable to rapamycin. In conclusion, our data show that GN initially induces DNA damage which subsequently leads to cytotoxicity primarily via apoptosis in VSMCs.
  9. Genotoxicity of goniothalamin in CHO cell line
    Umar-Tsafe N, Mohamed-Said MS, Rosli R, Din LB, Lai LC
    Mutat Res, 2004 Aug 8;562(1-2):91-102.
    PMID: 15279832
    Goniothalamin (GTN) is a styrylpyrrone derivative from Goniothalamus umbrosus and other Annonaceae species. It has been shown to have anti-cancer and apoptosis-inducing properties against various human tumour and animal cell lines. The compound has also been shown to be active in vivo against DMBA-induced rat mammary tumours and was reported as an anti-fertility agent in rats. The aim of our study was to assess the genotoxicity of GTN in CHO cells using the UKEMS guidelines. A metabolic activation fraction (S9) was prepared according to standard methods. The methylthiazoletetrazolium (MTT) screening assay was then carried out to determine the cytotoxicity index (IC50) of GTN. The average IC50 value was 12.45 (+/- 3.63)microM. The mitotic index (MI) assay was then performed to determine the clastogenicity indices (MI(C25), MI(C50) and MI(C100)) of GTN. The chromosome aberration (CA) induction assay using air-dried metaphase spread was then performed to investigate the clastogenic effects of goniothalamin. Benzo[a]pyrene (BaP) and ethylmethanesulphonate (EMS) were used as positive controls in the presence and absence of S9 metabolic activation, respectively. The anti-genotoxicity effect of GTN was also assessed using a combination of GTN and EMS, and GTN and BaP. Dose-responses of CA frequencies were determined for both, the genotoxicity and anti-genotoxicity effects. GTN on its own and when combined with positive controls, was found to induce and enhance CA, respectively. Chromatid and whole chromosome breaks/gaps, as well as interchanges, endoreduplications and ring chromosomes were the main types of aberration induced by GTN. The overall clastogenic effect of GTN was statistically significant. In conclusion, GTN is potentially a genotoxic or clastogenic substance without any anti-genotoxic properties.
  10. Fulltext A Study of the in vitro cytotoxic activity of Gelsemium elegans using human ovarian and breast cancer cell lines
    Abdul Wahab K, Ahmad FB, Din LB, Cheah SH, Mock SL
    Trop Biomed, 2004 Dec;21(2):139-44.
    PMID: 16493406 MyJurnal
    The crude methanol extracts of Gelsemium elegans leaves were assessed for their cytotoxic activity using the microculture 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for cellular viability. This study utilized two different types of human cancer cell lines, CaOV-3 (human ovarian cancer cells) and MDA-MB-231 (human estrogen receptor negative breast cancer cells), allowing for comparison of toxicity of G. elegans against these two cancer cells lines. Our results showed that the methanol extract of G. elegans exhibited high cytotoxicity against the human ovarian cancer cell line CaOV-3 with an IC50 value of 5microg/ml after 96 h incubation. However, G. elegans displayed discernibly less toxicity against the MDA-MB-231 cells with an IC50 value 40microg/ml after 96 h incubation and this effect was dose- and time-dependent, up to 72h and 20-30 microg/ml. In conclusion, our results demonstrated that G. elegans is potently cytotoxic against the human ovarian cancer cell line CaOV-3 and to a lesser extend towards the human breast carcinoma cancer MDA-MB-231 cells, suggesting that the extract is selective towards CaOV-3 cells and may have a chemotherapeutic role for ovarian cancer treatment in the future.
  11. Fulltext Synthesis of silver nanoparticles with antibacterial activity using the lichen Parmotrema praesorediosum
    Mie R, Samsudin MW, Din LB, Ahmad A, Ibrahim N, Adnan SN
    Int J Nanomedicine, 2014;9:121-7.
    PMID: 24379670 DOI: 10.2147/IJN.S52306
    Development of a green chemistry process for the synthesis of silver nanoparticles has become a focus of interest. This would offer numerous benefits, including ecofriendliness and compatibility for biomedical applications. Here we report the synthesis of silver nanoparticles from the reduction of silver nitrate and an aqueous extract of the lichen Parmotrema praesorediosum as a reductant as well as a stabilizer. The physical appearance of these silver nanoparticles was characterized using ultraviolet-visible spectroscopy, electron microscopy, energy-dispersive spectroscopy, and X-ray diffraction techniques. The results show that silver nanoparticles synthesized using P. praesorediosum have an average particle size of 19 nm with a cubic structure. The antibacterial activity of the synthesized silver nanoparticles was tested against eight micro-organisms using the disk diffusion method. The results reveal that silver nanoparticles synthesized using P. praesorediosum have potential antibacterial activity against Gram-negative bacteria.
  12. Caspases-3 and -7 are activated in goniothalamin-induced apoptosis in human Jurkat T-cells
    Inayat-Hussain SH, Osman AB, Din LB, Ali AM, Snowden RT, MacFarlane M, et al.
    FEBS Lett, 1999 Aug 13;456(3):379-83.
    PMID: 10462048
    Goniothalamin, a plant styrylpyrone derivative isolated from Goniothalamus andersonii, induced apoptosis in Jurkat T-cells as assessed by the externalisation of phosphatidylserine. Immunoblotting showed processing of caspases-3 and -7 with the appearance of their catalytically active large subunits of 17 and 19 kDa, respectively. Activation of these caspases was further evidenced by detection of poly(ADP-ribose) polymerase cleavage (PARP). Pre-treatment with the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone (Z-VAD.FMK) blocked apoptosis and the resultant cleavage of these caspases and PARP. Our results demonstrate that activation of at least two effector caspases is a key feature of goniothalamin-induced apoptosis in Jurkat T-cells.
  13. Fulltext Involvement of Seladin-1 in goniothalamin-induced apoptosis in urinary bladder cancer cells
    Yen HK, Fauzi AR, Din LB, McKelvey-Martin VJ, Meng CK, Inayat-Hussain SH, et al.
    BMC Complement Altern Med, 2014;14:295.
    PMID: 25107315 DOI: 10.1186/1472-6882-14-295
    Selective Alzheimer Disease Indicator-1 (or Seladin-1) is a multifunctional protein first discovered by downregulation of its expression in Alzheimer's disease. Interestingly, the expression of this protein is upregulated in several cancers, including primary bladder cancer. However, its role in cancer formation has yet to be discovered. Goniothalamin is a natural product that has been demonstrated to induce apoptosis in various cancer cell lines. In this study, we have elucidated the role of Seladin-1 in goniothalamin-induced cytotoxicity towards human urinary bladder cancer cell line RT4.
  14. Fulltext Goniothalamin-induced oxidative stress, DNA damage and apoptosis via caspase-2 independent and Bcl-2 independent pathways in Jurkat T-cells
    Inayat-Hussain SH, Chan KM, Rajab NF, Din LB, Chow SC, Kizilors A, et al.
    Toxicol Lett, 2010 Mar 1;193(1):108-14.
    PMID: 20026395 DOI: 10.1016/j.toxlet.2009.12.010
    Goniothalamin (GTN) isolated from Goniothalamus sp. has been demonstrated to induce apoptosis in a variety of cancer cell lines including Jurkat T leukemia cells. However, the mechanism of GTN-induced apoptosis upstream of mitochondria is still poorly defined. In this study, GTN caused a decrease in GSH with an elevation of reactive oxygen species as early as 30 min and DNA damage as assessed by Comet assay. Analysis using topoisomerase II processing of supercoiled pBR 322 DNA showed that GTN caused DNA damage via a topoisomerase II-independent pathway suggesting that cellular oxidative stress may contribute to genotoxicity. A 12-fold increase of caspase-2 activity was observed in GTN-treated Jurkat cells after 4h treatment and this was confirmed using Western blotting. Although the caspase-2 inhibitor Z-VDVAD-FMK inhibited the proteolytic activity of caspase-2, apoptosis ensued confirming that caspase-2 activity was not crucial for GTN-induced apoptosis. However, GTN-induced apoptosis was completely abrogated by N-acetylcysteine further confirming the role of oxidative stress. Since cytochrome c release was observed as early as 1h without any appreciable change in Bcl-2 protein expression, we further investigated whether overexpression of Bcl-2 confers resistance in GTN-induced cytotoxicity. Using a panel of Jurkat Bcl-2 transfectants, GTN cytotoxicity was not abrogated in these cells. In conclusion, GTN induces DNA damage and oxidative stress resulting in apoptosis which is independent of both caspase-2 and Bcl-2.
  15. Pterulamides I-VI, linear peptides from a Malaysian Pterula sp
    Lang G, Mitova MI, Cole AL, Din LB, Vikineswary S, Abdullah N, et al.
    J Nat Prod, 2006 Oct;69(10):1389-93.
    PMID: 17067148
    Six new linear peptides, pterulamides I-VI (1-6), were isolated from the fruiting bodies of a Malaysian Pterula species. The structures were elucidated by MS and 2D NMR experiments, and the absolute configurations of the constituent amino acids established using Marfey's method. The pterulamides are mainly assembled from nonpolar N-methylated amino acids and, most interestingly, have non-amino-acid N-terminal groups, among them the unusual cinnamoyl, (E)-3-methylsulfinylpropenoyl, and (E)-3-methylthiopropenoyl groups. Furthermore, pterulamides I-V are the first natural peptides with a methylamide C-terminus. Pterulamides I and IV are cytotoxic against the P388 cell line with IC50 values of 0.55 and 0.95 microg/mL (0.79 and 1.33 microM), respectively.
  16. Potential immunosuppressive and antiinflammatory activities of Malaysian medicinal plants characterized by reduced cell surface expression of cell adhesion molecules
    Tanaka S, Yoichi S, Ao L, Matumoto M, Morimoto K, Akimoto N, et al.
    Phytother Res, 2001 Dec;15(8):681-6.
    PMID: 11746860
    In the search for agents effective against immune-mediated disorders and inflammation, we have screened Malaysian medicinal plants for the ability to inhibit the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on the surface of murine endothelial cells (F-2), and mouse myeloid leukaemia cells (M1), respectively. Of 41 kinds (29 species, 24 genera, 16 families) of Malaysian plants tested, 10 and 19 plant samples significantly downregulated the expression of ICAM-1 and VCAM-1, respectively. Bioassay-directed fractionation of an extract prepared from the bark of Goniothalamus andersonii showed that its ingredients, goniothalamin (1) and goniodiol (2) inhibited the cell surface expression of both ICAM-1 and VCAM-1. The present results suggest that Malaysian medicinal plants may be abundant natural resources for immunosuppressive and antiinflammatory substances.
  17. Fulltext RACK-1 overexpression protects against goniothalamin-induced cell death
    Inayat-Hussain SH, Wong LT, Chan KM, Rajab NF, Din LB, Harun R, et al.
    Toxicol Lett, 2009 Dec 15;191(2-3):118-22.
    PMID: 19698770 DOI: 10.1016/j.toxlet.2009.08.012
    Goniothalamin, a styryllactone, has been shown to induce cytotoxicity via apoptosis in several tumor cell lines. In this study, we have examined the potential role of several genes, which were stably transfected into T-cell lines and which regulate apoptosis in different ways, on goniothalamin-induced cell death. Overexpression of full-length receptor for activated protein C-kinase 1 (RACK-1) and pc3n3, which up-regulates endogenous RACK-1, in both Jurkat and W7.2 T cells resulted in inhibition of goniothalamin-induced cell death as assessed by MTT and clonogenic assays. However, overexpression of rFau (antisense sequence to Finkel-Biskis-Reilly murine sarcoma virus-associated ubiquitously expressed gene) in W7.2 cells did not confer resistance to goniothalamin-induced cell death. Etoposide, a clinically used cytotoxic agent, was equipotent in causing cytotoxicity in all the stable transfectants. Assessment of DNA damage by Comet assay revealed goniothalamin-induced DNA strand breaks as early as 1 h in vector control but this effect was inhibited in RACK-1 and pc3n3 stably transfected W7.2 cells. This data demonstrate that RACK-1 plays a crucial role in regulating cell death signalling pathways induced by goniothalamin.
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