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  1. 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.
    Matched MeSH terms: Pyrones/toxicity*
  2. Hawariah A, Stanslas J
    Anticancer Res, 1998 Nov-Dec;18(6A):4383-6.
    PMID: 9891496
    Previous studies have shown that a styrylpyrone derivative (SPD) from a local tropical plant had antiprogestin and antiestrogenic effects in early pregnant mice models (Azimahtol et al. 1991). Antiprogestins and antiestrogens can be exploited as a therapeutic approach to breast cancer treatment and thus the antitumor activity of SPD was tested in three different human breast cancer cell lines that is: MCF- 7, T47D and MDA-MB-231, employing, the antiproliferative assay of Lin and Hwang (1991) slightly modified. SPD (10(-10) - 10(-6) M) exhibited strong antiproliferative activity in estrogen and progestin-dependent MCF-7 cells (EC50 = 2.24 x 10(-7) M) and in hormone insensitive MDA-MB-231 (EC50 = 5.62 x 10(-7) M), but caused only partial inhibition of the estrogen- insensitive T47D cells (EC50 = 1.58 x 10(-6) M). However, tamoxifen showed strong inhibition of MCF-7 cells (EC50 = 1.41 x 10(-6) M) and to a lesser extent the T47D cells (EC50 = 2.5 x 10(-6) M) but did not affect the MDA-MB-231 cells. SPD at 1 microM exerted a beffer antiestrogenic activity than 1 microM tamoxifen in suppressing the growth of MCF-7 cells stimulated by 1 nM estradiol. Combined treatment of both SPD and tamoxifen at 1 microM showed additional inhibition on the growth of MCF-7 cells in culture. The antiproliferative properties of SPD are effective on both receptor positive and receptor negative mammary cancer cells, and thus appear to be neither dependent on cellular receptor status nor cellular hormone responses. This enhances in vivo approaches as tumors are heterogenous masses with varying receptor status.
    Matched MeSH terms: Pyrones/toxicity*
  3. Syed Azhar SNA, Ashari SE, Salim N
    Int J Nanomedicine, 2018;13:6465-6479.
    PMID: 30410332 DOI: 10.2147/IJN.S171532
    Introduction: Kojic monooleate (KMO) is an ester derived from a fungal metabolite of kojic acid with monounsaturated fatty acid, oleic acid, which contains tyrosinase inhibitor to treat skin disorders such as hyperpigmentation. In this study, KMO was formulated in an oil-in-water nanoemulsion as a carrier for better penetration into the skin.

    Methods: The nanoemulsion was prepared by using high and low energy emulsification technique. D-optimal mixture experimental design was generated as a tool for optimizing the composition of nanoemulsions suitable for topical delivery systems. Effects of formulation variables including KMO (2.0%-10.0% w/w), mixture of castor oil (CO):lemon essential oil (LO; 9:1) (1.0%-5.0% w/w), Tween 80 (1.0%-4.0% w/w), xanthan gum (0.5%-1.5% w/w), and deionized water (78.8%-94.8% w/w), on droplet size as a response were determined.

    Results: Analysis of variance showed that the fitness of the quadratic polynomial fits the experimental data with F-value (2,479.87), a low P-value (P<0.0001), and a nonsignificant lack of fit. The optimized formulation of KMO-enriched nanoemulsion with desirable criteria was KMO (10.0% w/w), Tween 80 (3.19% w/w), CO:LO (3.74% w/w), xanthan gum (0.70% w/w), and deionized water (81.68% w/w). This optimum formulation showed good agreement between the actual droplet size (110.01 nm) and the predicted droplet size (111.73 nm) with a residual standard error <2.0%. The optimized formulation with pH values (6.28) showed high conductivity (1,492.00 µScm-1) and remained stable under accelerated stability study during storage at 4°C, 25°C, and 45°C for 90 days, centrifugal force as well as freeze-thaw cycles. Rheology measurement justified that the optimized formulation was more elastic (shear thinning and pseudo-plastic properties) rather than demonstrating viscous characteristics. In vitro cytotoxicity of the optimized KMO formulation and KMO oil showed that IC50 (50% inhibition of cell viability) value was >100 µg/mL.

    Conclusion: The survival rate of 3T3 cell on KMO formulation (54.76%) was found to be higher compared to KMO oil (53.37%) without any toxicity sign. This proved that the KMO formulation was less toxic and can be applied for cosmeceutical applications.

    Matched MeSH terms: Pyrones/toxicity
  4. 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.
    Matched MeSH terms: Pyrones/toxicity*
  5. 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.
    Matched MeSH terms: Pyrones/toxicity*
  6. 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.
    Matched MeSH terms: Pyrones/toxicity*
  7. 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.
    Matched MeSH terms: Pyrones/toxicity*
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