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Fulltext Synthesis of new cytotoxic aminoanthraquinone derivatives via nucleophilic substitution reactions

Nor SM, Sukari MA, Azziz SS, Fah WC, Alimon H, Juhan SF

Molecules, 2013 Jul 08;18(7):8046-62.
PMID: 23884135 DOI: 10.3390/molecules18078046

Aminoanthraquinones were successfully synthesized via two reaction steps. 1,4-Dihydroxyanthraquinone (1) was first subjected to methylation, reduction and acylation to give an excellent yield of anthracene-1,4-dione (3), 1,4-dimethoxyanthracene-9,10-dione (5) and 9,10-dioxo-9,10-dihydroanthracene-1,4-diyl diacetate (7). Treatment of 1, 3, 5 and 7 with BuNH2 in the presence of PhI(OAc)2 as catalyst produced seven aminoanthraquinone derivatives 1a, b, 3a, and 5a-d. Amination of 3 and 5 afforded three new aminoanthraquinones, namely 2-(butylamino)anthracene-1,4-dione (3a), 2-(butylamino)anthracene-9,10-dione (5a) and 2,3-(dibutylamino)anthracene-9,10-dione (5b). All newly synthesised aminoanthraquinones were examined for their cytotoxic activity against MCF-7 (estrogen receptor positive human breast) and Hep-G2 (human hepatocellular liver carcinoma) cancer cells using MTT assay. Aminoanthraquinones 3a, 5a and 5b exhibited strong cytotoxicity towards both cancer cell lines (IC50 1.1-13.0 µg/mL).

Matched MeSH terms: Hep G2 Cells/drug effects
Cytotoxic effect of organotin(IV) benzylisopropyldithiocarbamate compounds on Chang liver cell and hepatocarcinoma HepG2 cell

Awang N, Kamaludin NF, Ghazali AR

Pak J Biol Sci, 2011 Aug 01;14(15):768-74.
PMID: 22303582

Cancer is one of the main causes of mortality and morbidity in world. New compounds are currently being synthesized to combat this disease. The organotins are gaining more attention as anti-cancer agents due to their potent cytotoxicity properties. In this study, a series of newly synthesized organotins namely dimethyltin (IV) (compound 1), dibutyltin (IV) (compound 2) and triphenyltin (IV) benzylisopropyldithiocarbamate (compound 3) were assessed for their cytotoxic activities against human Chang liver cells and hepatocarcinoma HepG2 cells. The cytotoxicity of these organotins in both cells upon 24 h treatment was assessed using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Compound 2 and 3 exhibited potent cytotoxic activities towards both cells where the IC50 values were less then 10 microM. The IC50 value for compound 2 was 2.5 microM in Chang liver cells and 7.0 microM in HepG2 cells whereas compound 3 exhibited an IC50 value of 1.5 microM in Chang liver cells and 2.5 microM in HepG2 cells. Therefore, compound 2 and 3 were more toxic against human Chang liver cells as compared to hepatocarcinoma HepG2 cells. Interestingly, compound 1 did not have any IC50 value in both cells and hence can be classified as non-toxic. In conclusion, organotin (IV) benzylisopropyldithiocarbamate with insertion of dibutyl and triphenyl functional group possess potent cytotoxicity properties. Structural modification of these compounds can be carried out in further studies to produce less or non toxic effects towards normal human cell.

Matched MeSH terms: Hep G2 Cells/drug effects*
Hot water extract of Chlorella vulgaris induced DNA damage and apoptosis

Yusof YA, Saad SM, Makpol S, Shamaan NA, Ngah WZ

Clinics (Sao Paulo), 2010;65(12):1371-7.
PMID: 21340229

OBJECTIVES: The aim of this study was to determine the antiproliferative and apoptotic effects of hot water extracts of Chlorella vulgaris on hepatoma cell line HepG2.
INTRODUCTION: The search for food and spices that can induce apoptosis in cancer cells has been a major study interest in the last decade. Chlorella vulgaris, a unicellular green algae, has been reported to have antioxidant and anti-cancer properties. However, its chemopreventive effects in inhibiting the growth of cancer cells have not been studied in great detail.
METHODS: HepG2 liver cancer cells and WRL68 normal liver cells were treated with various concentrations (0-4 mg/ml) of hot water extract of C. vulgaris after 24 hours incubation. Apoptosis rate was evaluated by TUNEL assay while DNA damage was assessed by Comet assay. Apoptosis proteins were evaluated by Western blot analysis.
RESULTS: Chlorella vulgaris decreased the number of viable HepG2 cells in a dose dependent manner (p < 0.05), with an IC50 of 1.6 mg/ml. DNA damage as measured by Comet assay was increased in HepG2 cells at all concentrations of Chlorella vulgaris tested. Evaluation of apoptosis by TUNEL assay showed that Chlorella vulgaris induced a higher apoptotic rate (70%) in HepG2 cells compared to normal liver cells, WRL68 (15%). Western blot analysis showed increased expression of pro-apoptotic proteins P53, Bax and caspase-3 in the HepG2 cells compared to normal liver cells WRL68, and decreased expression of the anti-apoptotic protein Bcl-2.
CONCLUSIONS: Chlorella vulgaris may have anti-cancer effects by inducing apoptosis signaling cascades via an increased expression of P53, Bax and caspase-3 proteins and through a reduction of Bcl-2 protein, which subsequently lead to increased DNA damage and apoptosis.

Matched MeSH terms: Hep G2 Cells/drug effects*
Fulltext In vitro cytotoxic, antioxidant, and antimicrobial activities of Mesua beccariana (Baill.) Kosterm., Mesua ferrea Linn., and Mesua congestiflora extracts

Teh SS, Ee GC, Mah SH, Yong YK, Lim YM, Rahmani M, et al.

Biomed Res Int, 2013;2013:517072.
PMID: 24089682 DOI: 10.1155/2013/517072

The in vitro cytotoxicity tests on the extracts of Mesua beccariana, M. ferrea, and M. congestiflora against Raji, SNU-1, HeLa, LS-174T, NCI-H23, SK-MEL-28, Hep-G2, IMR-32, and K562 were achieved using MTT assay. The methanol extracts of Mesua beccariana showed its potency towards the proliferation of B-lymphoma cell (Raji). In addition, only the nonpolar to semipolar extracts (hexane to ethyl acetate) of the three Mesua species indicated cytotoxic effects on the tested panel of human cancer cell lines. Antioxidant assays were evaluated using DPPH scavenging radical assay and Folin-Ciocalteu method. The methanol extracts of M. beccariana and M. ferrea showed high antioxidant activities with low EC₅₀ values of 12.70 and 9.77 μg/mL, respectively, which are comparable to that of ascorbic acid (EC₅₀ = 5.62 μg/mL). Antibacterial tests were carried out using four Gram positive and four Gram negative bacteria on Mesua beccariana extracts. All the extracts showed negative results in the inhibition of Gram negative bacteria. Nevertheless, methanol extracts showed some activities against Gram positive bacteria which are Bacillus cereus, methicillin-sensitive Staphylococcus aureus (MSSA), and methicillin-resistant Staphylococcus aureus (MRSA), while the hexane extract also contributed some activities towards Bacillus cereus.

Matched MeSH terms: Hep G2 Cells/drug effects
Andrographolide and 14-deoxy-11, 12-didehydroandrographolide inhibit cytochrome P450s in HepG2 hepatoma cells

Ooi JP, Kuroyanagi M, Sulaiman SF, Muhammad TS, Tan ML

Life Sci, 2011 Feb 28;88(9-10):447-54.
PMID: 21219911 DOI: 10.1016/j.lfs.2010.12.019

Cytochrome P450 (CYP) enzymes have been implicated in a large number of preventable drug-herb interactions. Andrographis paniculata Nees, a tropical herb widely used for various health conditions contains two major diterpenoids, andrographolide and 14-Deoxy-11, 12-Didehydroandrographolide. These compounds were evaluated systematically for their effects on CYP1A2, CYP2D6 and CYP3A4 expressions in HepG2 cells.

Matched MeSH terms: Hep G2 Cells/drug effects*
Regulation of low-density lipoprotein receptor and 3-hydroxy-3-methylglutaryl coenzyme A reductase gene expression by thymoquinone-rich fraction and thymoquinone in HepG2 cells

Al-Naqeep G, Ismail M, Allaudin Z

J Nutrigenet Nutrigenomics, 2009;2(4-5):163-72.
PMID: 19887822 DOI: 10.1159/000227264

BACKGROUND AND AIM: Nigella sativa and its active constituent thymoquinone (TQ) have been exploited for their various health benefits. This work was aimed to investigate the regulatory effects of TQ-rich fraction (TQRF) and commercial TQ on the low-density lipoprotein receptor (LDLR) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) genes in HepG2 cells.
METHODS AND RESULTS: TQRF was extracted from N. sativa seeds using supercritical fluid extraction. The regulatory effects of TQRF at 80 microg/ml and TQ at 2 microg/ml on LDLR and HMGCR gene expression were investigated in HepG2 cells using quantitative real-time PCR. The TQ content in TQRF was 2.77% (w/w) and was obtained at a temperature of 40 degrees C and a pressure of 600 bar. Treatment of cells with TQRF and TQ resulted in a 7- and 2-fold upregulation of LDLR mRNA level, respectively, compared with untreated cells. The mRNA level of HMGCR was downregulated by 71 and 12%, respectively, compared with untreated cells.
CONCLUSION: TQRF and TQ regulated genes involved in cholesterol metabolism by two mechanisms, the uptake of low-density lipoprotein cholesterol via the upregulation of the LDLR gene and inhibition of cholesterol synthesis via the suppression of the HMGCR gene.

Matched MeSH terms: Hep G2 Cells/drug effects
Fulltext Aporphine alkaloids from the leaves of Phoebe grandis (Nees) Mer. (Lauraceae) and their cytotoxic and antibacterial activities

Omar H, Hashim NM, Zajmi A, Nordin N, Abdelwahab SI, Azizan AH, et al.

Molecules, 2013 Jul 29;18(8):8994-9009.
PMID: 23899833 DOI: 10.3390/molecules18088994

The oxoaporphine alkaloid lysicamine (1), and three proaporphine alkaloids, litsericinone (2), 8,9,11,12-tetrahydromecambrine (3) and hexahydromecambrine A (4) were isolated from the leaves of Phoebe grandis (Nees) Merr. (Lauraceae). Compounds 2 and 3 were first time isolated as new naturally occurring compounds from plants. The NMR data for the compounds 2-4 have never been reported so far. Compounds 1 and 2 showed significant cytotoxic activity against a MCF7 (human estrogen receptor (ER+) positive breast cancer) cell line with IC₅₀ values of 26 and 60 µg/mL, respectively. Furthermore, in vitro cytotoxic activity against HepG2 (human liver cancer) cell line was evaluated for compounds 1-4 with IC₅₀ values of 27, 14, 81 and 20 µg/mL, respectively. Lysicamine (1) displayed strong antibacterial activity against Bacillus subtilis (B145), Staphylococcus aureus (S1434) and Staphylococus epidermidis (a clinically isolated strain) with inhibition zones of 15.50 ± 0.57, 13.33 ± 0.57 and 12.00 ± 0.00 mm, respectively. However, none of the tested pathogenic bacteria were susceptible towards compounds 2 and 3.

Matched MeSH terms: Hep G2 Cells/drug effects
Nutrigenomic effects of germinated brown rice and its bioactives on hepatic gluconeogenic genes in type 2 diabetic rats and HEPG2 cells

Imam MU, Ismail M

Mol Nutr Food Res, 2013 Mar;57(3):401-11.
PMID: 23307605 DOI: 10.1002/mnfr.201200429

SCOPE: Chronic sustained hyperglycemia underlies the symptomatology and complications of type 2 diabetes mellitus, and dietary components contribute to it. Germinated brown rice (GBR) improves glycemic control but the mechanisms involved are still the subject of debate. We now show one mechanism by which GBR lowers blood glucose.
METHODS AND RESULTS: Effects of GBR, brown rice, and white rice (WR) on fasting plasma glucose and selected genes were studied in type 2 diabetic rats. GBR reduced plasma glucose and weight more than metformin, while WR worsened glycemia over 4 weeks of intervention. Through nutrigenomic suppression, GBR downregulated gluconeogenic genes (Fbp1 and Pck1) in a manner similar to, but more potently than, metformin, while WR upregulated the same genes. Bioactives (gamma-amino butyric acid, acylated steryl glycoside, oryzanol, and phenolics) were involved in GBR's downregulation of both genes. Plasma glucose, Fbp1 and Pck1 changes significantly affected the weight of rats (p = 0.0001).
CONCLUSION: The fact that GBR downregulates gluconeogenic genes similar to metformin, but produces better glycemic control in type 2 diabetic rats, suggests other mechanisms are involved in GBR's antihyperglycemic properties. GBR as a staple could potentially provide enhanced glycemic control in type 2 diabetes mellitus better than metformin.

Matched MeSH terms: Hep G2 Cells/drug effects
A bismuth diethyldithiocarbamate compound promotes apoptosis in HepG2 carcinoma, cell cycle arrest and inhibits cell invasion through modulation of the NF-κB activation pathway

Ishak DH, Ooi KK, Ang KP, Akim AM, Cheah YK, Nordin N, et al.

J Inorg Biochem, 2014 Jan;130:38-51.
PMID: 24176918 DOI: 10.1016/j.jinorgbio.2013.09.018

The compound with R=CH2CH3 in Bi(S2CNR2)3 (1) is highly cytotoxic against a range of human carcinoma, whereas that with R=CH2CH2OH (2) is considerably less so. Both 1 and 2 induce apoptosis in HepG2 cells with some evidence for necrosis induced by 2. Based on DNA fragmentation, caspase activities and human apoptosis PCR-array analysis, both the extrinsic and intrinsic pathways of apoptosis have been shown to occur. While both compounds activate mitochondrial and FAS apoptotic pathways, compound 1 was also found to induce another death receptor-dependent pathway by induction of CD40, CD40L and TNF-R1 (p55). Further, 1 highly expressed DAPK1, a tumour suppressor, with concomitant down-regulation of XIAP and NF-κB. Cell cycle arrest at the S and G2/M phases correlates with the inhibition of the growth of HepG2 cells. The cell invasion rate of 2 is 10-fold higher than that of 1, a finding correlated with the down-regulation of survivin and XIAP expression by 1. Compounds 1 and 2 interact with DNA through different binding motifs with 1 interacting with AT- or TA-specific sites followed by inhibition of restriction enzyme digestion; 2 did not interfere with any of the studied restriction enzymes.

Matched MeSH terms: Hep G2 Cells/drug effects