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Standardized Polyalthia longifolia leaf extract (PLME) inhibits cell proliferation and promotes apoptosis: The anti-cancer study with various microscopy methods

Vijayarathna S, Chen Y, Kanwar JR, Sasidharan S

Biomed Pharmacother, 2017 Jul;91:366-377.
PMID: 28463800 DOI: 10.1016/j.biopha.2017.04.112

Over the years a number of microscopy methods have been developed to assess the changes in cells. Some non-invasive techniques such as holographic digital microscopy (HDM), which although does not destroy the cells, but helps to monitor the events that leads to initiation of apoptotic cell death. In this study, the apoptogenic property and the cytotoxic effect of P. longifolia leaf methanolic extract (PLME) against the human cervical carcinoma cells (HeLa) was studied using light microscope (LM), holographic digital microscopy (HDM), scanning electron microscope (SEM) and transmission electron microscope (TEM). The average IC50 value of PLME against HeLa cells obtained by MTT and CyQuant assay was 22.00μg/mL at 24h. However, noncancerous Vero cells tested with PLME exhibited no cytotoxicity with the IC50 value of 51.07μg/mL at 24h by using MTT assay. Cytological observations showed nuclear condensation, cell shrinkage, multinucleation, abnormalities of mitochondrial cristae, membrane blebbing, disappearance of microvilli and filopodia, narrowing of lamellipodia, holes, formation of numerous smaller vacuoles, cytoplasmic extrusions and formation of apoptotic bodies as confirmed collectively by HDM, LM, SEM and TEM. In conclusion, PLME was able to produce distinctive morphological features of HeLa cell death that corresponds to apoptosis.

Matched MeSH terms: Inhibitory Concentration 50
Fulltext Synthesis and biological profile of substituted benzimidazoles

Vashist N, Sambi SS, Narasimhan B, Kumar S, Lim SM, Shah SAA, et al.

Chem Cent J, 2018 Dec 01;12(1):125.
PMID: 30506405 DOI: 10.1186/s13065-018-0498-y

BACKGROUND: A series of benzimidazole derivatives was developed and its chemical scaffolds were authenticated by NMR, IR, elemental analyses and physicochemical properties. The synthesized compounds were screened for their antimicrobial and antiproliferative activities.
RESULTS AND DISCUSSION: The synthesized benzimidazole compounds were evaluated for their antimicrobial activity using the tube dilution method and were found to exhibit good antimicrobial potential against selected Gram negative and positive bacterial and fungal species. The compounds were also assessed for their anticancer activity exhibited using the SRB assay and were found to elicit antiproliferative activity against MCF7 breast cancer cell line, which was comparable to the standard drug.
CONCLUSION: Antimicrobial screening results indicated that compounds 1, 2 and 19 to be promising antimicrobial agents against selected microbial species and comparable to standard drugs which included norfloxacin and fluconazole. The anticancer screening results revealed that compounds, 12, 21, 22 and 29 to show the highest activity against MCF7 and their IC50 values were more potent than 5-fluorouracil.

Matched MeSH terms: Inhibitory Concentration 50
Phenolic contents, antioxidant and cytotoxic activities of Elaeocarpus floribundus Blume

Utami R, Khalid N, Sukari MA, Rahmani M, Abdul AB, Dachriyanus

Pak J Pharm Sci, 2013 Mar;26(2):245-50.
PMID: 23455191

Elaeocarpus floribundus is higher plant that has been used as traditional medicine for treating several diseases. There is no previous report on phytochemicals and bioactivity studies of this species. In this investigation, triterpenoids friedelin, epifriedelanol and β-sitosterol were isolated from its leaves and stem bark. Determination of total phenolic content of methanolic extract of leaves and stem bark was carried out using Folin-Ciocalteu reagent. All extracts and isolated compounds were subjected to screening of antioxidant activity using DPPH free radical scavenging method and cytotoxic activities by MTT assay towards human T4 lymphoblastoid (CEM-SS) and human cervical (HeLa) cancer cells. In the total phenolic content determination, methanolic extract of leaves gave higher value of 503.08±16.71 mg GAE/g DW than stem bark with value of 161.5±24.81 mg GAE/g DW. Polar extracts of leaves and stem bark possessed promising antioxidant activity with methanol extract of stem bark exhibited strongest activity with IC50 value of 7.36±0.01 μg/ml. In the cytotoxic activity assay, only chloroform extract of leaves showed significant activity with IC50 value of 25.6±0.06 μg/ml against CEM-SS cancer cell, while friedelin and epifriedelanol were found to be active against the two cancer cells with IC50 values ranging from 3.54 to 11.45 μg/ml.

Matched MeSH terms: Inhibitory Concentration 50
Vindogentianine, a hypoglycemic alkaloid from Catharanthus roseus (L.) G. Don (Apocynaceae)

Tiong SH, Looi CY, Arya A, Wong WF, Hazni H, Mustafa MR, et al.

Fitoterapia, 2015 Apr;102:182-8.
PMID: 25665941 DOI: 10.1016/j.fitote.2015.01.019

Vindogentianine, a new indole alkaloid together with six known alkaloids, vindoline, vindolidine, vindolicine, vindolinine, perivine and serpentine were isolated from leaf extract (DA) of Catharanthus roseus (L.) G. Don. Their structures were elucidated by spectroscopic methods; NMR, MS, UV and IR. Vindogentianine is a dimer containing a vindoline moiety coupled to a gentianine moiety. After 24h incubation, vindogentianine exhibited no cytotoxic effect in C2C12 mouse myoblast and β-TC6 mouse pancreatic cells (IC50>50μg/mL). Real-time cell proliferation monitoring also indicated vindogentianine had little or no effect on C2C12 mouse myoblast cell growth at the highest dose tested (200μg/mL), without inducing cell death. Vindogentianine exhibited potential hypoglycemic activity in β-TC6 and C2C12 cells by inducing higher glucose uptake and significant in vitro PTP-1B inhibition. However, in vitro α-amylase and α-glucosidase inhibition assay showed low inhibition under treatment of vindogentianine. This suggests that hypoglycemic activity of vindogentianine may be due to the enhancement of glucose uptake and PTP-1B inhibition, implying its therapeutic potential against type 2 diabetes.

Matched MeSH terms: Inhibitory Concentration 50
Fulltext Inhibitory potency of 8-methoxypsoralen on cytochrome P450 2A6 (CYP2A6) allelic variants CYP2A6 15, CYP2A6 16, CYP2A6 21 and CYP2A6 22: differential susceptibility due to different sequence locations of the mutations

Tiong KH, Mohammed Yunus NA, Yiap BC, Tan EL, Ismail R, Ong CE

PLoS One, 2014;9(1):e86230.
PMID: 24475091 DOI: 10.1371/journal.pone.0086230

Human cytochrome P450 2A6 (CYP2A6) is a highly polymorphic isoform of CYP2A subfamily. Our previous kinetic study on four CYP2A6 allelic variants (CYP2A6 15, CYP2A6 16, CYP2A6 21 and CYP2A6 22) have unveiled the functional significance of sequence mutations in these variants on coumarin 7-hydroxylation activity. In the present study, we further explored the ability of a typical CYP2A6 inhibitor, 8-methoxypsoralen (8-MOP), in inhibition of these alleles and we hypothesized that translational mutations in these variants are likely to give impact on 8-MOP inhibitory potency. The CYP2A6 variant and the wild type proteins were subjected to 8-MOP inhibition to yield IC50 values. In general, a similar trend of change in the IC50 and Km values was noted among the four mutants towards coumarin oxidation. With the exception of CYP2A6 16, differences in IC50 values were highly significant which implied compromised interaction of the mutants with 8-MOP. Molecular models of CYP2A6 were subsequently constructed and ligand-docking experiments were performed to rationalize experimental data. Our docking study has shown that mutations have induced enlargement of the active site volume in all mutants with the exception of CYP2A6 16. Furthermore, loss of hydrogen bond between 8-MOP and active site residue Asn297 was evidenced in all mutants. Our data indicate that the structural changes elicited by the sequence mutations could affect 8-MOP binding to yield differential enzymatic activities in the mutant CYP2A6 proteins.

Matched MeSH terms: Inhibitory Concentration 50
Chemical composition and cytotoxic properties of Clinacanthus nutans root extracts

Teoh PL, Cheng AY, Liau M, Lem FF, Kaling GP, Chua FN, et al.

Pharm Biol, 2017 Dec;55(1):394-401.
PMID: 27931178

CONTEXT: Clinacanthus nutans Lindau (Acanthaceae) is a medicinal plant that has been reported to have anti-inflammatory, antiviral, antimicrobial and antivenom activities. In Malaysia, it has been widely claimed to be effective in various cancer treatments but scientific evidence is lacking.
OBJECTIVE: This study investigates the chemical constituents, anti-proliferative, and apoptotic properties of C. nutans root extracts.
MATERIALS AND METHODS: The roots were subjected to solvent extraction using methanol and ethyl acetate. The anti-proliferative effects of root extracts were tested at the concentrations of 10 to 50 μg/mL on MCF-7 and HeLa by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay for 72 h. Morphological changes were observed under light microscope. Pro-apoptotic effects of root extracts were examined using flow cytometric analysis and RT-PCR. The chemical compositions of root extracts were detected using GC-MS.
RESULTS: The proliferation of MCF-7 cells was inhibited with the IC50 values of 35 and 30 μg/mL, respectively, for methanol and ethyl acetate root extracts. The average inhibition of HeLa cells was ∼25%. Induction of apoptosis in MCF-7 was supported by chromatin condensation, down-regulation of BCL2 and unaltered expression of BAX. However, only ethyl acetate extract caused the loss of mitochondrial membrane potential. GC-MS analysis revealed the roots extracts were rich with terpenoids and phytosterols.
DISCUSSION AND CONCLUSIONS: The results demonstrated that root extracts promote apoptosis by suppressing BCL2 via mitochondria-dependent or independent manner. The identified compounds might work solely or cooperatively in regulating apoptosis. However, further studies are required to address this.

Matched MeSH terms: Inhibitory Concentration 50
Development of a single-chain fragment variable fused-mutant HALT-1 recombinant immunotoxin against G12V mutated KRAS colorectal cancer cells

Teo MYM, Ng JJC, Fong JY, Hwang JS, Song AA, Lim RLH, et al.

PeerJ, 2021;9:e11063.
PMID: 33959410 DOI: 10.7717/peerj.11063

Background: KRAS oncogenes harboring codon G12 and G13 substitutions are considered gatekeeper mutations which drive oncogenesis in many cancers. To date, there are still no target-specific vaccines or drugs available against this genotype, thus reinforcing the need towards the development of targeted therapies such as immunotoxins.
Methods: This study aims to develop a recombinant anti-mKRAS scFv-fused mutant Hydra actinoporin-like-toxin-1 (mHALT-1) immunotoxin that is capable of recognizing and eradicating codon-12 mutated k-ras antigen abnormal cells. One G13D peptide mimotope (164-D) and one G12V peptide mimotope (68-V) were designed to elicit antigen specific IgG titres against mutated K-ras antigens in immunised Balb/c mice. The RNA was extracted from splenocytes following ELISA confirmation on post-immunized mice sera and was reverse transcribed into cDNA. The scFv combinatorial library was constructed from cDNA repertoire of variable regions of heavy chain (VH) and light chain (VL) fusions connected by a flexible glycine-serine linker, using splicing by overlap extension PCR (SOE-PCR). Anti-mKRAS G12V and G13D scFvs were cloned in pCANTAB5E phagemid and superinfected with helper phage. After few rounds of bio-panning, a specific mKRAS G12V and G13D scFv antibody against G12V and G13D control mimotope was identified and confirmed using ELISA without any cross-reactivity with other mimotopes or controls. Subsequently, the anti-mKRAS scFv was fused to mHALT-1 using SOE-PCR and cloned in pET22b vector. Expressed recombinant immunotoxins were analyzed for their effects on cell proliferation by the MTT assay and targeted specificity by cell-based ELISA on KRAS-positive and KRAS-negative cancer cells.
Results: The VH and VL genes from spleen RNA of mice immunized with 164-D and 68-V were amplified and randomly linked together, using SOE-PCR producing band sizes about 750 bp. Anti-mKRAS G12V and G13D scFvs were constructed in phagemid pCANTAB5E vectors with a library containing 3.4 × 106 and 2.9 × 106 individual clones, respectively. After three rounds of bio-panning, the anti-mKRAS G12V-34 scFv antibody against G12V control mimotope was identified and confirmed without any cross-reactivity with other controls using ELISA. Anti-mKRAS G12V-34 scFv fragment was fused to mHALT-1 toxin and cloned in pET22b vector with expression as inclusion bodies in E. coli BL21(DE3) (molecular weight of ~46.8 kDa). After successful solubilization and refolding, the mHALT-1-scFv immunotoxin exhibited cytotoxic effects on SW-480 colorectal cancer cells with IC50 of 25.39 μg/mL, with minimal cytotoxicity effect on NHDF cells.
Discussion: These results suggested that the development of such immunotoxins is potentially useful as an immunotherapeutic application against KRAS-positive malignancies.

Matched MeSH terms: Inhibitory Concentration 50
Novel furan-containing peptide-based inhibitors of protein arginine deiminase type IV (PAD4)

Teo CY, Tejo BA, Leow ATC, Salleh AB, Abdul Rahman MB

Chem Biol Drug Des, 2017 Dec;90(6):1134-1146.
PMID: 28581157 DOI: 10.1111/cbdd.13033

Protein arginine deiminase type IV (PAD4) is responsible for the posttranslational conversion of peptidylarginine to peptidylcitrulline. Citrullinated protein is the autoantigen in rheumatoid arthritis, and therefore, PAD4 is currently a promising therapeutic target for the disease. Recently, we reported the importance of the furan ring in the structure of PAD4 inhibitors. In this study, the furan ring was incorporated into peptides to act as the "warhead" of the inhibitors for PAD4. IC50 studies showed that the furan-containing peptide-based inhibitors were able to inhibit PAD4 to a better extent than the furan-containing small molecules that were previously reported. The best peptide-based inhibitor inhibited PAD4 reversibly and competitively with an IC50 value of 243.2 ± 2.4 μm. NMR spectroscopy and NMR-restrained molecular dynamic simulations revealed that the peptide-based inhibitor had a random structure. Molecular docking studies showed that the peptide-based inhibitor entered the binding site and interacted with the essential amino acids involved in the catalytic activity. The peptide-based inhibitor could be further developed into a therapeutic drug for rheumatoid arthritis.

Matched MeSH terms: Inhibitory Concentration 50
Fulltext Cytotoxicity and structure-activity relationships of xanthone derivatives from Mesua beccariana, Mesua ferrea and Mesua congestiflora towards nine human cancer cell lines

Teh SS, Ee GC, Mah SH, Lim YM, Ahmad Z

Molecules, 2013 Feb 04;18(2):1985-94.
PMID: 23381024 DOI: 10.3390/molecules18021985

The cytotoxic structure-activity relationships among a series of xanthone derivatives from Mesua beccariana, Mesua ferrea and Mesua congestiflora were studied. Eleven xanthone derivatives identified as mesuarianone (1), mesuasinone (2), mesuaferrin A (3), mesuaferrin B (4), mesuaferrin C (5), 6-deoxyjacareubin (6), caloxanthone C (7), macluraxanthone (8), 1,5-dihydroxyxanthone (9), tovopyrifolin C (10) and α-mangostin (11) were isolated from the three Mesua species. The human cancer cell lines tested were Raji, SNU-1, K562, LS-174T, SK-MEL-28, IMR-32, HeLa, Hep G2 and NCI-H23. Mesuaferrin A (3), macluraxanthone (8) and α-mangostin (11) showed strong cytotoxicities as they possess significant inhibitory effects against all the cell lines. The structure-activity relationship (SAR) study revealed that the diprenyl, dipyrano and prenylated pyrano substituent groups of the xanthone derivatives contributed towards the cytotoxicities.

Matched MeSH terms: Inhibitory Concentration 50
Fulltext Induction of apoptosis by Eurycoma longifolia jack extracts

Tee TT, Azimahtol HL

Anticancer Res, 2005 May-Jun;25(3B):2205-13.
PMID: 16158965

Extracts of the plant Eurycoma longifolia have been shown to possess cytotoxic, antimalarial, anti-ulcer, antipyretic and plant growth inhibition activities. The present study investigated the effects of extracts and their chromatographic fractions from the root of E. longifolia on the growth of a human breast cancer cell line, MCF-7. Our data indicated that E. longifolia extracts and fractions exert a direct antiproliferative activity on MCF-7. The bioassay-guided root fractionation resulted in the isolation of three active fractions, F5, F6 and F7, which displayed IC50 values of (6.17+/-0.38) microg/ml, (4.40+/-0.42) microg/ml and (20.00+/-0.08) microg/ml, respectively. The resultant from F7 purification, F16, exhibited a higher cytotoxic activity towards MCF-7, (IC50=15.23+/-0.66 microg/ml) and a certain degree of selectivity against a normal breast cell line, MCF-10A (IC50=66.31-0.47 microg/ml). F16 significantly increased apoptosis in MCF-7 cells, as evaluated by the Tdt-mediated dUTP nick end labelling assay and nuclear morphology. Western blotting revealed down-regulation of the anti-apoptotic Bcl-2 protein expression. F16, however, did not affect the expression of the pro-apoptotic protein, Bax. These results, therefore, suggest that F16 has antiproliferative effects on MCF-7 cells by inducing apoptosis through the modulation of Bcl-2 protein levels.

Matched MeSH terms: Inhibitory Concentration 50
Xanthenone-based hydrazones as potent α-glucosidase inhibitors: Synthesis, solid state self-assembly and in silico studies

Tariq QU, Malik S, Khan A, Naseer MM, Khan SU, Ashraf A, et al.

Bioorg Chem, 2019 03;84:372-383.
PMID: 30530108 DOI: 10.1016/j.bioorg.2018.11.053

Xanthenone based hydrazone derivatives (5a-n) have been synthesized as potential α-glucosidase inhibitors. All synthesized compounds (5a-n) are characterized by their FTIR, 1H NMR, 13C NMR and HRMS, and in case of 5g also by X-ray crystallographic technique. The compounds unveiled a varying degree of α-glucosidase inhibitory activity when compared with standard acarbose (IC50 = 375.38 ± 0.12 µM). Amongst the series, compound 5l (IC50 = 62.25 ± 0.11 µM) bearing a trifluoromethyl phenyl group is found to be the most active compound. Molecular modelling is performed to establish the binding pattern of the more active compound 5l, which revealed the significance of substitution pattern. The pharmacological properties of molecules are also calculated by MedChem Designer which determines the ADME (absorption, distribution, metabolism, excretion) properties of molecules. The solid state self-assembly of compound 5g is discussed to show the conformation and role of iminoamide moiety in the molecular packing.

Matched MeSH terms: Inhibitory Concentration 50
Fulltext Antioxidant and LC-QToF-MS/MS analysis of polyphenols in polar and non-polar extracts from Strobilanthes crispus and Clinacanthus nutans

Tan, H. M., Leong, K. H., Song, J., Mohd Sufian, N. S. F., Mohd Hazli, U. H. A., Chew, L. Y., et al.

International Food Research Journal, 2020;27(5):903-914.
MyJurnal

Strobilanthes crispus and Clinacanthus nutans are popular herbal plants in the Southeast
Asian region. The present work was aimed at determining the antioxidant activities and the
associated components in the leaf extracts of both species using polar and non-polar solvents
namely water, methanol, ethyl acetate, and hexane. The total phenolic content (TPC) and total
flavonoid content (TFC) were higher in the leaf extracts of S. crispus as compared to C.
nutans. Among the solvents, methanol was the best solvent in extracting the antioxidant
components for S. crispus (TPC: 159.85 ± 0.89 mg GAE/g extract and TFC: 955.47 ± 2.66 mg
RE/g extract). However, for C. nutans, its methanolic extract yielded the highest TPC (36.39
± 0.17 mg GAE/g extract), whereas ethyl acetate yielded the highest TFC (229.61 ± 7.81 mg
RE/g extract). The high levels of both TPC and TFC contributed to the antioxidant activities
of S. crispus extract as reflected in the methanolic extract attaining the highest level of
antioxidant activities, measured by ferric reducing antioxidant power (FRAP) (6.84 ± 1.12
mmol Fe2+/g extract), DPPH radical scavenging (IC50: 203.60 ± 7.28 μg/mL), and Trolox
equivalent antioxidant capacity (TEAC) (1.01 ± 0.01 mmol TE/g extract) assays. This
contrasted with C. nutans which showed lower antioxidant activities owing to its lower TPC
and TFC. Correlation analysis revealed significant correlations (p < 0.05, r = 0.915 - 0.985)
between both TPC and TFC in S. crispus and antioxidant activities. However, only TPC of C.
nutans showed a significant correlation with FRAP values (r = 0.934). Further tentative
identification of the constituents in the extracts using HPLC-ESI-QToF-MS/MS revealed the
existence of 20 polyphenolic compounds in both S. crispus and C. nutans, which were likely
responsible for their antioxidant activities. In addition, 15 polyphenolic compounds classified
as chalcones, isoflavanoids, flavones, and flavonols have not been previously reported in both
species. The methanolic extracts of both species yielded a higher content of antioxidants, with
S. crispus offering a richer source of dietary antioxidants as compared to C. nutans. However,
further study is needed to identify their bioactivities in relation to their bioactive components.

Matched MeSH terms: Inhibitory Concentration 50
Fulltext Antioxidant properties and antiproliferative effect of brewers’ rice extract (temukut) on selected cancer cell lines

Tan, B.L., Suhaniza, H.J., Lai, C. C., Norazalina, S., Roselina, K., Norhaizan, M.E.

International Food Research Journal, 2013;20(5):2117-2124.
MyJurnal

Temukut, or brewers’ rice, is a mixture of broken rice, rice bran, and rice germ. Extensive studies have been conducted on rice bran, which possesses various health benefits. Temukut, however has been less well studied. The present study aimed to investigate the antioxidant and growth inhibition properties of temukut extract using colon cancer (HT-29), ovary cancer (Caov-3), and liver cancer (HepG2) cell lines. The antioxidant activity was determined by the β-carotene bleaching assay, analysis of the DPPH radical scavenging capacity, and a FRAP assay. The total phenolic compounds, oryzanol, vitamin E, and phytic acid levels in temukut were also investigated. The antiproliferative activity was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. There was a significant difference in the cytotoxicity of two types of temukut extract (water and methanol) for HT-29 and Caov-3 cells (p < 0.05) but not for HepG2 cells. The HepG2 cell line is the least sensitive to temukut, (IC50 = 55.30 μg/mL), whereas the highest sensitivity was observed in Caov-3 cells (IC50 =36.67 μg/mL). No cytotoxic effect of temukut was observed on normal cells (BalBlc3T3). Although the content of the phytochemicals studied (total phenolic compounds, vitamin E, oryzanol, and phytic acid) in temukut was lower than that in rice bran, as has been previously reported, the present study demonstrated temukut’s potential to inhibit the proliferation of HT-29, Caov-3, and HepG2 cells.

Matched MeSH terms: Inhibitory Concentration 50
Fulltext Cytoprotective and Cytotoxic Effects of Rice Bran Extracts in Rat H9c2(2-1) Cardiomyocytes

Tan XW, Bhave M, Fong AY, Matsuura E, Kobayashi K, Shen LH, et al.

Oxid Med Cell Longev, 2016;2016:6943053.
PMID: 27239253 DOI: 10.1155/2016/6943053

This study was aimed at preliminarily assessing the cytoprotective and antioxidative effects of rice bran extracts (RBEs) from a Sarawak local rice variety (local name: "BJLN") and a commercial rice variety, "MR219," on oxidative stress in rat H9c2(2-1) cardiomyocytes. The cardiomyocytes were incubated with different concentrations of RBE and hydrogen peroxide (H2O2), respectively, to identify their respective IC50 values and safe dose ranges. Two nonlethal and close-to-IC50 doses of RBE were selected to evaluate their respective effects on H2O2 induced oxidative stress in cardiomyocytes. Both RBEs showed dose-dependent cytotoxicity effects on cardiomyocytes. H2O2 induction of cardiomyocytes pretreated with RBE further revealed the dose-dependent cytoprotective and antioxidative effects of RBE via an increase in IC50 values of H2O2. Preliminary analyses of induction effects of RBE and H2O2 on cellular antioxidant enzyme, catalase (CAT), also revealed their potential in regulating these activities and expression profile of related gene on oxidative stress in cardiomyocytes. Pretreated cardiomyocytes significantly upregulated the enzymatic activity and expression level of CAT under the exposure of H2O2 induced oxidative stress. This preliminary study has demonstrated the potential antioxidant effects of RBE in alleviating H2O2-mediated oxidative injuries via upregulation in enzymatic activities and expression levels of CAT.

Matched MeSH terms: Inhibitory Concentration 50
Chemical composition and cytotoxic activity of Garcinia atroviridis Griff. ex T. Anders. essential oils in combination with tamoxifen

Tan WN, Lim JQ, Afiqah F, Nik Mohamed Kamal NNS, Abdul Aziz FA, Tong WY, et al.

Nat Prod Res, 2018 Apr;32(7):854-858.
PMID: 28782393 DOI: 10.1080/14786419.2017.1361951

Garcinia atroviridis Griff. ex T. Anders. is used as a medication agent in folkloric medicine. The present study was to examine the chemical composition of the stem bark and leaf of G. atroviridis as well as their cytotoxic effects against MCF-7 cells. The constituents obtained by hydrodistillation were identified using GC-MS. The stem bark oil (EO-SB) composed mainly the palmitoleic acid (51.9%) and palmitic acid (21.9%), while the leaf oil (EO-L) was dominated by (E)-β-farnesene (58.5%) and β-caryophyllene (16.9%). Treatment of MCF-7 cells using EO-L (100 μg/mL) caused more than 50% cell death while EO-SB did not induce cytotoxic effect. EO-L has stimulated the growth of BEAS-2B normal cells, but not in MCF-7 cancerous cells. The IC50 of EO-L in MCF-7 and BEAS-2B cells were 71 and 95 μg/mL, respectively. A combination treatment of EO-L and tamoxifen induced more cell death than the treatment with drug alone at lower doses.

Matched MeSH terms: Inhibitory Concentration 50
Fulltext Identification of Antidiabetic Metabolites from Paederia foetida L. Twigs by Gas Chromatography-Mass Spectrometry-Based Metabolomics and Molecular Docking Study

Tan DC, Kassim NK, Ismail IS, Hamid M, Ahamad Bustamam MS

Biomed Res Int, 2019;2019:7603125.
PMID: 31275982 DOI: 10.1155/2019/7603125

Paederia foetida L. (Rubiaceae) is a climber which is widely distributed in Asian countries including Malaysia. The plant is traditionally used to treat various diseases including diabetes. This study is to evaluate the enzymatic inhibition activity of Paederia foetida twigs extracts and to identify the metabolites responsible for the bioactivity by gas chromatography-mass spectrometry (GC-MS) metabolomics profiling. Three different twig extracts, namely, hexane (PFH), chloroform (PFC), and methanol (PFM), were submerged for their α-amylase and α-glucosidase inhibition potential in 5 replicates for each. Results obtained from the loading column scatter plot of orthogonal partial least square (OPLS) model revealed the presence of 12 bioactive compounds, namely, dl-α-tocopherol, n-hexadecanoic acid, 2-hexyl-1-decanol, stigmastanol, 2-nonadecanone, cholest-8(14)-en-3-ol, 4,4-dimethyl-, (3β,5α)-, stigmast-4-en-3-one, stigmasterol, 1-ethyl-1-tetradecyloxy-1-silacyclohexane, ɣ-sitosterol, stigmast-7-en-3-ol, (3β,5α,24S)-, and α-monostearin. In silico molecular docking was carried out using the crystal structure α-amylase (PDB ID: 4W93) and α-glucosidase (PDB ID: 3WY1). α-Amylase-n-hexadecanoic acid exhibited the lowest binding energy of -2.28 kcal/mol with two hydrogen bonds residue, namely, LYS178 and TYR174, along with hydrophobic interactions involving PRO140, TRP134, SER132, ASP135, and LYS172. The binding interactions of α-glucosidase-n-hexadecanoic acid complex ligand also showed the lowest binding energy among 5 major compounds with the energy value of -4.04 kcal/mol. The complex consists of one hydrogen bond interacting residue, ARG437, and hydrophobic interactions with ALA444, ASP141, GLN438, GLU432, GLY374, LEU373, LEU433, LYS352, PRO347, THR445, HIS348, and PRO351. The study provides informative data on the potential antidiabetic inhibitors identified in Paederia foetida twigs, indicating the plant has the therapeutic effect properties to manage diabetes.

Matched MeSH terms: Inhibitory Concentration 50
Fulltext Inhibition of enterovirus 71 (EV-71) infections by a novel antiviral peptide derived from EV-71 capsid protein VP1

Tan CW, Chan YF, Sim KM, Tan EL, Poh CL

PLoS One, 2012;7(5):e34589.
PMID: 22563456 DOI: 10.1371/journal.pone.0034589

Enterovirus 71 (EV-71) is the main causative agent of hand, foot and mouth disease (HFMD). In recent years, EV-71 infections were reported to cause high fatalities and severe neurological complications in Asia. Currently, no effective antiviral or vaccine is available to treat or prevent EV-71 infection. In this study, we have discovered a synthetic peptide which could be developed as a potential antiviral for inhibition of EV-71. Ninety five synthetic peptides (15-mers) overlapping the entire EV-71 capsid protein, VP1, were chemically synthesized and tested for antiviral properties against EV-71 in human Rhabdomyosarcoma (RD) cells. One peptide, SP40, was found to significantly reduce cytopathic effects of all representative EV-71 strains from genotypes A, B and C tested, with IC(50) values ranging from 6-9.3 µM in RD cells. The in vitro inhibitory effect of SP40 exhibited a dose dependent concentration corresponding to a decrease in infectious viral particles, total viral RNA and the levels of VP1 protein. The antiviral activity of SP40 peptide was not restricted to a specific cell line as inhibition of EV-71 was observed in RD, HeLa, HT-29 and Vero cells. Besides inhibition of EV-71, it also had antiviral activities against CV-A16 and poliovirus type 1 in cell culture. Mechanism of action studies suggested that the SP40 peptide was not virucidal but was able to block viral attachment to the RD cells. Substitutions of arginine and lysine residues with alanine in the SP40 peptide at positions R3A, R4A, K5A and R13A were found to significantly decrease antiviral activities, implying the importance of positively charged amino acids for the antiviral activities. The data demonstrated the potential and feasibility of SP40 as a broad spectrum antiviral agent against EV-71.

Matched MeSH terms: Inhibitory Concentration 50
Polysulfonate suramin inhibits Zika virus infection

Tan CW, Sam IC, Chong WL, Lee VS, Chan YF

Antiviral Res, 2017 07;143:186-194.
PMID: 28457855 DOI: 10.1016/j.antiviral.2017.04.017

Zika virus (ZIKV) is an arthropod-borne flavivirus that causes newborn microcephaly and Guillian-Barré syndrome in adults. No therapeutics are available to treat ZIKV infection or other flaviviruses. In this study, we explored the inhibitory effect of glycosaminoglycans and analogues against ZIKV infection. Highly sulfated heparin, dextran sulfate and suramin significantly inhibited ZIKV infection in Vero cells. De-sulfated heparin analogues lose inhibitory effect, implying that sulfonate groups are critical for viral inhibition. Suramin, an FDA-approved anti-parasitic drug, inhibits ZIKV infection with 3-5 log10 PFU viral reduction with IC50value of ∼2.5-5 μg/ml (1.93 μM-3.85 μM). A time-of-drug-addition study revealed that suramin remains potent even when administrated at 1-24 hpi. Suramin inhibits ZIKV infection by preventing viral adsorption, entry and replication. Molecular dynamics simulation revealed stronger interaction of suramin with ZIKV NS3 helicase than with the envelope protein. Suramin warrants further investigation as a potential antiviral candidate for ZIKV infection. Heparan sulfate (HS) is a cellular attachment receptor for multiple flaviviruses. However, no direct ZIKV-heparin interaction was observed in heparin-binding analysis, and downregulate or removal of cellular HS with sodium chlorate or heparinase I/III did not inhibit ZIKV infection. This indicates that cell surface HS is not utilized by ZIKV as an attachment receptor.

Matched MeSH terms: Inhibitory Concentration 50
Fulltext Cytotoxic and anticancer properties of the Malaysian mangrove pit viper (Trimeresurus purpureomaculatus) venom and its disintegrin (purpureomaculin)

Tan CH, Liew JL, Navanesan S, Sim KS, Tan NH, Tan KY

J Venom Anim Toxins Incl Trop Dis, 2020;26:e20200013.
PMID: 32742279 DOI: 10.1590/1678-9199-JVATITD-2020-0013

Background: The Asiatic pit vipers from the Trimeresurus complex are medically important venomous snakes. These pit vipers are often associated with snakebite that leads to fatal coagulopathy and tissue necrosis. The cytotoxic venoms of Trimeresurus spp.; however, hold great potential for the development of peptide-based anticancer drugs.
Methods: This study investigated the cytotoxic effect of the venom from Trimeresurus purpureomaculatus, the mangrove pit viper (also known as shore pit viper) which is native in Malaysia, across a panel of human cancer cell lines from breast, lung, colon and prostate as well as the corresponding normal cell lines of each tissue.
Results: The venom exhibited dose-dependent cytotoxic activities on all cell lines tested, with median inhibition concentrations (IC50) ranging from 0.42 to 6.98 µg/mL. The venom has a high selectivity index (SI = 14.54) on breast cancer cell line (MCF7), indicating that it is significantly more cytotoxic toward the cancer than to normal cell lines. Furthermore, the venom was fractionated using C18 reversed-phase high-performance liquid chromatography and the anticancer effect of each protein fraction was examined. Fraction 1 that contains a hydrophilic low molecular weight (approximately 7.5 kDa) protein was found to be the most cytotoxic and selective toward the breast cancer cell line (MCF7). The protein was identified using liquid chromatography-tandem mass spectrometry as a venom disintegrin, termed purpureomaculin in this study.
Conclusion: Taken together, the findings revealed the potent and selective cytotoxicity of a disintegrin protein isolated from the Malaysian T. purpureomaculatus venom and suggested its anticancer potential in drug discovery.

Matched MeSH terms: Inhibitory Concentration 50
6-Shogaol inhibits breast and colon cancer cell proliferation through activation of peroxisomal proliferator activated receptor γ (PPARγ)

Tan BS, Kang O, Mai CW, Tiong KH, Khoo AS, Pichika MR, et al.

Cancer Lett, 2013 Aug 9;336(1):127-39.
PMID: 23612072 DOI: 10.1016/j.canlet.2013.04.014

6-Shogaol has been shown to possess many antitumor properties including inhibition of cancer cell growth, inhibition of cancer metastasis, induction of apoptosis in cancer cells and induction of cancer cell differentiation. Despite its prominent antitumor effects, the direct molecular target of 6-shogaol has remained elusive. To identify the direct targets of 6-shogaol, a comprehensive antitumor profile of 6-shogaol (NSC752389) was tested in the NCI-60 cell line in an in vitro screen. The results show that 6-shogaol is COMPARE negative suggesting that it functions via a mechanism of action distinct from existing classes of therapeutic agents. Further analysis using microarray gene profiling and Connectivity Map analysis showed that MCF-7 cells treated with 6-shogaol display gene expression signatures characteristic of peroxisome proliferator activated receptor γ (PPARγ) agonists, suggesting that 6-shogaol may activate the PPARγ signaling pathway for its antitumor effects. Indeed, treatment of MCF-7 and HT29 cells with 6-shogaol induced PPARγ transcriptional activity, suppressed NFκB activity, and induced apoptosis in breast and colon cancer cells in a PPARγ-dependent manner. Furthermore, 6-shogaol is capable of binding to PPARγ with a binding affinity comparable to 15-delta prostaglandin J2, a natural ligand for PPARγ. Together, our findings suggest that the antitumor effects of 6-shogaol are mediated through activation of PPARγ and imply that activation of PPARγ might be beneficial for breast and colon cancer treatment.

Matched MeSH terms: Inhibitory Concentration 50

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