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Contrasting sirtuin and poly(ADP-ribose)polymerase activities of selected 2,4,6-trisubstituted benzimidazoles

Yeong KY, Tan SC, Mai CW, Leong CO, Chung FF, Lee YK, et al.

Chem Biol Drug Des, 2018 01;91(1):213-219.
PMID: 28719017 DOI: 10.1111/cbdd.13072

Both sirtuin and poly(ADP-ribose)polymerase (PARP) family of enzymes utilize NAD+ as co-substrate. Inhibitors of sirtuins and PARPs are important tools in drug discovery as they are reported to be linked to multiple diseases such as cancer. New potent sirtuin inhibitors (2,4,6-trisubstituted benzimidazole) were discovered from reported PARP inhibitor scaffold. Interestingly, the synthesized compounds have contrasting sirtuin and PARP-1 inhibitory activities. We showed that modification on benzimidazoles may alter their selectivity toward sirtuin or PARP-1 enzymes. This offers an opportunity for further discovery and development of new promising sirtuin inhibitors. Molecular docking studies were carried out to aid the rationalization of these observations. Preliminary antiproliferative studies of selected compounds against nasopharyngeal cancer cells also showed relatively promising results.

Matched MeSH terms: Adenosine Diphosphate Ribose
Induction of ROS‑mediated cell death and activation of the JNK pathway by a sulfonamide derivative

Ahmad R, Vaali-Mohammed MA, Elwatidy M, Al-Obeed O, Al-Khayal K, Eldehna WM, et al.

Int J Mol Med, 2019 Jul 23.
PMID: 31364730 DOI: 10.3892/ijmm.2019.4284

The emergence of colorectal cancer in developed nations can be attributed to dietary habits, smoking, a sedentary lifestyle and obesity. Several treatment regimens are available for primary and metastatic colorectal cancer; however, these treatment options have had limited impact on cure and disease‑free survival, and novel agents need to be developed for treating colorectal cancer. Thus, the objective of this study was to explore the anticancer mechanism of a benzo(1,3)dioxol‑based derivative of sulfonamide. The compound's inhibitory effect on cell proliferation was determined using the MTT assay and the xCelligence RTDP machine. Alternations in the expression of Bcl‑2 and inhibitor of apoptosis protein families were detected by western blotting. Apoptotic marker protein expression, including cytochrome c and cleaved poly(ADP‑ribose)polymerase was measured in the cytosolic extract of cells. Apoptosis and necrosis were detected by flow cytometry and immunofluorescence. Reactive oxygen species (ROS), and activation of caspase‑3 and caspase‑7 were measured using flow cytometry. Activation of the JNK pathway was detected by western blotting. We investigated the molecular mechanism of action of the sulfonamide derivative on colorectal cancer cells and found that the compound possesses a potent anticancer effect, which is primarily exerted by inducing apoptosis and necrosis. Interestingly, this compound exhibited little antiproliferative effect against the normal colonic epithelial cell line FHC. Furthermore, our results showed that the compound could significantly increase ROS production. Apoptosis induction could be attenuated by the free oxygen radical scavenger N‑acetyl cysteine (NAC), indicating that the antiproliferative effect of this compound on colorectal cancer cells is at least partially dependent on the redox balance. In addition, JNK signaling was activated by treatment with this derivative, which led to the induction of apoptosis. On the contrary, a JNK inhibitor could suppress the cell death induced by this compound. Our findings thus suggested a novel anticancer mechanism of a benzo(1,3)dioxol‑based derivative of sulfonamide for colorectal cancer cells and may have therapeutic potential for the treatment of colorectal cancer; however, further investigation is required.

Matched MeSH terms: Adenosine Diphosphate Ribose
Fulltext Discovery of Ruthenium(II) Metallocompound and Olaparib Synergy for Cancer Combination Therapy

Yusoh NA, Tiley PR, James SD, Harun SN, Thomas JA, Saad N, et al.

J Med Chem, 2023 May 25;66(10):6922-6937.
PMID: 37185020 DOI: 10.1021/acs.jmedchem.3c00322

Synergistic drug combinations can extend the use of poly(ADP-ribose) polymerase inhibitors (PARPi) such as Olaparib to BRCA-proficient tumors and overcome acquired or de novo drug resistance. To identify new synergistic combinations for PARPi, we screened a "micro-library" comprising a mix of commercially available drugs and DNA-binding ruthenium(II) polypyridyl complexes (RPCs) for Olaparib synergy in BRCA-proficient triple-negative breast cancer cells. This identified three hits: the natural product Curcumin and two ruthenium(II)-rhenium(I) polypyridyl metallomacrocycles. All combinations identified were effective in BRCA-proficient breast cancer cells, including an Olaparib-resistant cell line, and spheroid models. Mechanistic studies indicated that synergy was achieved via DNA-damage enhancement and resultant apoptosis. Combinations showed low cytotoxicity toward non-malignant breast epithelial cells and low acute and developmental toxicity in zebrafish embryos. This work identifies RPC metallomacrocycles as a novel class of agents for cancer combination therapy and provides a proof of concept for the inclusion of metallocompounds within drug synergy screens.
Fulltext Regulation of apoptotic effects by erythrocarpine E, a cytotoxic limonoid from Chisocheton erythrocarpus in HSC-4 human oral cancer cells

Nagoor NH, Shah Jehan Muttiah N, Lim CS, In LL, Mohamad K, Awang K

PLoS One, 2011;6(8):e23661.
PMID: 21858194 DOI: 10.1371/journal.pone.0023661

The aim of this study was to determine the cytotoxic and apoptotic effects of erythrocarpine E (CEB4), a limonoid extracted from Chisocheton erythrocarpus on human oral squamous cell carcinoma. Based on preliminary dimethyl-2-thiazolyl-2,5-diphenyl-2H-tetrazolium bromide (MTT) assays, CEB4 treated HSC-4 cells demonstrated a cytotoxic effect and inhibited cell proliferation in a time and dose dependent manner with an IC(50) value of 4.0±1.9 µM within 24 h of treatment. CEB4 was also found to have minimal cytotoxic effects on the normal cell line, NHBE with cell viability levels maintained above 80% upon treatment. Annexin V-fluorescein isothiocyanate (FITC), poly-ADP ribose polymerase (PARP) cleavage and DNA fragmentation assay results showed that CEB4 induces apoptosis mediated cell death. Western blotting results demonstrated that the induction of apoptosis by CEB4 appeared to be mediated through regulation of the p53 signalling pathway as there was an increase in p53 phosphorylation levels. CEB4 was also found to up-regulate the pro-apoptotic protein, Bax, while down-regulating the anti-apoptotic protein, Bcl-2, suggesting the involvement of the intrinsic mitochondrial pathway. Reduced levels of initiator procaspase-9 and executioner caspase-3 zymogen were also observed following CEB4 exposure, hence indicating the involvement of cytochrome c mediated apoptosis. These results demonstrate the cytotoxic and apoptotic ability of erythrocarpine E, and suggest its potential development as a cancer chemopreventive agent.
Fulltext Effect of ribose-induced Maillard reaction on physical and mechanical properties of bovine gelatin films prepared by oven drying

Samira, S., Thuan-Chew Tan, T.C., Azhar, M.E.

International Food Research Journal, 2014;21(1):269-276.
MyJurnal

The effect of ribose-induced Maillard reaction on the physical and mechanical properties of gelatin films was investigated. Bovine gelatin solution (5 g/100 mL) containing glycerol and sorbitol (1:1) was mixed with 20% (R20), 40% ribose (R40), or 40% sucrose (S40) (weight % is based on gelatin dry weight) followed by heating (90ºC, 2 h) and oven drying to produce dried gelatin films. R20 and R40 films were brownish in color with lower light transparency, while CF (control film; without sugars) and S40 were colorless and had higher transparency. Tensile strength and Young Modulus values of the films were in the order; CF > R20 > R40 > S40, while elongation at break was in the order; R40 > S40 > R20 > CF. Water solubility and swelling percentages of the films were in the order; CF > S40 > R20 > R40, indicating the occurrence of insoluble “Maillard complexes” within R20 and R40 films. R20 and R40 films showed maximum light absorption at wavelength of 200 − 350 nm, whilst S40 and CF showed maximum absorbance at 200 − 250 nm. The addition of ribose yielded gelatin films with increased protection against UV light, even though the presence of sugars might had disrupted the inter connection of junction zones and decrease in mechanical properties. Occurrence of the Maillard reaction within R20 and R40 films could be the main reason for differences in physical and mechanical properties of films containing ribose that were formed from heated film-forming solutions.

Matched MeSH terms: Ribose
Fulltext Characterization of the ribose-induced maillard reaction in minced chicken and minced pork: a potential means of species differentiation

Tan, T.C., Abbas, F.M.A., Azhar, M.E.

International Food Research Journal, 2012;19(2):481-489.
MyJurnal

The addition of ribose to minced chicken or minced pork followed by heating at 95oC yielded minced
meat with different pH, colour (CIE L*, b*) and absorbance values that can be used as indicators for species differentiation. The higher intensity of the Maillard reaction parameters in minced chicken was due to the higher protein and lysine contents, and the presence of more water-soluble proteins within the minced chicken during heating. Cluster analysis using Maillard reaction parameters showed that the two types of minced meat could be classified into two different groups. A confidence interval (95% confidence) analysis revealed that the absorbance, CIE L* values, and CIE b* values could be used as indicators for differentiation between the two types of minced meat, as the intervals between these Maillard reaction parameters for the two minced meats were far apart.

Matched MeSH terms: Ribose
Cardiac glycoside cerberin exerts anticancer activity through PI3K/AKT/mTOR signal transduction inhibition

Hossan MS, Chan ZY, Collins HM, Shipton FN, Butler MS, Rahmatullah M, et al.

Cancer Lett, 2019 07 01;453:57-73.
PMID: 30930233 DOI: 10.1016/j.canlet.2019.03.034

Natural products possess a significant role in anticancer therapy and many currently-used anticancer drugs are of natural origin. Cerberin (CR), a cardenolide isolated from the fruit kernel of Cerbera odollam, was found to potently inhibit cancer cell growth (GI50 values 60% bioavailability and rapid absorption; doses of 1-10 mg/kg CR were predicted to maintain efficacious unbound plasma concentrations (>GI50 value). CR's potent and selective anti-tumour activity, and its targeting of key signalling mechanisms pertinent to tumourigenesis support further preclinical evaluation of this cardiac glycoside.
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.
Effect of cooking on physical and sensory properties of fresh yellow alkaline noodles prepared by partial substitution of wheat flour with soy protein isolate and treated with cross-linking agents

Yeoh SY, Alkarkhi AF, Ramli SB, Easa AM

Int J Food Sci Nutr, 2011 Jun;62(4):410-7.
PMID: 21306189 DOI: 10.3109/09637486.2010.539555

Yellow alkaline noodles (YAN) prepared by partial substitution of wheat flour with soy protein isolate and treated with microbial transglutaminase (MTG) and ribose were investigated during cooking. Cooking caused an increase in lightness but a decrease in redness and yellowness, pH, tensile strength and elasticity values of noodles. The extents of these changes were influenced by formulation and cross-linking treatments. The pH and lightness for YAN-ribose were lowest but the yellowness and redness were the highest whilst the tensile strength and elasticity values remained moderate. For YAN-MTG, the color and pH values were moderate, but tensile strength and elasticity values were the highest. YAN prepared with both cross-linking agents had physical values between YAN-ribose and YAN-MTG. Although certain sensory parameters showed differences in score, the overall acceptability of all 10-min-cooked YAN was similar. It is possible to employ cross-linking agents to improve physical properties of cooked YAN.

Matched MeSH terms: Ribose
Using response surface methodology to optimize process parameters and cross-linking agents for production of combined-cross-linked bovine serum albumin gels

Gan CY, Alkarkhi AF, Easa AM

J Biosci Bioeng, 2009 Apr;107(4):366-72.
PMID: 19332294 DOI: 10.1016/j.jbiosc.2008.12.007

D-optimal design was employed to optimize the mixture of cross-linking agents formulation: microbial transglutaminase (MTGase) and ribose, and the processing parameters (i.e. incubation and heating time) in the mixture in order to obtain combined-cross-linked bovine serum albumin gels that have high gel strength, pH close to neutral and yet medium in browning. Analysis of variance (ANOVA) showed that the contribution of quadratic term to the model over the linear was significant for pH and L* value, whereas linear model was significant for gel strength. Optimization study using response surface methodology (RSM) was performed to the mixture components and process variables and the optimum conditions obtained were: MTGase of 1.34-1.43 g/100 mL, ribose of 1.07-1.16 g/100 mL, incubation time of 5 h at 40 degrees C and heating time of 3 h at 90 degrees C.

Matched MeSH terms: Ribose/chemistry
Assessment of cross-linking in combined cross-linked soy protein isolate gels by microbial transglutaminase and Maillard reaction

Gan CY, Cheng LH, Easa AM

J Food Sci, 2009 Mar;74(2):C141-6.
PMID: 19323728 DOI: 10.1111/j.1750-3841.2009.01053.x

Soy protein isolate (SPI) gels were produced using single cross-linking agents (SCLA) of microbial transglutaminase (MTG) via incubation for 5 or 24 h (SCLA-MTG). When powdered SCLA-MTG gels were heated for 2 h with ribose (R2) (2 g/100 mL), dark brown gels were formed, and these were designated as combined cross-linking agent (CCLA) gels: MTG5(R2) and MTG24(R2). The results showed that the levels of Maillard-derived browning and cross-links of MTG5(R2) and MTG24(R2) gels were significantly (P < 0.05) lower than a control gel produced without MTG (SCLA-R2) even though the percentage of ribose remaining after heating of these gels was similar, indicating that a similar amount of ribose was consumed during heating. epsilon-(gamma-glutamyl)lysine bonds formed during incubation of SPI with MTG may have reduced the free amino group of SPI to take part in the Maillard reaction; nevertheless, ribose took part in the Maillard reaction and initiated the Maillard cross-linkings within the CCLA gels.

Matched MeSH terms: Ribose/analysis
In-vitro digestibility and amino acid composition of soy protein isolate cross-linked with microbial transglutaminase followed by heating with ribose

Gan CY, Cheng LH, Azahari B, Easa AM

Int J Food Sci Nutr, 2009;60 Suppl 7:99-108.
PMID: 19194813 DOI: 10.1080/09637480802635090

Cross-linked soy protein isolate (SPI) gels were produced via single-treatment of SPI with microbial transglutaminase (MTG) for 5 h or 24 h, or with ribose for 2 h, or via combined-treatments of SPI with MTG followed by heating with ribose. Assessment of gel strength and solubility concluded that measures which increased protein cross-links resulted in improved gel strength; however, in most cases the digestibility and amino acid content of the gels were reduced. The combined treated gel of SPI/MTG for 24 h/ribose was more easily digested by digestive enzymes and retained higher amounts of amino acids compared with the control Maillard gels of SPI with ribose. MTG consumed lysine and glutamine and reduced the availability of amino acids for the Maillard reaction with ribose. MTG was able to preserve the nutritional value of SPI against the destructive effect of the Maillard reaction and cross-links.

Matched MeSH terms: Ribose/chemistry*
Assessment of the ribose-induced Maillard reaction as a means of gelatine powder identification and quality control

Tan TC, AlKarkhi AF, Easa AM

Food Chem, 2012 Oct 15;134(4):2430-6.
PMID: 23442706 DOI: 10.1016/j.foodchem.2012.04.049

The addition of ribose to bovine or porcine gelatine solutions followed by heating at 95 °C yielded brown solutions with different pH, colour (CIE L(*) and b(*)) and absorbance (A(420*) values. These differences were used for gelatine powder identification, differentiation and quality control. Differentiation analysis of the Maillard reaction parameters was conducted using cluster analysis (CA) and confidence intervals (CI). The potential use of the method as a quality control procedure was evaluated by using statistical process control (SPC). CA revealed that the two types of gelatine could be classified into two different groups. CI (95% confidence) revealed that the absorbance and colour values could be used as indicators for differentiation between the two types of gelatine because the intervals between the Maillard reaction parameters of the samples were far apart. The methodology demonstrated good reproducibility because it behaved predictably based on the X¯-S charts generated from the SPC charts.

Matched MeSH terms: Ribose/chemistry*
In vitro assessment of ribose modified two-step etch-and-rinse dentine adhesive

Daood U, Tsoi JKH, Neelakantan P, Matinlinna JP, Omar HAK, Al-Nabulsi M, et al.

Dent Mater, 2018 08;34(8):1175-1187.
PMID: 29779627 DOI: 10.1016/j.dental.2018.05.005

OBJECTIVE: Collagen fibrils aid in anchoring resin composite restorations to the dentine substrate. The aim of the study was to investigate effect of non-enzymatic glycation on bond strength and durability of demineralized dentine specimens in a modified two-step etch-and-rinse dentine adhesive.
METHODS: Dentine surfaces were etched with 37% phosphoric acid, bonded with respective in vitro ethanol and acetone adhesives modified with (m/m, 0, 1%, 2% and 3% ribose), restored with restorative composite-resin, and sectioned into resin-dentine slabs and beams to be stored for 24h or 12 months in artificial saliva. Bond-strength testing was performed with bond failure analysis. Pentosidine assay was performed on demineralized ribose modified dentine specimens with HPLC sensitive fluorescent detection. The structural variations of ribose-modified dentine were analysed using TEM and human dental pulpal cells were used for cell viability. Three-point bending test of ribose-modified dentine beams were performed and depth of penetration of adhesives evaluated with micro-Raman spectroscopy. The MMP-2 and cathepsin K activities in ribose-treated dentine powder were also quantified using ELISA. Bond strength data was expressed using two-way ANOVA followed by Tukey's test. Paired T tests were used to analyse the specimens for pentosidine crosslinks. The modulus of elasticity and dentinal MMP-2 and cathepsin K concentrations was separately analyzed using one-way ANOVA.
RESULTS: The incorporation of RB in the experimental two-step etch-and-rinse adhesive at 1% improved the adhesive bond strength without adversely affecting the degree of polymerisation. The newly developed adhesive increases the resistance of dentine collagen to degradation by inhibiting endogenous matrix metalloproteinases and cysteine cathepsins. The application of RB to acid-etched dentine helps maintain the mechanical properties.
SIGNIFICANCE: The incorporation of 1%RB can be considered as a potential candidate stabilizing resin dentine bond.

Matched MeSH terms: Ribose/chemistry*
Molecular structure, chemical properties and biological activities of Pinto bean pod polysaccharide

Kamarudin F, Gan CY

Int J Biol Macromol, 2016 Jul;88:280-7.
PMID: 27044345 DOI: 10.1016/j.ijbiomac.2016.04.003

Pinto bean pod polysaccharide (PBPP) was successfully extracted with yield of 38.5g/100g and the PBPP gave total carbohydrate and uronic acid contents of 286.2mg maltose equivalent/g and 374.3mgGal/g, respectively. The Mw of PBPP was 270.6kDa with intrinsic viscosity of 0.262dm(3)/g, which composed of mannose (2.5%), galacturonic acid (15.0%), rhamnose (4.0%), glucose (9.0%), galactose (62.2%), xylose (2.9%) and arabinose (4.3%) with trace amount of ribose and fucose. The result suggested that PBPP has a spherical conformation with a highly branched structure. Fourier Transform Infrared analysis showed that PBPP has a similar structure as commercial pectin with an esterification degree of 59.9%, whereas scanning electron microscopy study showed that the crude polysaccharide formed a thin layer of film that was made of multiple micro strands of fibre. PBPP exhibited substantial free radical scavenging activity (7.7%), metal reducing capability (2.04mmol/dm(3)) and α-amylase inhibitory activity (97.6%) at a total amount of 1mg. PBPP also exhibited high water- and oil-holding capacities (3.6g/g and 2.8g/g, respectively). At a low concentration, PBPP exhibited emulsifying activity of 39.6% with stability of 38.6%. Apart from that, PBPP was able to show thickening capability at low concentration (0.005kg/dm(3)).

Matched MeSH terms: Ribose
Fulltext Synergy of ruthenium metallo-intercalator, [Ru(dppz)2(PIP)]2+, with PARP inhibitor Olaparib in non-small cell lung cancer cells

Yusoh NA, Chia SL, Saad N, Ahmad H, Gill MR

Sci Rep, 2023 Jan 26;13(1):1456.
PMID: 36702871 DOI: 10.1038/s41598-023-28454-x

Poly(ADP-ribose) polymerase (PARP) are critical DNA repair enzymes that are activated as part of the DNA damage response (DDR). Although inhibitors of PARP (PARPi) have emerged as small molecule drugs and have shown promising therapeutic effects, PARPi used as single agents are clinically limited to patients with mutations in germline breast cancer susceptibility gene (BRCA). Thus, novel PARPi combination strategies may expand their usage and combat drug resistance. In recent years, ruthenium polypyridyl complexes (RPCs) have emerged as promising anti-cancer candidates due to their attractive DNA binding properties and distinct mechanisms of action. Previously, we reported the rational combination of the RPC DNA replication inhibitor [Ru(dppz)2(PIP)]2+ (dppz = dipyrido[3,2-a:2',3'-c]phenazine, PIP = 2-(phenyl)-imidazo[4,5-f][1,10]phenanthroline), "Ru-PIP", with the PARPi Olaparib in breast cancer cells. Here, we expand upon this work and examine the combination of Ru-PIP with Olaparib for synergy in lung cancer cells, including in 3D lung cancer spheroids, to further elucidate mechanisms of synergy and additionally assess toxicity in a zebrafish embryo model. Compared to single agents alone, Ru-PIP and Olaparib synergy was observed in both A549 and H1975 lung cancer cell lines with mild impact on normal lung fibroblast MRC5 cells. Employing the A549 cell line, synergy was confirmed by loss in clonogenic potential and reduced migration properties. Mechanistic studies indicated that synergy is accompanied by increased double-strand break (DSB) DNA damage and reactive oxygen species (ROS) levels which subsequently lead to cell death via apoptosis. Moreover, the identified combination was successfully able to inhibit the growth of A549 lung cancer spheroids and acute zebrafish embryos toxicity studies revealed that this combination showed reduced toxicity compared to single-agent Ru-PIP.
Fulltext Combining PARP Inhibition with Platinum, Ruthenium or Gold Complexes for Cancer Therapy

Yusoh NA, Ahmad H, Gill MR

ChemMedChem, 2020 Nov 18;15(22):2121-2135.
PMID: 32812709 DOI: 10.1002/cmdc.202000391

Platinum drugs are heavily used first-line chemotherapeutic agents for many solid tumours and have stimulated substantial interest in the biological activity of DNA-binding metal complexes. These complexes generate DNA lesions which trigger the activation of DNA damage response (DDR) pathways that are essential to maintain genomic integrity. Cancer cells exploit this intrinsic DNA repair network to counteract many types of chemotherapies. Now, advances in the molecular biology of cancer has paved the way for the combination of DDR inhibitors such as poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) and agents that induce high levels of DNA replication stress or single-strand break damage for synergistic cancer cell killing. In this review, we summarise early-stage, preclinical and clinical findings exploring platinum and emerging ruthenium anti-cancer complexes alongside PARPi in combination therapy for cancer and also describe emerging work on the ability of ruthenium and gold complexes to directly inhibit PARP activity.
Fulltext F16, a fraction from Eurycoma longifolia jack extract, induces apoptosis via a caspase-9-independent manner in MCF-7 cells

Tee TT, Cheah YH, Hawariah LP

Anticancer Res, 2007 Sep-Oct;27(5A):3425-30.
PMID: 17970090

F16 is a plant-derived pharmacologically active fraction extracted from Eurycoma longifolia Jack. Previously, we have reported that F16 inhibited the proliferation of MCF-7 human breast cancer cells by inducing apoptotic cell death while having some degree of cytoselectivity on a normal human breast cell line, MCF-10A. In this study, we attempted to further elucidate the mode of action of F16. We found that the intrinsic apoptotic pathway was invoked, with the reduction of Bcl-2 protein. Then, executioner caspase-7 was cleaved and activated in response to F16 treatment. Furthermore, apoptosis in the MCF- 7 cells was accompanied by the specific proteolytic cleavage of poly(ADP-ribose) polymerase-1 (PARP-1). Surprisingly, caspase-9 and p53 were unchanged with F16 treatment. We believe that the F16-induced apoptosis in MCF-7 cells occurs independently of caspase-9 and p53. Taken together, these results suggest that F16 from E. longifolia exerts anti-proliferative action and growth inhibition on MCF-7 cells through apoptosis induction and that it may have anticancer properties.
Fulltext Antiproliferative property and apoptotic effect of xanthorrhizol on MDA-MB-231 breast cancer cells

Cheah YH, Nordin FJ, Tee TT, Azimahtol HL, Abdullah NR, Ismail Z

Anticancer Res, 2008 Nov-Dec;28(6A):3677-89.
PMID: 19189649

Xanthorrhizol is a natural sesquiterpenoid compound isolated from the rhizome of Curcuma xanthorrhizza Roxb (Zingerberaceae). Recent studies of xanthorrhizol in cell cultures strongly support the role of xanthorrhizol as an antiproliferative agent. In our study, we tested the antiproliferative effect of xanthorrhizol using different breast cancer cell lines. The invasive breast cancer cell line, MDA-MB-231, was then selected for further investigations. Treatment with xanthorrhizol caused 50% growth inhibition on MDA-MB-231 cells at 8.67 +/- 0.79 microg/ml as determined by sulforhodamine B (SRB) assay. Hoechst 33258 nuclear staining assay showed the rate of apoptosis of MDA-MB-231 cells to increase in response to xanthorrhizol treatment. Immunofluorescence staining using antibody MitoCapture and fluorescein isothiocyanate (FITC)-labeled cytochrome c revealed the possibility of altered mitochondrial transmembrane potential and the release of cytochrome c respectively. This was further confirmed by Western-blotting, where cytochrome c was showed to migrate from mitochondrial fraction to the cytosol fraction of treated MDA-MB-231 cells. Caspase activity assay showed the involvement of caspase-3 and caspase-9, but not caspase-6 or caspase-8 in MDA-MB-231 apoptotic cell death. Subsequently, cleavage of PARP-1 protein is suggested. These data suggest treatment with xanthorrhizol modulates MDA-MB-231 cell apoptosis through the mitochondria-mediated pathway subsequent to the disruption of mitochondrial transmembrane potential, release of cytochrome c, activation of caspase-3 and caspase-9, and the modulation of PARP-1 protein.
A critical role of TRPM2 channel in Aβ42 -induced microglial activation and generation of tumor necrosis factor-α

Alawieyah Syed Mortadza S, Sim JA, Neubrand VE, Jiang LH

Glia, 2018 03;66(3):562-575.
PMID: 29143372 DOI: 10.1002/glia.23265

Amyloid β (Aβ)-induced neuroinflammation plays an important part in Alzheimer's disease (AD). Emerging evidence supports a role for the transient receptor potential melastatin-related 2 (TRPM2) channel in Aβ-induced neuroinflammation, but how Aβ induces TRPM2 channel activation and this relates to neuroinflammation remained poorly understood. We investigated the mechanisms by which Aβ42 activates the TRPM2 channel in microglial cells and the relationships to microglial activation and generation of tumor necrosis factor-α (TNF-α), a key cytokine implicated in AD. Exposure to 10-300 nM Aβ42 induced concentration-dependent microglial activation and generation of TNF-α that were ablated by genetically deleting (TRPM2 knockout ;TRPM2-KO) or pharmacologically inhibiting the TRPM2 channel, revealing a critical role of this channel in Aβ42 -induced microglial activation and generation of TNF-α. Mechanistically, Aβ42 activated the TRPM2 channel via stimulating generation of reactive oxygen species (ROS) and activation of poly(ADPR) polymerase-1 (PARP-1). Aβ42 -induced generation of ROS and activation of PARP-1 and TRPM2 channel were suppressed by inhibiting protein kinase C (PKC) and NADPH oxidases (NOX). Aβ42 -induced activation of PARP-1 and TRPM2 channel was also reduced by inhibiting PYK2 and MEK/ERK. Aβ42 -induced activation of PARP-1 was attenuated by TRPM2-KO and moreover, the remaining PARP-1 activity was eliminated by inhibiting PKC and NOX, but not PYK2 and MEK/ERK. Collectively, our results suggest that PKC/NOX-mediated generation of ROS and subsequent activation of PARP-1 play a role in Aβ42 -induced TRPM2 channel activation and TRPM2-dependent activation of the PYK2/MEK/ERK signalling pathway acts as a positive feedback to further facilitate activation of PARP-1 and TRPM2 channel. These findings provide novel insights into the mechanisms underlying Aβ-induced AD-related neuroinflammation.

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