Displaying publications 121 - 134 of 134 in total

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  1. 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: Caspase 3
  2. Fulltext Formononetin: A Review of Its Anticancer Potentials and Mechanisms
    Tay KC, Tan LT, Chan CK, Hong SL, Chan KG, Yap WH, et al.
    Front Pharmacol, 2019;10:820.
    PMID: 31402861 DOI: 10.3389/fphar.2019.00820
    Cancer, a complex yet common disease, is caused by uncontrolled cell division and abnormal cell growth due to a variety of gene mutations. Seeking effective treatments for cancer is a major research focus, as the incidence of cancer is on the rise and drug resistance to existing anti-cancer drugs is major concern. Natural products have the potential to yield unique molecules and combinations of substances that may be effective against cancer with relatively low toxicity/better side effect profile compared to standard anticancer therapy. Drug discovery work with natural products has demonstrated that natural compounds display a wide range of biological activities correlating to anticancer effects. In this review, we discuss formononetin (C16H12O4), which originates mainly from red clovers and the Chinese herb Astragalus membranaceus. The compound comes from a class of 7-hydroisoflavones with a substitution of methoxy group at position 4. Formononetin elicits antitumorigenic properties in vitro and in vivo by modulating numerous signaling pathways to induce cell apoptosis (by intrinsic pathway involving Bax, Bcl-2, and caspase-3 proteins) and cell cycle arrest (by regulating mediators like cyclin A, cyclin B1, and cyclin D1), suppress cell proliferation [by signal transducer and activator of transcription (STAT) activation, phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT), and mitogen-activated protein kinase (MAPK) signaling pathway], and inhibit cell invasion [by regulating growth factors vascular endothelial growth factor (VEGF) and Fibroblast growth factor 2 (FGF2), and matrix metalloproteinase (MMP)-2 and MMP-9 proteins]. Co-treatment with other chemotherapy drugs such as bortezomib, LY2940002, U0126, sunitinib, epirubicin, doxorubicin, temozolomide, and metformin enhances the anticancer potential of both formononetin and the respective drugs through synergistic effect. Compiling the evidence thus far highlights the potential of formononetin to be a promising candidate for chemoprevention and chemotherapy.
    Matched MeSH terms: Caspase 3
  3. Lipopolysaccharide Pre-conditioning Attenuates Pro-inflammatory Responses and Promotes Cytoprotective Effect in Differentiated PC12 Cell Lines via Pre-activation of Toll-Like Receptor-4 Signaling Pathway Leading to the Inhibition of Caspase-3/Nuclear Factor-κappa B Pathway
    Sangaran PG, Ibrahim ZA, Chik Z, Mohamed Z, Ahmadiani A
    Front Cell Neurosci, 2020;14:598453.
    PMID: 33551748 DOI: 10.3389/fncel.2020.598453
    Lipopolysacharide (LPS) pre-conditioning (PC), has been shown to exert protective effects against cytotoxic effects. Therefore, we hypothesized, the tolerance produced by LPS PC will be resulted by the alterations and modifications in gene and protein expression. With reference to the results of MTT assays, AO/PI staining, and Annexin V-FITC analyses of LPS concentration (0.7815-50 μg/mL) and time-dependent (12-72 h) experiments, the pre-exposure to 3 μg/mL LPS for 12 h protected the differentiated PC12 cells against 0.75 mg/mL LPS apoptotic concentration. LPS-treated cells secreted more inflammatory cytokines like IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-6, IL-17, IFN-γ, and TNF-α than LPS-PC cells. The production of inflammatory mediators ROS and NO was also higher in the LPS-induced cells compared to LPS-PC cells. Conversely, anti-inflammatory cytokines (like IL-10, IL-13, CNTF, and IL-1Ra) were upregulated in the LPS-PC cells but not in the LPS-induced cells. Meanwhile, the LPS initiated caspase-8 which in turn activates effector caspase 3/7. When the activities of caspases in the LPS-induced cells were inhibited using z-VADfmk and z-DEVDfmk, the expressions of c-MYC and Hsp70 were increased, but p53 was reduced. The potential molecules associated with protective and destructive effect was measured by RT2 Profiler PCR array to elucidate the signaling pathways and suggested inhibition NF-κB/caspase-3 signaling pathway regulates the cytoprotective genes and proto-oncogenes. In conclusion, this study provides a basis for future research to better understand the molecular mechanism underlying LPS pre-conditioning /TLR4 pre-activation and its functional role in offering cytoprotective response in neuronal environment.
    Matched MeSH terms: Caspase 3
  4. Phyllanthus niruri leaves aqueous extract improves kidney functions, ameliorates kidney oxidative stress, inflammation, fibrosis and apoptosis and enhances kidney cell proliferation in adult male rats with diabetes mellitus
    Giribabu N, Karim K, Kilari EK, Salleh N
    J Ethnopharmacol, 2017 Jun 09;205:123-137.
    PMID: 28483637 DOI: 10.1016/j.jep.2017.05.002
    ETHNOPHARMACOLOGICAL RELEVANCE: Phylanthus niruri has been used to treat ailments related to the urogenital organs. In this study, this herb was hypothesized to help to ameliorate kidney disease in diabetes mellitus (DM).

    AIMS: To investigate P. niruri leaves aqueous extract (PN) effects on kidney functions, histopathological changes and levels of oxidative stress, inflammation, fibrosis, apoptosis and proliferation in DM.

    METHODS: PN was orally administered to streptozotocin-nicotinamide-induced male diabetic rats for 28 days. At the end of the treatment, fasting blood glucose (FBG) and kidney functions were measured. Kidney somatic index, histopathological changes and levels of RAGE, Nrf2, oxidative stress markers (TBARS, SOD, CAT and GPx), inflammatory markers (NFkβ-p65, Ikk-β, TNF-α, IL-1β and IL-6), apoptosis markers (caspase-3, caspase-9 and Bax), fibrosis markers (TGF-β1, VEGF and FGF-1) and proliferative markers (PCNA and Ki-67) were determined by biochemical assays, qPCR, Western blotting, immunohistochemistry or immunofluorescence.

    RESULTS: Administration of PN helps to maintain near normal FBG, creatinine clearance (CCr), blood urea nitrogen (BUN), BUN/Cr ratio, serum electrolytes, uric acid and urine protein levels in DM. Decreased RAGE, TBARS and increased Nrf2, SOD-1, CAT and GPx-1 were observed in PN-treated diabetic rat kidneys. Expression of inflammatory, fibrosis and apoptosis markers in the kidney reduced but expression of proliferative markers increased following PN treatment. Lesser histopathological changes were observed in the kidney of PN-treated diabetic rats.

    CONCLUSION: PN helps to preserve near normal kidney function and prevents histopathological changes via ameliorating oxidative stress, inflammation, fibrosis and apoptosis while enhancing proliferation of the kidney in DM.

    Matched MeSH terms: Caspase 3
  5. 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.
    Matched MeSH terms: Caspase 3
  6. Effects of tocotrienols on cell viability and apoptosis in normal murine liver cells (BNL CL.2) and liver cancer cells (BNL 1ME A.7R.1), in vitro
    Har CH, Keong CK
    Asia Pac J Clin Nutr, 2005;14(4):374-80.
    PMID: 16326644
    The effects of tocotrienols on murine liver cell viability and their apoptotic events were studied over a dose range of 0-32 microg mL(-1). Normal murine liver cells (BNL CL.2) and murine liver cancer cells (BNL 1ME A.7R.1) were treated with tocotrienols (T(3)), alpha tocopherol (alpha-T) and the chemo drug, Doxorubicin (Doxo, as a positive control). Cell viability assay showed that T(3) significantly (P < or = 0.05) lowered the percentage of BNL 1ME A.7R.1 cell viability in a dose-responsive manner (8-16 microg mL(-1)), whereas T did not show any significant (P>0.05) inhibition in cell viability with increasing treatment doses of 0-16 microg mL(-1). The IC(50) for tocotrienols were 9.8, 8.9, 8.1, 9.7, 8.1 and 9.3 microg mL(-1) at 12, 24, 36, 48, 60 and 72 hours respectively. Early apoptosis was detected 6 hours following T(3) treatment of BNL 1ME A.7R.1 liver cancer cells, using Annexin V-FITC fluorescence microscopy assay for apoptosis, but none were observed for the non-treated liver cancer cells at the average IC(50) of 8.98 microg mL(-1) tocotrienols for liver cancer cells. Several apoptotic bodies were detected in BNL 1ME A.7R.1 liver cancer cells at 6 hours post-treatment with tocotrienols (8.98 microg mL(-1)) using Acridine Orange/Propidium Iodide fluorescence assay. However, only a couple of apoptotic bodies were seen in the non-treated liver cancer cells and the BNL CL.2 normal liver cells. Some mitotic bodies were also observed in the T(3)-treated BNL 1ME A.7R.1 liver cancer cells but were not seen in the untreated BNL 1ME A.7R.1 cells and the BNL CL.2 liver cells. Following T(3)-treatment (8.98 microg mL(-1)) of the BNL 1ME A.7R.1 liver cancer cells, 24.62%, 25.53% and 44.90% of the cells showed elevated active caspase 3 activity at 9, 12 and 24 hours treatment period, respectively. DNA laddering studies indicated DNA fragmentation occurred in the T(3)-treated liver cancer cells, BNL 1ME A.7R.1 but not in non-treated liver cancer cells and the T(3)-treated and non-treated normal liver cells. These results suggest that tocotrienols were able to reduce the cell viability in the murine liver cancer cells at a dose of 8-32 microg mL(-1) and that this decrease in percentage cell viability may be due to apoptosis.
    Matched MeSH terms: Caspase 3
  7. Fulltext Chlorophytum borivilianum (Safed Musli) root extract prevents impairment in characteristics and elevation of oxidative stress in sperm of streptozotocin-induced adult male diabetic Wistar rats
    Giribabu N, Kumar KE, Rekha SS, Muniandy S, Salleh N
    BMC Complement Altern Med, 2014;14:291.
    PMID: 25104050 DOI: 10.1186/1472-6882-14-291
    We hypothesized that C. borivilianum root, known to improve male reproductive performance, prevents impairment in characteristics, morphology and elevation of oxidative stress in sperm of diabetics. We therefore investigated the effect of aqueous root extract of C. borivilianum on these parameters in diabetic rat model.
    Matched MeSH terms: Caspase 3/metabolism
  8. Fingolimod affects gene expression profile associated with LPS-induced memory impairment
    Omidbakhsh R, Rajabli B, Nasoohi S, Khallaghi B, Mohamed Z, Naidu M, et al.
    Exp Brain Res, 2014 Nov;232(11):3687-96.
    PMID: 25098558 DOI: 10.1007/s00221-014-4052-4
    Lipopolysaccharide is an endotoxin to induce sickness behavior in several animal models to explore the link between immune activation and cognition. Neuroinflammation playing a pivotal role in disease progress is evidently influenced by sphingosine-1-phosphate. As one of the sphingosine analogs in clinical use for multiple sclerosis, fingolimod (FTY720) was shown to substantially affect gene expression profile in the context of AD in our previous experiments. The present study was designed to evaluate the drug efficacy in the context of the mere inflammatory context leading to memory impairment. FTY720 was repeatedly administered for a few days before or after intracerebral lipopolysaccharide (LPS) injection in rats. Animal's brains were then assigned to histological as well as multiplex mRNA assay following memory performance test. Both FTY720 pre-treatment and post-treatment were similarly capable of ameliorating LPS-induced memory impairment as assessed by passive avoidance test. Such amending effects may be partly accountable by the concomitant alterations in transcriptional levels of mitogen-activated protein kinases as well as inflammatory genes determined by QuantiGene Plex analysis. These findings confirming FTY720 application benefits suggest its efficacy may not differ significantly while considered either as a preventive or as a therapeutic approach against neuroinflammation.
    Matched MeSH terms: Caspase 3/metabolism
  9. Fulltext Induction of selective cytotoxicity and apoptosis in human T4-lymphoblastoid cell line (CEMss) by boesenbergin a isolated from boesenbergia rotunda rhizomes involves mitochondrial pathway, activation of caspase 3 and G2/M phase cell cycle arrest
    Ng KB, Bustamam A, Sukari MA, Abdelwahab SI, Mohan S, Buckle MJ, et al.
    BMC Complement Altern Med, 2013;13:41.
    PMID: 23432947 DOI: 10.1186/1472-6882-13-41
    Boesenbergia rotunda (Roxb.) Schlecht (family zingiberaceae) is a rhizomatous herb that is distributed from north-eastern India to south-east Asia, especially in Indonesia, Thailand and Malaysia. Previous research has shown that the crude extract of this plant has cytotoxic properties. The current study examines the cytotoxic properties of boesenbergin A isolated from Boesenbergia rotunda.
    Matched MeSH terms: Caspase 3/metabolism*
  10. Fulltext The chemopotential effect of Annona muricata leaves against azoxymethane-induced colonic aberrant crypt foci in rats and the apoptotic effect of Acetogenin Annomuricin E in HT-29 cells: a bioassay-guided approach
    Zorofchian Moghadamtousi S, Rouhollahi E, Karimian H, Fadaeinasab M, Firoozinia M, Ameen Abdulla M, et al.
    PLoS One, 2015;10(4):e0122288.
    PMID: 25860620 DOI: 10.1371/journal.pone.0122288
    Annona muricata has been used in folk medicine for the treatment of cancer and tumors. This study evaluated the chemopreventive properties of an ethyl acetate extract of A. muricata leaves (EEAML) on azoxymethane-induced colonic aberrant crypt foci (ACF) in rats. Moreover, the cytotoxic compound of EEAML (Annomuricin E) was isolated, and its apoptosis-inducing effect was investigated against HT-29 colon cancer cell line using a bioassay-guided approach. This experiment was performed on five groups of rats: negative control, cancer control, EEAML (250 mg/kg), EEAML (500 mg/kg) and positive control (5-fluorouracil). Methylene blue staining of colorectal specimens showed that application of EEAML at both doses significantly reduced the colonic ACF formation compared with the cancer control group. Immunohistochemistry analysis showed the down-regulation of PCNA and Bcl-2 proteins and the up-regulation of Bax protein after administration of EEAML compared with the cancer control group. In addition, an increase in the levels of enzymatic antioxidants and a decrease in the malondialdehyde level of the colon tissue homogenates were observed, suggesting the suppression of lipid peroxidation. Annomuricin E inhibited the growth of HT-29 cells with an IC50 value of 1.62 ± 0.24 μg/ml after 48 h. The cytotoxic effect of annomuricin E was further substantiated by G1 cell cycle arrest and early apoptosis induction in HT-29 cells. Annomuricin E triggered mitochondria-initiated events, including the dissipation of the mitochondrial membrane potential and the leakage of cytochrome c from the mitochondria. Prior to these events, annomuricin E activated caspase 3/7 and caspase 9. Upstream, annomuricin E induced a time-dependent upregulation of Bax and downregulation of Bcl-2 at the mRNA and protein levels. In conclusion, these findings substantiate the usage of A. muricata leaves in ethnomedicine against cancer and highlight annomuricin E as one of the contributing compounds in the anticancer activity of A. muricata leaves.
    Matched MeSH terms: Caspase 3/metabolism
  11. BARF1 gene silencing triggers caspase-dependent mitochondrial apoptosis in Epstein-Barr virus-positive malignant cells
    Mohidin TB, Ng CC
    J Biosci, 2015 Mar;40(1):41-51.
    PMID: 25740140
    Epstein-Barr virus (EBV)-encoded BARF1 (BamH1-A Rightward Frame-1) is expressed in EBV-positive malignancies such as nasopharyngeal carcinoma, EBV-associated gastric cancer, B-cell lymphoma and nasal NK/T-cell lymphoma, and has been shown to have an important role in oncogenesis. However, the mechanism by which BARF1 elicits its biological effects is unclear. We investigated the effects of BARF1 silencing on cell proliferation and apoptosis in EBV-positive malignant cells. We observed that BARF1 silencing significantly inhibits cell proliferation and induces apoptosis-mediated cell death by collapsing the mitochondrial membrane potential in AG876 and Hone-Akata cells. BARF1 knockdown up-regulates the expression of pro-apoptotic proteins and downregulates the expression of anti-apoptotic proteins. In BARF1-down-regulated cells, the Bcl-2/BAX ratio is decreased. The caspase inhibitor z-VAD-fmk was found to rescue siBARF1-induced apoptosis in these cells. Immunoblot analysis showed significant increased levels of cleaved caspase 3 and caspase 9. We observed a significant increase in cytochrome c level as well as the formation of apoptosome complex in BARF1-silenced cells. In conclusion, siRNA-mediated BARF1 down-regulation induces caspase-dependent apoptosis via the mitochondrial pathway through modulation of Bcl-2/BAX ratio in AG876 and Hone-Akata cells. Targeting BARF1 using siRNA has the potential to be developed as a novel therapeutic strategy in the treatment of EBV-associated malignancies.
    Matched MeSH terms: Caspase 3/metabolism
  12. A novel synthetic analogue of ω-3 17,18-epoxyeicosatetraenoic acid activates TNF receptor-1/ASK1/JNK signaling to promote apoptosis in human breast cancer cells
    Dyari HRE, Rawling T, Chen Y, Sudarmana W, Bourget K, Dwyer JM, et al.
    FASEB J, 2017 12;31(12):5246-5257.
    PMID: 28798154 DOI: 10.1096/fj.201700033R
    A saturated analog of the cytochrome P450-mediated ω-3-17,18-epoxide of ω-3-eicosapentaenoic acid (C20E) activated apoptosis in human triple-negative MDA-MB-231 breast cancer cells. This study evaluated the apoptotic mechanism of C20E. Increased cytosolic cytochrome c expression and altered expression of pro- and antiapoptotic B-cell lymphoma-2 proteins indicated activation of the mitochondrial pathway. Caspase-3 activation by C20E was prevented by pharmacological inhibition and silencing of the JNK and p38 MAP kinases (MAPK), upstream MAPK kinases MKK4 and MKK7, and the upstream MAPK kinase kinase apoptosis signal-regulating kinase 1 (ASK1). Silencing of the death receptor TNF receptor 1 (TNFR1), but not Fas, DR4, or DR5, and the adapters TRADD and TNF receptor-associated factor 2, but not Fas-associated death domain, prevented C20E-mediated apoptosis. B-cell lymphoma-2 homology 3-interacting domain death agonist (Bid) cleavage by JNK/p38 MAPK linked the extrinsic and mitochondrial pathways of apoptosis. In further studies, an antibody against the extracellular domain of TNFR1 prevented apoptosis by TNF-α but not C20E. These findings suggest that C20E acts intracellularly at TNFR1 to activate ASK1-MKK4/7-JNK/p38 MAPK signaling and to promote Bid-dependent mitochondrial disruption and apoptosis. Inin vivostudies, tumors isolated from C20E-treated nu/nu mice carrying MDA-MB-231 xenografts showed increased TUNEL staining and decreased Ki67 staining, reflecting increased apoptosis and decreased proliferation, respectively. ω-3-Epoxy fatty acids like C20E could be incorporated into treatments for triple-negative breast cancers.-Dyari, H. R. E., Rawling, T., Chen, Y., Sudarmana, W., Bourget, K., Dwyer, J. M., Allison, S. E., Murray, M. A novel synthetic analogue of ω-3 17,18-epoxyeicosatetraenoic acid activates TNF receptor-1/ASK1/JNK signaling to promote apoptosis in human breast cancer cells.
    Matched MeSH terms: Caspase 3/metabolism
  13. Mechanism of Chemoprevention against Colon Cancer Cells Using Combined Gelam Honey and Ginger Extract via mTOR and Wnt/β-catenin Pathways
    Wee LH, Morad NA, Aan GJ, Makpol S, Wan Ngah WZ, Mohd Yusof YA
    Asian Pac J Cancer Prev, 2015;16(15):6549-56.
    PMID: 26434873
    The PI3K-Akt-mTOR, Wnt/β-catenin and apoptosis signaling pathways have been shown to be involved in genesis of colorectal cancer (CRC). The aim of this study was to elucidate whether combination of Gelam honey and ginger might have chemopreventive properties in HT29 colon cancer cells by modulating the mTOR, Wnt/β-catenin and apoptosis signaling pathways. Treatment with Gelam honey and ginger reduced the viability of the HT29 cells dose dependently with IC50 values of 88 mg/ml and 2.15 mg/ml respectively, their while the combined treatment of 2 mg/ml of ginger with 31 mg/ml of Gelam honey inhibited growth of most HT29 cells. Gelam honey, ginger and combination induced apoptosis in a dose dependent manner with the combined treatment exhibiting the highest apoptosis rate. The combined treatment downregulated the gene expressions of Akt, mTOR, Raptor, Rictor, β-catenin, Gsk3β, Tcf4 and cyclin D1 while cytochrome C and caspase 3 genes were shown to be upregulated. In conclusion, the combination of Gelam honey and ginger may serve as a potential therapy in the treatment of colorectal cancer through inhibiton of mTOR, Wnt/β catenin signaling pathways and induction of apoptosis pathway.
    Matched MeSH terms: Caspase 3/genetics
  14. Fulltext Artonin E Induces Apoptosis via Mitochondrial Dysregulation in SKOV-3 Ovarian Cancer Cells
    Rahman MA, Ramli F, Karimian H, Dehghan F, Nordin N, Ali HM, et al.
    PLoS One, 2016;11(3):e0151466.
    PMID: 27019365 DOI: 10.1371/journal.pone.0151466
    Artonin E is a prenylated flavonoid isolated from the stem bark of Artocarpus elasticus Reinw.(Moraceae). This study aimed to investigate the apoptotic mechanisms induced by artonin E in a metastatic human ovarian cancer cell line SKOV-3 in vitro. MTT assay, clonogenic assay, acridine orange and propidium iodide double staining, cell cycle and annexin V analyses were performed to explore the mode of artonin E-induced cell death at different time points. DNA laddering, activation of caspases-3, -8, and -9, multi-parametric cytotoxicity-3 analysis by high-content screening, measurement of reactive oxygen species generation, and Western blot were employed to study the pathways involved in the apoptosis. MTT results showed that artonin E inhibited the growth of SKOV-3 cells, with IC50 values of 6.5±0.5 μg/mL after 72 h treatment, and showed less toxicity toward a normal human ovarian cell line T1074, with IC50 value of 32.5±0.5 μg/mL. Results showed that artonin E induced apoptosis and cell cycle arrest at the S phase. This compound also promoted the activation of caspases-3, -8, and -9. Further investigation into the depletion of mitochondrial membrane potential and release of cytochrome c revealed that artonin E treatment induced apoptosis via regulation of the expression of pro-survival and pro-apoptotic Bcl-2 family members. The expression levels of survivin and HSP70 proteins were also down regulated in SKOV-3 cells treated with artonin E. We propose that artonin E induced an antiproliferative effect that led to S phase cell cycle arrest and apoptosis through dysregulation of mitochondrial pathways, particularly the pro- and anti-apoptosis signaling pathways.
    Matched MeSH terms: Caspase 3/metabolism
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