Displaying publications 1 - 20 of 94 in total

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  1. Fulltext Investigation into the Molecular Mechanisms underlying the Anti-proliferative and Anti-tumorigenesis activities of Diosmetin against HCT-116 Human Colorectal Cancer
    Koosha S, Mohamed Z, Sinniah A, Alshawsh MA
    Sci Rep, 2019 03 26;9(1):5148.
    PMID: 30914796 DOI: 10.1038/s41598-019-41685-1
    Diosmetin (Dis) is a bioflavonoid with cytotoxicity properties against variety of cancer cells including hepatocarcinoma, breast and colorectal (CRC) cancer. The exact mechanism by which Dis acts against CRC however, still remains unclear, hence in this study, we investigated the possible molecular mechanisms of Dis in CRC cell line, HCT-116. Here, we monitored the viability of HCT-116 cells in the presence of Dis and investigated the underlying mechanism of Dis against HCT-116 cells at the gene and protein levels using NanoString and proteome profiler array technologies. Findings demonstrated that Dis exhibits greater cytotoxic effects towards HCT-116 CRC cells (IC50 = 3.58 ± 0.58 µg/ml) as compared to the normal colon CCD-841 cells (IC50 = 51.95 ± 0.11 µg/ml). Arrests of the cells in G2/M phase confirms the occurrence of mitotic disruption via Dis. Activation of apoptosis factors such as Fas and Bax at the gene and protein levels along with the release of Cytochrome C from mitochondria and cleavage of Caspase cascades indicate the presence of turbulence as a result of apoptosis induction in Dis-treated cells. Moreover, NF-ƙB translocation was inhibited in Dis-treated cells. Our results indicate that Dis can target HCT-116 cells through the mitotic disruption and apoptosis induction.
    Matched MeSH terms: G2 Phase Cell Cycle Checkpoints/drug effects*; M Phase Cell Cycle Checkpoints/drug effects*
  2. Mechanisms of S-phase arrest and mitochondrial dysfunction in complex III by DHODH inhibitors in tumorigenic TNBC cells
    Shahhiran MAA, Abdul Kadir MF, Nor Rashid N, Abdul-Rahman PS, Othman S
    Histochem Cell Biol, 2024 Nov 18;163(1):3.
    PMID: 39557682 DOI: 10.1007/s00418-024-02339-0
    Dihydroorotate dehydrogenase (DHODH) inhibitors have recently gained increasing research interest owing to their potential for treating breast cancers. We explored their effects in different breast cancer subtypes, focusing on mitochondrial dysfunction. The sensitivity of different subtypes to the inhibitors was investigated with respect to DHODH expression, tumorigenic, and receptor status. Analysis of respiratory complexes, cell cycle, reactive oxygen species (ROS), and cell differentiation were performed. Four cell lines with different receptor status were included, namely MCF-7, MDAMB-231, SKBR-3, and MCF-10A. We showed that MCF-7 and MDAMB-231 cells of the subtypes (ER+/PR+/HER2-) and (ER-/PR-/HER2-), respectively, were responsive to brequinar. Brequinar (BQR) caused cell cycle arrest in the S-phase in sensitive subtypes of breast cells but induced cell differentiation only in poorly differentiated breast cells. All cell subtypes showed increased generation of ROS, both intracellular and mitochondrial ROS with a greater increase seen in mitochondrial ROS in response to DHODH inhibitor, subsequently contributing to mitochondrial dysfunction. BQR also disrupts the function of complex III in ER+/PR+ and triple negative breast cancer (TNBC) subtypes. Collectively, we have found that MDAMB-231 TNBC cell was the most affected by DHODH inhibition in terms of sensitivity, cell cycle arrest, induction of cell differentiation, production of ROS, and mitochondrial complexes disruption. In conclusion, these findings suggest that DHODH inhibitors can potentially become a valuable targeted therapy for TNBC subtype and further consolidates its therapeutic potential as part of the combinatorial therapy against this resilient breast cancer subtype.
    Matched MeSH terms: Cell Cycle Checkpoints/drug effects; S Phase Cell Cycle Checkpoints/drug effects
  3. G2/M cell cycle arrest on HT-29 cancer cells and toxicity assessment of triphenylphosphanegold(I) carbonimidothioates, Ph3PAu[SC(OR)=NPh], R=Me, Et, and iPr, during zebrafish development
    Ooi KK, Yeo CI, Mahandaran T, Ang KP, Akim AM, Cheah YK, et al.
    J Inorg Biochem, 2017 01;166:173-181.
    PMID: 27865929 DOI: 10.1016/j.jinorgbio.2016.11.008
    Phosphanegold(I) thiolates, Ph3PAu[SC(OR)=NPh], R=Me (1), Et (2) and iPr (3), were previously shown to be significantly cytotoxic toward HT-29 cancer cells and to induce cell death by both intrinsic and extrinsic apoptotic pathways whereby 1 activated the p73 gene, and each of 2 and 3 activated p53; 2 also caused apoptotic cell death via the c-Jun N-terminal kinase/mitogen-activated protein kinase pathway. Apoptosis pathways have been further evaluated by mitochondrial cytochrome c measurements and annexin V screening, confirming apoptotic pathways of cell death. Cell cycle analysis showed the majority of treated HT-29 cells were arrested at the G2/M checkpoint after 24h; results of both assays were confirmed by changes in populations of relevant genes (PCR array analysis). Cell invasion studies showed inhibition of metastasis through Matrigel™ matrix to 17-22% cf. untreated cells. LC50values were determined in zebrafish (8.36, 8.17, and 7.64μM for 1-3). Finally, the zebrafish tolerated doses of 1 and 2 up to 0.625μM, and 3 was tolerated at even higher doses of up to 1.25μM.
    Matched MeSH terms: G2 Phase Cell Cycle Checkpoints/drug effects*; M Phase Cell Cycle Checkpoints/drug effects*
  4. Fulltext In-Vitro and In-Silico Evaluations of Heterocyclic-Containing Diarylpentanoids as Bcl-2 Inhibitors Against LoVo Colorectal Cancer Cells
    Leong SW, Chia SL, Abas F, Yusoff K
    Molecules, 2020 Aug 26;25(17).
    PMID: 32858795 DOI: 10.3390/molecules25173877
    In the present study, we investigated the in-vitro anti-cancer potential of six diarylpentanoids against a panel of BRAF- and KRAS-mutated colorectal cancer cell lines including T84, SW620, LoVo, HT29, NCI-H508, RKO, and LS411N cells. Structure-activity relationship study suggested that the insertions of tetrahydro-4H-thiopyran-4-one and brominated phenyl moieties are essential for better cytotoxicity. Among the evaluated analogs, 2e has been identified as the lead compound due to its low IC50 values of approximately 1 µM across all cancer cell lines and high chemotherapeutic index of 7.1. Anti-proliferative studies on LoVo cells showed that 2e could inhibit cell proliferation and colony formations by inducing G2/M cell cycle arrest. Subsequent cell apoptosis assay confirmed that 2e is a Bcl-2 inhibitor that could induce intrinsic cell apoptosis by creating a cellular redox imbalance through its direct inhibition on the Bcl-2 protein. Further molecular docking studies revealed that the bromophenyl moieties of 2e could interact with the Bcl-2 surface pocket through hydrophobic interaction, while the tetrahydro-4H-thiopyran-4-one fragment could form additional Pi-sulfur and Pi-alkyl interactions in the same binding site. In all, the present results suggest that 2e could be a potent lead that deserves further modification and investigation in the development of a new Bcl-2 inhibitor.
    Matched MeSH terms: G2 Phase Cell Cycle Checkpoints/drug effects*; M Phase Cell Cycle Checkpoints/drug effects*
  5. Fulltext Anticancer activity of grassy Hystrix brachyura bezoar and its mechanisms of action: An in vitro and in vivo based study
    Khan AYF, Ahmed QU, Narayanamurthy V, Razali S, Asuhaimi FA, Saleh MSM, et al.
    Biomed Pharmacother, 2019 Jun;114:108841.
    PMID: 30981106 DOI: 10.1016/j.biopha.2019.108841
    Porcupine bezoar (PB) is a calcified undigested material generally found in porcupine's (Hystrix brachyura) gastrointestinal tract. The bezoar is traditionally used in South East Asia and Europe for the treatment of cancer, poisoning, dengue, typhoid, etc. However, limited scientific studies have been performed to verify its anticancer potential to substantiate its traditional claims in the treatment of cancers. Hence, this study was aimed at investigating the in vitro and in vivo anticancer properties of two grassy PB aqueous extract (PB-A and PB-B) using A375 cancer cell line and zebrafish model, respectively. This paper presents the first report on in vitro A375 cell viability assay, apoptosis assay, cell cycle arrest assay, migration assay, invasion assay, qPCR experimental assay and in vivo anti-angiogenesis assay using the grassy PBs. Experimental findings revealed IC50 value are 26.59 ± 1.37 μg/mL and 30.12 ± 3.25 μg/mL for PB-A and PB-B respectively. PBs showed anti-proliferative activity with no significant cytotoxic effect on normal human dermal fibroblast (NHDF). PBs were also found to induce apoptosis via intrinsic pathway and arrest cell cycle at G2/M phase. Additionally, the findings indicated its ability to debilitate migration and invasion of A375 cells. Further evaluation using embryo zebrafish model revealed LC50 = 450.0 ± 2.50 μg/mL and 58.7 ± 5.0 μg/mL for PB-A and PB-B which also exerted anti-angiogenesis effect in zebrafish. Moreover, stearic acid, ursodeoxycholic acid and pregnenolone were identified as possible metabolites that might contribute to the anticancer effect of the both PBs. Overall, this study demonstrated that PB-A and PB-B possess potential in vitro and in vivo anticancer effects which are elicited through selective cytotoxic effect, induction of apoptosis, inhibition of migration and invasion and anti-angiogenesis. This study provides scientific evidence that the porcupine bezoar do possess anti-cancer efficacy and further justifies its traditional utility. However, more experiments with higher vertebrae models are still warranted to validate its traditional claims as an anticancer agent.
    Matched MeSH terms: Cell Cycle Checkpoints/drug effects; G2 Phase Cell Cycle Checkpoints/drug effects
  6. Cetuximab-conjugated chitosan-pectinate (modified) composite nanoparticles for targeting colon cancer
    Sabra R, Billa N, Roberts CJ
    Int J Pharm, 2019 Dec 15;572:118775.
    PMID: 31678385 DOI: 10.1016/j.ijpharm.2019.118775
    In the present study, we successfully developed a cetuximab-conjugated modified citrus pectin-chitosan nanoparticles for targeted delivery of curcumin (Cet-MCPCNPs) for the treatment of colorectal cancer. In vitro analyses revealed that nanoparticles were spherical with size of 249.33 ± 5.15 nm, a decent encapsulation efficiency (68.43 ± 2.4%) and a 'smart' drug release profile. 61.37 ± 0.70% of cetuximab was adsorbed to the surface of the nanoparticles. Cellular uptake studies displayed enhanced internalization of Cet-MCPCNPs in Caco-2 (EGFR +ve) cells, which ultimately resulted in a significant reduction in cancer cell propagation. The cell cycle analysis indicated that Cet- MCPCNPs induced cell death in enhanced percentage of Caco-2 cells by undergoing cell cycle arrest in the G2/M phase. These data suggest that Cet-MCPCNPs represent a new and promising targeting approach for the treatment of colorectal cancer.
    Matched MeSH terms: Cell Cycle Checkpoints/drug effects; G2 Phase Cell Cycle Checkpoints/drug effects
  7. Fulltext Artonin E induces p53-independent G1 cell cycle arrest and apoptosis through ROS-mediated mitochondrial pathway and livin suppression in MCF-7 cells
    Etti IC, Rasedee A, Hashim NM, Abdul AB, Kadir A, Yeap SK, et al.
    Drug Des Devel Ther, 2017;11:865-879.
    PMID: 28356713 DOI: 10.2147/DDDT.S124324
    Artonin E is a prenylated flavonoid compound isolated from the stem bark of Artocarpus elasticus. This phytochemical has been previously reported to be drug-like with full compliance to Lipinski's rule of five and good physicochemical properties when compared with 95% of orally available drugs. It has also been shown to possess unique medicinal properties that can be utilized in view of alleviating most human disease conditions. In this study, we investigated the cytotoxic mechanism of Artonin E in MCF-7 breast cancer cells, which has so far not been reported. In this context, Artonin E significantly suppressed the breast cancer cell's viability while inducing apoptosis in a dose-dependent manner. This apoptosis induction was caspase dependent, and it is mediated mainly through the intrinsic pathway with the elevation of total reactive oxygen species. Gene and protein expression studies revealed significant upregulation of cytochrome c, Bax, caspases 7 and 9, and p21 in Artonin E-treated MCF-7 cells, while MAPK and cyclin D were downregulated. Livin, a member of the inhibitors of apoptosis, whose upregulation has been noted to precede chemotherapeutic resistance and apoptosis evasion was remarkably repressed. In all, Artonin E stood high as a potential agent in the treatment of breast cancer.
    Matched MeSH terms: Cell Cycle Checkpoints/drug effects; G1 Phase Cell Cycle Checkpoints/drug effects*
  8. Fulltext Dicranopteris linearis extract inhibits the proliferation of human breast cancer cell line (MDA-MB-231) via induction of S-phase arrest and apoptosis
    Baharuddin AA, Roosli RAJ, Zakaria ZA, Md Tohid SF
    Pharm Biol, 2018 Dec;56(1):422-432.
    PMID: 30301390 DOI: 10.1080/13880209.2018.1495748
    CONTEXT: Dicranopteris linearis (Burm.f.) Underw. (Gleicheniaceae) has been scientifically proven to exert various pharmacological activities. Nevertheless, its anti-proliferative potential has not been extensively investigated.

    OBJECTIVE: To investigate the anti-proliferative potential of D. linearis leaves and determine possible mechanistic pathways.

    MATERIALS AND METHODS: MTT assay was used to determine the cytotoxic effects of D. linearis methanol (MEDL) and petroleum ether (PEEDL) extracts at concentrations of 100, 50, 25, 12.5, 6.25 and 3.125 µg/mL against a panel of cancer cell lines (breast [MCF-7 and MDA-MB-231], cervical [HeLa], colon [HT-29], hepatocellular [HepG2] and lung [A549]), as compared to negative (untreated) and positive [5-fluorouracil (5-FU)-treated] control groups. Mouse fibroblast cells (3T3) were used as normal cells. The mode of cell death was examined using morphological analysis via acridine orange (AO) and propidium iodide (PI) double staining. Cell cycle arrest was determined using flow cytometer, followed by annexin V-PI apoptosis detection kit.

    RESULTS: MEDL demonstrated the most significant growth inhibition against MDA-MB-231 cells (IC50 22.4 µg/mL). PEEDL showed no cytotoxic effect. Induction of apoptosis by MEDL was evidenced via morphological analysis and acridine orange propidium iodide staining. MEDL could induce S phase cell cycle arrest after 72 h of incubation. Early apoptosis induction in MDA-MB-231 cells was confirmed by annexin V-FITC and PI staining. Significant increase in apoptotic cells were detected after 24 h of treatment with 15.07% cells underwent apoptosis, and the amount escalated to 18.24% with prolonged 48 h incubation.

    CONCLUSIONS: MEDL has potential as a potent cytotoxic agent against MDA-MB-231 adenocarcinoma.

    Matched MeSH terms: Cell Cycle Checkpoints/drug effects*; S Phase Cell Cycle Checkpoints/drug effects*
  9. Fulltext Induction of Apoptosis and Cytotoxicity by Raphasatin in Human Breast Adenocarcinoma MCF-7 Cells
    Ibrahim MD, Kntayya SB, Mohd Ain N, Iori R, Ioannides C, Abdull Razis AF
    Molecules, 2018 Nov 27;23(12).
    PMID: 30486382 DOI: 10.3390/molecules23123092
    Glucoraphasatin (GRH), a glucosinolate present abundantly in the plants of the Brassicaceae family, is hydrolyzed by myrosinase to raphasatin, which is considered responsible for its cancer chemopreventive activity; however, the underlying mechanisms of action have not been investigated, particularly in human cell lines. The aims of this study are to determine the cytotoxicity of raphasatin, and to evaluate its potential to cause apoptosis and modulate cell cycle arrest in human breast adenocarcinoma MCF-7 cells. The cytotoxicity was determined following incubation of the cells with glucoraphasatin or raphasatin (0⁻100 µM), for 24, 48, and 72 h. GRH displayed no cytotoxicity as exemplified by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. When myrosinase was added to the incubation system to convert GRH to raphasatin, cytotoxicity was evident. Exposure of the cells to raphasatin stimulated apoptosis, as was exemplified by cell shrinkage, membrane blebbing, chromatin condensation, and nuclear fragmentation. Moreover, using Annexin V-FITC assay, raphasatin induced apoptosis, as witnessed by changes in cellular distribution of cells, at different stages of apoptosis; in addition, raphasatin caused the arrest of the MCF-7 cells at the G₂ + M phase. In conclusion, raphasatin demonstrated cancer chemopreventive potential against human breast adenocarcinoma (MCF-7) cells, through induction of apoptosis and cell cycle arrest.
    Matched MeSH terms: G2 Phase Cell Cycle Checkpoints/drug effects; M Phase Cell Cycle Checkpoints/drug effects
  10. Fulltext A review of molecular mechanisms of the anti-leukemic effects of phenolic compounds in honey
    Abubakar MB, Abdullah WZ, Sulaiman SA, Suen AB
    Int J Mol Sci, 2012;13(11):15054-73.
    PMID: 23203111 DOI: 10.3390/ijms131115054
    Hematologic malignancies constitute about 9% of all new cases of cancers as reported via the GLOBOCAN series by International Agency for Research on Cancer (IARC) in 2008. So far, the conventional therapeutic and surgical approaches to cancer therapy have not been able to curtail the rising incidence of cancers, including hematological malignancies, worldwide. The last decade has witnessed great research interest in biological activities of phenolic compounds that include anticancer, anti-oxidation and anti-inflammation, among other things. A large number of anticancer agents combat cancer through cell cycle arrest, induction of apoptosis and differentiation, as well as through inhibition of cell growth and proliferation, or a combination of two or more of these mechanisms. Various phenolic compounds from different sources have been reported to be promising anticancer agents by acting through one of these mechanisms. Honey, which has a long history of human consumption both for medicinal and nutritional uses, contains a variety of phenolic compounds such as flavonoids, phenolic acids, coumarins and tannins. This paper presents a review on the molecular mechanisms of the anti-leukemic activity of various phenolic compounds on cell cycle, cell growth and proliferation and apoptosis, and it advocates that more studies should be conducted to determine the potential role of honey in both chemoprevention and chemotherapy in leukemia.
    Matched MeSH terms: Cell Cycle Checkpoints/drug effects
  11. Possible Anticancer Mechanisms of Some Costus speciosus Active Ingredients Concerning Drug Discovery
    El-Far AH, Badria FA, Shaheen HM
    Curr Drug Discov Technol, 2016;13(3):123-143.
    PMID: 27515456
    Costus speciosus is native to South East Asia, especially found in India, Srilanka, Indonesia and Malaysia. C. speciosus have numerous therapeutic potentials against a wide variety of complains. The therapeutic properties of C. speciosus are attributed to the presence of various ingredients such as alkaloids, flavonoids, glycosides, phenols, saponins, sterols and sesquiterpenes. This review presented the past, present, and the future status of C. speciosus active ingredients to propose a future use as a potential anticancer agent. All possible up-regulation of cellular apoptotic molecules as p53, p21, p27, caspases, reactive oxygen species (ROS) generation and others attribute to the anticancer activity of C. speciosus along the down-regulation of anti-apoptotic agents such as Akt, Bcl2, NFKB, STAT3, JAK, MMPs, actin, surviving and vimentin. Eventually, we recommend further investigation of different C. speciosus extracts, using some active ingredients and evaluate the anticancer effect of these chemicals against different cancers.
    Matched MeSH terms: Cell Cycle Checkpoints/drug effects
  12. Synthesis and formulation studies of griseofulvin analogues with improved solubility and metabolic stability
    Petersen AB, Andersen NS, Konotop G, Hanafiah NH, Raab MS, Krämer A, et al.
    Eur J Med Chem, 2017 Apr 21;130:240-247.
    PMID: 28258034 DOI: 10.1016/j.ejmech.2017.02.055
    Griseofulvin (1) is an important antifungal agent that has recently received attention due to its antiproliferative activity in mammalian cancer cells. Comprehensive SAR studies have led to the identification of 2'-benzyloxy griseofulvin 2, a more potent analogue with low micromolar anticancer potency in vitro. Analogue 2 was also shown to retard tumor growth through inhibition of centrosomal clustering in murine xenograft models of colon cancer and multiple myeloma. However, similar to griseofulvin, compound 2 exhibited poor metabolic stability and aqueous solubility. In order to improve the poor pharmacokinetic properties, 11 griseofulvin analogues were synthesized and evaluated for biological activity and physiological stabilities including SGF, plasma, and metabolic stability. Finally, the most promising compounds were investigated in respect to thermodynamic solubility and formulation studies. The 2'-benzylamine analogue 10 proved to be the most promising compound with low μM in vitro anticancer potency, a 200-fold increase in PBS solubility over compound 2, and with improved metabolic stability. Furthermore, this analogue proved compatible with formulations suitable for both oral and intravenous administration. Finally, 2'-benzylamine analogue 10 was confirmed to induce G2/M cell cycle arrest in vitro.
    Matched MeSH terms: Cell Cycle Checkpoints/drug effects
  13. Fulltext Promotion of HepG2 cell apoptosis by flower of Allium atroviolaceum and the mechanism of action
    Khazaei S, Abdul Hamid R, Mohd Esa N, Ramachandran V, Aalam GT, Etemad A, et al.
    BMC Complement Altern Med, 2017 Feb 10;17(1):104.
    PMID: 28187719 DOI: 10.1186/s12906-017-1594-6
    BACKGROUND: Liver cancer is a high incidence and fatal disease, the fifth most frequent cancer worldwide that is usually diagnosed at an advanced stage. The number of deaths from liver cancer has not declined even following various therapies. Plant secondary metabolites and their semi-synthetic derivatives play a principal role in anti-cancer drug therapy, since they are effective in the treatment of specific characteristics while also reducing side effects. Allium atroviolaceum, a plant of the genus Allium has been used in folk medicine to protect against several diseases. However, cytotoxicity and the anti-proliferative effect of Allium atroviolaceum remain unclear. This work aims to investigate the anticancer properties of Allium atroviolaceum and the mechanism of action.

    METHODS: To evaluate the in vitro cytotoxicity of flower of Allium atroviolaceum, methanol extract at a dose range from 100 to 3.12 μg/ml was assessed against the HepG2 hepatocarcinoma cell line, and also on normal 3T3 cells, by monitoring proliferation using the MTT assay method. A microscopy study was undertaken to observe morphological changes of HepG2 cells after treatment and cell cycle arrest and apoptosis were studied using flow cytometry. The apoptosis mechanism of action was assessed by the level of caspase-3 activity and expression of apoptosis related genes, Bcl-2, Cdk1 and p53. The combination effect of the methanolic extract with doxorubicin was also investigated by determination of a combination index.

    RESULTS: The results demonstrated growth inhibition of cells in both dose- and time-dependent manners, while no cytotoxic effect on normal cell 3T3 was found. The results revealed the occurrence of apoptosis, illustrated by sub-G0 cell cycle arrest, the change in morphological feature and annexin-V and propidium iodide staining, which is correlated with Bcl-2 downregulation and caspase-3 activity, but p53-independent. In addition, a combination of Allium atroviolaceum and doxorubicin led to a significant synergistic effect.

    CONCLUSION: These findings suggest that Allium atroviolaceum flower extract has potential as a potent cytotoxic agent against HepG2 cell lines, as it has commendable anti-proliferative activities against human hepatocarcinoma and it can be considered as an effective adjuvant therapeutic agent after the clinical trials.

    Matched MeSH terms: Cell Cycle Checkpoints/drug effects
  14. Polyalthia longifolia Methanolic Leaf Extracts (PLME) induce apoptosis, cell cycle arrest and mitochondrial potential depolarization by possibly modulating the redox status in hela cells
    Vijayarathna S, Oon CE, Chen Y, Kanwar JR, Sasidharan S
    Biomed Pharmacother, 2017 May;89:499-514.
    PMID: 28249252 DOI: 10.1016/j.biopha.2017.02.075
    Medicinal plants have been accepted as a gold mine, with respect to the diversity of their phytochemicals. Many medicinal plants extracts are potential anticancer agents. Polyalthia longifolia var. angustifolia Thw. (Annonaceae) is one of the most significant native medicinal plants and is found throughout Malaysia. Hence, the present study was intended to assess the anticancer properties of P. longifolia leaf methanolic extract (PLME) and its underlying mechanisms. The Annexin V/PI flow cytometry analysis showed that PLME induces apoptosis in HeLa cells in dose-dependent manner whereas the PI flow cytometric analysis for cell cycle demonstrated the accumulation of cells at sub G0/G1, G0/G1 and G2/M phases. Investigation with JC-1 flow cytometry analysis indicated increase in mitochondria membrane potential depolarisation corresponding to increase in PLME concentrations. PLME was also shown to influence intracellular reactive oxygen species (ROS) by exerting anti-oxidant (half IC50) and pro-oxidant (IC50and double IC50) affect against HeLa cells. PLME treatment also displayed DNA damage in HeLa cells in concentration depended fashion. The proteomic profiling array exposed the expression of pro-apoptotic and anti-apoptotic proteins upon PLME treatment at IC50concentration in HeLa cells. Pro-apoptotic proteins; BAX, BAD, cytochrome c, caspase-3, p21, p27 and p53 were found to be significantly up-regulated while anti-apoptotic proteins; BCL-2 and BCL-w were found to be significantly down-regulated. This investigation postulated the role of p53 into mediating apoptosis, cell cycle arrest and mitochondrial potential depolarisation by modulating the redox status of HeLa cells.
    Matched MeSH terms: Cell Cycle Checkpoints/drug effects*
  15. In silico studies, synthesis and anticancer activity of novel diphenyl ether-based pyridine derivatives
    Verma R, Bairy I, Tiwari M, Bhat GV, Shenoy GG
    Mol Divers, 2019 Aug;23(3):541-554.
    PMID: 30430400 DOI: 10.1007/s11030-018-9889-1
    A series of novel 2-amino-4-(3-hydroxy-4-phenoxyphenyl)-6-(4-substituted phenyl) nicotinonitriles were synthesized and evaluated against HepG2, A-549 and Vero cell lines. Compounds 3b (IC50 16.74 ± 0.45 µM) and 3p (IC50 10.57 ± 0.54 µM) were found to be the most active compounds against A-549 cell line among the evaluated compounds. Further 3b- and 3p-induced apoptosis was characterized by AO/EB (acridine orange/ethidium bromide) nuclear staining method and also by DNA fragmentation study. A decrease in cell viability and initiation of apoptosis was clearly evident through the morphological changes in the A-549 cells treated with 3b and 3p when stained with this method. Fragmentation of DNA into nucleosomes was observed which further confirmed the cell apoptosis in cells treated with compound 3b. Flow cytometry studies confirmed the cell cycle arrest at G2/M phase in A549 cells treated with compound 3b. Further in silico studies performed supported the in vitro anticancer activity of these compounds as depicted by dock score and binding energy values.
    Matched MeSH terms: G2 Phase Cell Cycle Checkpoints/drug effects; M Phase Cell Cycle Checkpoints/drug effects
  16. Fulltext 10H-3,6-Diazaphenothiazine induces G2/M phase cell cycle arrest and caspase-dependent apoptosis and inhibits cell invasion of A2780 ovarian carcinoma cells through the regulation of NF-κB and (BIRC6-XIAP) complexes
    Zhang J, Ming C, Zhang W, Okechukwu PN, Morak-Młodawska B, Pluta K, et al.
    Drug Des Devel Ther, 2017;11:3045-3063.
    PMID: 29123378 DOI: 10.2147/DDDT.S144415
    The asymptomatic properties and high treatment resistance of ovarian cancer result in poor treatment outcomes and high mortality rates. Although the fundamental chemotherapy provides promising anticancer activities, it is associated with severe side effects. The derivative of phenothiazine, namely, 10H-3,6-diazaphenothiazine (PTZ), was synthesized and reported with ideal anticancer effects in a previous paper. In this study, detailed anticancer properties of PTZ was examined on A2780 ovarian cancer cells by investigating the cytotoxicity profiles, mechanism of apoptosis, and cell invasion. Research outcomes revealed PTZ-induced dose-dependent inhibition on A2780 cancer cells (IC50 =0.62 µM), with significant less cytotoxicity toward HEK293 normal kidney cells and H9C2 normal heart cells. Generation of reactive oxygen species (ROS) and polarization of mitochondrial membrane potential (ΔΨm) suggests PTZ-induced cell death through oxidative damage. The RT2 Profiler PCR Array on apoptosis pathway demonstrated PTZ-induced apoptosis via intrinsic (mitochondria-dependent) and extrinsic (cell death receptor-dependent) pathway. Inhibition of NF-κB and subsequent inhibition of (BIRC6-XIAP) complex activities reduced the invasion rate of A2780 cancer cells penetrating through the Matrigel™ Invasion Chamber. Lastly, the cell cycle analysis hypothesizes that the compound is cytostatic and significantly arrests cell proliferation at G2/M phase. Hence, the exploration of the underlying anticancer mechanism of PTZ suggested its usage as promising chemotherapeutic agent.
    Matched MeSH terms: G2 Phase Cell Cycle Checkpoints/drug effects; M Phase Cell Cycle Checkpoints/drug effects
  17. Inducing G2/M Cell Cycle Arrest and Apoptosis through Generation Reactive Oxygen Species (ROS)-Mediated Mitochondria Pathway in HT-29 Cells by Dentatin (DEN) and Dentatin Incorporated in Hydroxypropyl-β-Cyclodextrin (DEN-HPβCD)
    Ashwaq AS, Al-Qubaisi MS, Rasedee A, Abdul AB, Taufiq-Yap YH, Yeap SK
    Int J Mol Sci, 2016 Oct 18;17(10).
    PMID: 27763535
    Dentatin (DEN), purified from the roots of Clausena excavata Burm f., has poor aqueous solubility that reduces its therapeutic application. The aim of this study was to assess the effects of DEN-HPβCD (hydroxypropyl-β-cyclodextrin) complex as an anticancer agent in HT29 cancer cell line and compare with a crystal DEN in dimethyl sulfoxide (DMSO). The exposure of the cancer cells to DEN or DEN-HPβCD complex leads to cell growth inhibition as determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. To analyze the mechanism, in which DEN or DEN-HPβCD complex causes the death in human colon HT29 cancer cells, was evaluated by the enzyme-linked immunosorbent assay (ELIZA)-based assays for caspase-3, 8, 9, and reactive oxygen species (ROS). The findings showed that an anti-proliferative effect of DEN or DEN-HPβCD complex were via cell cycle arrest at the G2/M phase and eventually induced apoptosis through both mitochondrial and extrinsic pathways. The down-regulation of poly(ADP-ribose) polymerase (PARP) which leaded to apoptosis upon treatment, was investigated by Western-blotting. Hence, complexation between DEN and HPβCD did not diminish or eliminate the effective properties of DEN as anticancer agent. Therefore, it would be possible to resolve the conventional and current issues associated with the development and commercialization of antineoplastic agents in the future.
    Matched MeSH terms: G2 Phase Cell Cycle Checkpoints/drug effects*; M Phase Cell Cycle Checkpoints/drug effects*
  18. Fulltext The molecular mechanism of the anticancer effect of Artonin E in MDA-MB 231 triple negative breast cancer cells
    Etti IC, Abdullah R, Kadir A, Hashim NM, Yeap SK, Imam MU, et al.
    PLoS One, 2017;12(8):e0182357.
    PMID: 28771532 DOI: 10.1371/journal.pone.0182357
    Nature has provided us with a wide spectrum of disease healing phytochemicals like Artonin E, obtained from the root bark of Artocarpus elasticus. This molecule had been predicted to be drug-like, possessing unique medicinal properties. Despite strides made in chemotherapy, prognosis of the heterogenous aggressive triple negative breast cancer is still poor. This study was conducted to investigate the mechanism of inhibition of Artonin E, a prenylated flavonoid on MDA-MB 231 triple negative breast cancer cell, with a view of mitigating the hallmarks displayed by these tumors. The anti-proliferative effect, mode of cell death and the mechanism of apoptosis induction were investigated. Artonin E, was seen to effectively relinquish MDA-MB 231 breast cancer cells of their apoptosis evading capacity, causing a half-maximal growth inhibition at low concentrations (14.3, 13.9 and 9.8 μM) after the tested time points (24, 48 and 72 hours), respectively. The mode of cell death was observed to be apoptosis with defined characteristics. Artonin E was seen to induce the activation of both extrinsic and intrinsic caspases initiators of apoptosis. It also enhanced the release of total reactive oxygen species which polarized the mitochondrial membrane, compounding the release of cytochrome c. Gene expression studies revealed the upregulation of TNF-related apoptosis inducing ligand and proapoptotic genes with down regulation of anti-apoptotic genes and proteins. A G2/M cell cycle arrest was also observed and was attributed to the observed upregulation of p21 independent of the p53 status. Interestingly, livin, a new member of the inhibitors of apoptosis was confirmed to be significantly repressed. In all, Artonin E showed the potential as a promising candidate to combat the aggressive triple negative breast cancer.
    Matched MeSH terms: G2 Phase Cell Cycle Checkpoints/drug effects; M Phase Cell Cycle Checkpoints/drug effects
  19. Fulltext Apoptosis Induction by Polygonum minus is related to antioxidant capacity, alterations in expression of apoptotic-related genes, and S-phase cell cycle arrest in HepG2 cell line
    Mohd Ghazali MA, Al-Naqeb G, Krishnan Selvarajan K, Hazizul Hasan M, Adam A
    Biomed Res Int, 2014;2014:539607.
    PMID: 24955361 DOI: 10.1155/2014/539607
    Polygonum minus (Polygonaceae) is a medicinal herb distributed throughout eastern Asia. The present study investigated antiproliferative effect of P. minus and its possible mechanisms. Four extracts (petroleum ether, methanol, ethyl acetate, and water) were prepared by cold maceration. Extracts were subjected to phytochemical screening, antioxidant, and antiproliferative assays; the most bioactive was fractionated using vacuum liquid chromatography into seven fractions (F1-F7). Antioxidant activity was measured via total phenolic content (TPC), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and ferric reducing antioxidant power (FRAP) assays. Antiproliferative activity was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Most active fraction was tested for apoptosis induction and cell cycle arrest in HepG2 cells using flow cytometry and confocal microscopy. Apoptotic-related gene expression was studied by RT-PCR. Ethyl acetate extract was bioactive in initial assays. Its fraction, F7, exhibited highest antioxidant capacity (TPC; 113.16 ± 6.2 mg GAE/g extract, DPPH; EC50: 30.5 ± 3.2 μg/mL, FRAP; 1169 ± 20.3 μmol Fe (II)/mg extract) and selective antiproliferative effect (IC50: 25.75 ± 1.5 μg/mL). F7 induced apoptosis in concentration- and time-dependent manner and caused cell cycle arrest at S-phase. Upregulation of proapoptotic genes (Bax, p53, and caspase-3) and downregulation of antiapoptotic gene, Bcl-2, were observed. In conclusion, F7 was antiproliferative to HepG2 cells by inducing apoptosis, cell cycle arrest, and via antioxidative effects.
    Matched MeSH terms: Cell Cycle Checkpoints/drug effects*
  20. Neuroprotective effects of orientin on hydrogen peroxide‑induced apoptosis in SH‑SY5Y cells
    Law BN, Ling AP, Koh RY, Chye SM, Wong YP
    Mol Med Rep, 2014 Mar;9(3):947-54.
    PMID: 24366367 DOI: 10.3892/mmr.2013.1878
    Neurodegenerative diseases remain a global issue which affects the ageing population. Efforts towards determining their aetiologies to understand their pathogenic mechanisms are underway in order to identify a pathway through which therapeutic measures can be applied. One such pathogenic mechanism, oxidative stress (OS), is widely considered to be involved in neurodegenerative disease. Antioxidants, most notably flavonoids, have promising potential for therapeutic use as shown in in vitro and in vivo studies. In view of the importance of flavonoids for combating OS, this study investigated the neuroprotective effects of orientin, which has been reported to be capable of crossing the blood‑brain barrier. The maximum non‑toxic dose (MNTD) of orientin against SH‑SY5Y neuroblastoma cells was determined using a 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide (MTT) assay. The effects of the MNTD and the half MNTD (½MNTD) of orientin on cell cycle progression and intracellular reactive oxygen species (ROS) levels, as well as the activity of caspases 3/7, 8 and 9 after exposure to 150 µM of hydrogen peroxide (H2O2) were also determined using flow cytometry, a 2',7'‑dichlorodihydrofluorescein‑diacetate (DCFH‑DA) assay and caspase assay kits, respectively. The results revealed that orientin at ≤20 µM was not cytotoxic to SH‑SY5Y cells. After treatment with orientin at the MNTD, the percentage of apoptotic cells was significantly reduced compared with that in cells treated with 150 µM H2O2 alone. The results also showed that, although orientin at the MNTD and ½MNTD did not reduce intracellular ROS levels, it significantly inhibited the activity of caspases 3/7. Caspase 9 was significantly inactivated with orientin at the MNTD. Findings from this study suggest that the neuroprotection conferred by orientin was the result of the intracellular mediation of caspase activity.
    Matched MeSH terms: Cell Cycle Checkpoints/drug effects
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