Cells die by a variety of mechanisms. Terminally differentiated cells such as neurones die in a variety of disorders, in part, via parthanatos, a process dependent on the activity of poly ...(ADP‐ribose)‐polymerase (PARP). Parthanatos does not require the mediation of caspases for its execution, but is clearly mechanistically dependent on the nuclear translocation of the mitochondrial‐associated apoptosis‐inducing factor (AIF). The nuclear translocation of this otherwise beneficial mitochondrial protein, occasioned by poly (ADP‐ribose) (PAR) produced through PARP overactivation, causes large‐scale DNA fragmentation and chromatin condensation, leading to cell death. This review describes the multistep course of parthanatos and its dependence on PAR signalling and nuclear AIF translocation. The review also discusses potential targets in the parthanatos cascade as promising avenues for the development of novel, disease‐modifying, therapeutic agents.
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This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue‐8
Fluoxetine has been shown to induce anti-tumour activity. The aim of this study was to determine the effect of fluoxetine on HCT116+/+ and p53 gene-depleted HCT116-/- human colorectal cancer cells ...and the mechanisms, including potential p53-dependence, of its action. Fluoxetine-induced apoptosis was investigated by mitochondrial membrane potential assay, Annexin V assay, two-step cell cycle analysis using NC-3000™ system and pharmacological inhibition assays. Fluoxetine induced very selectively concentration-dependent apoptosis in human colorectal cancer cells by altering mitochondrial membrane potential and inducing translocation of phosphatidylserine to the outer membrane layer. Further evidence of the preponderance of apoptosis in fluoxetine-induced cell death is provided by the finding that the cell death was not blocked by inhibitors of parthanatos, a form of cell death that results from overactivation of the enzyme poly (ADP-ribose) polymerase (PARP) but is different from apoptosis. Data obtained indicate fluoxetine caused cell cycle event at Sub-G1 and G0/G1 phases in both cell lines. In terms of apoptosis, there is no significant difference between the responses of the two cell lines to fluoxetine.
In conclusion, fluoxetine's cytotoxicity induces mainly apoptosis and causes DNA fragmentation in human colorectal cancer cells, which seemed to be independent of the p53 protein, as no significant difference in death profiles in response to fluoxetine treatment was observed in both the p53-intact and the p53-deleted cell lines. Fluoxetine, therefore, has potential for being repurposed as a drug for the treatment of colon cancer and thus deserves further investigations in this context.
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•Mn(II), Cu(II), Zn(II) and Pt(II) dithiocarmabarete complexes were prepared and characterized.•Molecular structures of the Cu(II) (C2) and Pt(II) (C4) complexes are discussed.•In ...vitro cytotoxicity screening against human cervical (HeLa) and lung cancer (MRC5-SV2) cell lines and a normal lung cancer cell line (MRC5) was conducted.•Compounds exhibited significant toxicity against the cancer cell lines, with IC50 < 50 µM.
Mn(II), Cu(II), Zn(II) and Pt(II) complexes of 2-((p-tolylamino)methyl)phenolyldithiocarbamate were synthesized and characterized by elemental analyses and spectroscopic techniques. Spectroscopic studies indicate four coordinate geometry around the metal(II) ions and single crystal X-ray crystallography confirmed the molecular structures of Cu(II) and Pt(II) complexes as distorted square planar. In vitro cytotoxic effects of the complexes, indicative of potential anti-cancer properties, were evaluated using human cancer cell lines HeLa and MRC5-SV2, and a normal cell line, MRC5. The complexes exhibited significant toxicity against the cancer cell lines, with IC50 values of less than 50 µM after 48 h of exposure. Cu(II) and Zn(II) were the most potent and were virtually equipotent in their cytotoxicity against each of the two cancer cells, but only Zn(II) exhibited higher selectivity for a cancer cell than for a normal cell. Mn(II) complex was the least potent, while Pt(II) was the least cancer cell-selective, exhibiting significantly higher toxicity against the parental (normal) MRC-5 cell than against its cancer variant, MRC5-SV2. These compounds could, therefore, inspire the development of inorganic drug leads to generate novel anti-cancer drugs to be delivered directly to the cancerous tissue or through special delivery systems.
The kynurenine pathway is the major route for the oxidative degradation of the amino acid tryptophan. Activity of the pathway is involved in several disease conditions, both in the periphery and the ...central nervous system, including cancer, inflammatory disorders, neurological conditions, psychiatric disorders and neurodegenerative diseases. Three enzymes are now known to catalyze the first and rate-limiting step in the catabolism of tryptophan along this pathway: tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO, subsequently named IDO1), both of which have been extensively studied, and a third enzyme, indoleamine 2,3-dioxygenase 2 (IDO2), a relative newcomer to the kynurenine pathway field. The adjuvant chemotherapeutic agent, 1-methyl-D-tryptophan, was intially suggested to target IDO2, implying involvement of IDO2 in tumorigenesis. Subsequently this compound has been suggested to have alternative actions and the physiological and pathophysiological roles of IDO2 are unclear. Targeted genetic interventions and selective inhibitors provide approaches for investigating the biology of IDO2. This review focuses on the current knowledge of IDO2 biology and discusses tools that will assist in further characterizing the enzymes of the kynurenine pathway.
Kola nut (from Cola nitida) is popular in Nigeria and West Africa and is commonly consumed by pregnant women during the first trimester to alleviate morning sickness and dizziness. There is, however, ...a dearth of information on its effects on the developing brain. This study, therefore, investigated the potential effects of kola nut on the structure of the developing neonatal and juvenile cerebellum in the rat. Pregnant Wistar rats were administered water (as control) or crude (aqueous) kola nut extract at 400, 600, and 800 mg/kg body weight orally, from pregnancy to day 21 after birth. On postnatal days 1, 7, 14, 21 and 28, the pups were weighed, anaesthetised, sacrificed and perfused with neutral buffered formalin. Their brains were dissected out, weighed and the cerebellum preserved in 10% buffered formalin. Paraffin sections of the cerebellum were stained with haematoxylin and eosin for cerebellar cytoarchitecture, cresyl violet stain for Purkinje cell count, Glial Fibrillary Acidic Protein (GFAP) immunohistochemistry (IHC) for estimation of gliosis, and B-cell lymphoma 2 (Bcl-2) IHC for apoptosis induction. The kola nut-treated rats exhibited initial reduction in body and brain weights, persistent external granular layer, increased molecular layer thickness, and loss of Bergmann glia. Their Purkinje cells showed reduction in density, loss of dendrites and multiple layering, and their white matter showed neurodegeneration (spongiosis) and GFAP and Bcl-2 over-expression, with evidence of reactive astrogliosis. This study, therefore, demonstrates that kola nut, administered repeatedly at certain doses to pregnant dams, could disrupt normal postnatal cerebellar development in their pups. The findings suggest potential deleterious effects of excessive kola nut consumption on human brain and thus warrant further studies to understand the wider implications for human brain development.
Bioactivity-guided phytochemical fractionation of the methanol extract of Olax subscorpioidea root has led to the isolation of six triterpenes. Three of these compounds are previously undescribed ...triterpenoid saponins: oleanolic acid 3-O-α-L-rhamnopyranosyl-(1→3)-β-D-glucopyranosyl-(1 → 2)-6-O-methyl-β-D-glucuronopyranoside-28-O-β-D-glucopyranosyl ester (2), oleanolic acid 3-O-β-D-glucopyranosyl-(1 → 4)-β-D-glucopyranosyl-(1 → 3)-β-D-glucopyranoside (3), and oleanolic acid 3-O-β-D-glucopyranosyl-(1 → 4)-6-O-methyl-β-D-glucuronopyranoside ester (5). Other reported known compounds include two triterpene glycosides: oleanolic acid 3-O-β-D-glucopyranosyl-(1 → 4)-6-O-methyl-β-D-glucuronopyranoside-28-O-β-D-glucopyranosyl ester (1) and oleanolic acid 3-O-β-D-glucopyranosyl-(1 → 4)-β-D-glucuronopyranoside (4); and a triterpene acid, oleanolic acid (6). The structures of these compounds were elucidated by spectroscopic means. The isolated compounds were tested against human cervical cancer (HeLa), colorectal cancer (Caco-2) and breast cancer (MCF-7) cell lines using the in vitro 3-4,5-dimethylthiazole-2-yl 3,5-diphenyltetrazolium bromide (MTT) assay, with vincristine as positive control. The cytotoxicity assay showed that compounds 3 and 5 exhibited significant inhibitory effects on the HeLa cell line, with IC50 values of 7.42 ± 0.34 μM and 10.27 ± 1.26 μM; and moderate effects on MCF-7 (IC50 values, 36.67 ± 1.23 μM and 43.83 ± 0.65 μM) and Caco-2 (IC50 values, 35.83 ± 0.55 μM and 39.03 ± 4.38 μM, respectively) cell lines. They were also more selectively cytotoxic than vincristine against the cancer cell lines, when compared with cytotoxicity against the normal lung cell line MRC5.
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•Methanol extract of Olax subscorpioidea root gave significant cytotoxic effects.•Six triterpenoid compounds were isolated and characterised from the active solid-phase extraction (SPE) fraction using series of preparative HPLC.•Three of the isolated triterpene glycosides have not been previously described.•All the compounds were found in this specie for the first time.•Two of the new compounds gave lower IC50 values than the fraction.
The plant Peristrophe bicalyculata (Retz) Nees is used for the treatment of cancer. While its leaf extracts have been shown to inhibit the growth of some cancer cells, there is little information ...supporting the constituents’ anti-tumour potential. This study, therefore, investigated the effects of the plant’s leaf extracts on cancer cells and the associated cellular/molecular mechanisms. Extracts were prepared using hexane (PBH), chloroform (PBC), ethyl acetate (PBE) and methanol (PBM) and constituents were identified by Liquid Chromatography-Mass Spectrometry (LC-MS). Their cytotoxic effects on human cervical (HeLa) and lung cancer (MRC5-SV2) cells were assessed using the MTT and LDH release assays. Reactive oxygen species (ROS) production was assessed using 2′,7′-dichlorofluorescein diacetate (DCFDA) and mitochondrial membrane potential by staining with JC-1 (5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolyl-carbocyanine iodide). Caspase activation was determined using a Caspase-Glo-3/7 assay, and DNA damage by the Comet assay. Changes to mRNA expression were assessed using Quantitative Real-Time PCR. PBC, PBE and PBM reduced cell viability and induced LDH release, with IC50 values (48 h, MTT, in μg/ml), respectively, of 6.21 ± 0.70, 23.39 ± 3.92, and 22.43 ± 3.58 (HeLa); and 1.98 ± 0.33, 8.57 ± 1.91 and 28.24 ± 5.57 (MRC5-SV2). PBC induced ROS, while PBC, PBE and PBM impaired mitochondrial membrane potential and induced caspase 3/7 activation. PBC and PBE induced DNA damage, and PBE induced caspase-3 mRNA expression. Constituents of the extracts included derivatives of gallic acid, dipeptides, diterpenoids and flavones. We conclude that P. bicalyculata contains cytotoxic principles that could be potential leads for developing novel anti-cancer agents.
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•Peristrophe bicalyculata is used in traditional anti-cancer remedies.•Its anti-cancer effects and mechanisms have not been sufficiently investigated.•Extracts cytotoxic through oxidative stress, DNA damage, and apoptosis.•Various chemical constituents, including diterpenes and flavonoids, were identified.•Work provides rationale for using its extracts in traditional anti-cancer remedies.
Reactions of 2,6-bis(benzimidazol-2-yl)pyridine (L1), 2,6-bis(benzoxazol-2-yl)pyridine (L2), and 2,6-bis(benzothiazol-2-yl)pyridine (L3) with Pd(NCMe)2Cl2 in the presence of NaBF4 afforded the ...corresponding Pd(II) complexes, Pd(L1)ClBF4, PdL1; Pd(L2)ClBF4, PdL2; Pd(L3)ClBF4, PdL3; respectively, while reaction of bis(1H-benzimidazol-2-yl)methylamine (L4) with Pd(NCMe)2Cl2 afforded complex Pd(L4)ClCl, PdL4. Characterisation of the complexes was accomplished using NMR, IR, MS, elemental analyses and single crystal X-ray crystallography. Ligand substitution kinetics of these complexes by biological nucleophiles thiourea (Tu), L-methionine (L-Met) and guanosine 5′-diphosphate disodium salt (5-GMP) were examined under pseudo-first order conditions. The reactivity of the complexes decreased in the order: PdL1 > PdL2 > PdL3 > PdL4, ascribed to electronic effects. Density functional theory (DFT) supported this trend. Studies of interaction of the Pd(II) complexes with calf thymus DNA (CT-DNA) revealed strong binding affinities via intercalative binding mode. Molecular docking studies established associative non-covalent interactions between the Pd complexes and DNA. The in vitro cytotoxic activities of PdL1–PdL4 were assessed in cancer cell lines HeLa and MRC5-SV2 and a normal cell line MRC-5, using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. PdL1 exhibited cytotoxic potency and selectivity against HeLa cell that was comparable to cisplatin's. Complex PdL1, unlike cisplatin, did not significantly induce caspase-dependent apoptosis.
Structural, substitution kinetics, DNA interactions and cytotoxicity of tridentate bis(benzazole) palladium(II) complexes have been studied. Some complexes exhibited cytotoxic potency and selectivity against HeLa cell that was comparable to cisplatin. Display omitted
•Pd(II) complexes of 2,6-bis(benzazole) synthesised and characterised•Substitution kinetics of the Pd(II) complexes controlled by electronic effects•Pd(II) complexes exhibit strong interactions with the calf-thymus DNA.•Pd2,6-bis(benzimidazol-2-yl)pyridineCl: comparable cytotoxicity/selectivity to cisplatin•Good correlation between substitution kinetics and cytotoxicity
•Metal(II) complexes of 2-(((4-methoxyphenyl)phenolyl dithiocarbamate were synthesized and characterized.•In vitro cytotoxicity screening for anticancer potential was carried out.•All complexes ...except Cu(II) were cytotoxic to the HeLa cell.•Co(II) and Zn(II) were the most potent, with IC50 values of 12.9 and 15.1 μM.•Zn(II) was the best complex in terms of the potency of cytotoxic effect and cancer cell selectivity.
Mn(II), Co(II), Cu(II), Zn(II) and Pt(II) complexes of 2-(((4-methoxyphenyl)amino)methyl)phenolyl dithiocarbamato were synthesized and characterized by elemental analysis and spectroscopic techniques. Spectroscopic studies confirmed that two molecules of the dithiocarbamato anions coordinate the metal ions as bidentate chelating ligands. In vitro anticancer screening of the compounds was conducted in the human cervical adenocarcinoma cell (HeLa) and in the human foetal lung cancer cell (MRC5-SV2) and its normal (non-cancer) parental line (MRC5). All complexes except Cu(II) were cytotoxic to HeLa in the preliminary screen. When tested in the MRC5-SV2 cancer cell, Co(II) and Zn(II) were the most potent, with IC50 values (µM) of 12.9 ± 1.2 and 15.1 ± 2.4, respectively, while Mn(II) and Pt(II) had IC50 values of 31.5 ± 3.8 and 25.5 ± 4.4, respectively, compared to 8.6 ± 0.3 for the anti-cancer drug cisplatin. Zn(II) was the most cancer cell-selective, with a selectivity index (SI) of 2.0, followed by Co(II) with a SI of 1.4. Mn(II) was not cancer cell-selective, while Pt(II) was more cytotoxic against normal cells, with a SI of 0.2. The varied anticancer potencies of the metal complexes derived from the same ligand can provide direction for further research into the development of inorganic complexes as anti-cancer drugs.
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