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1.
Annonacin,a mono-tetrahydrofuran acetogenin,arrests cancer cells at the G1 phase and causes cytotoxicity in a Bax- and caspase-3-related pathway 总被引:3,自引:0,他引:3
Annonaceous acetogenins are a group of potential anti-neoplastic agents isolated from Annonaceae plants. In this study, we purified annonacin, a cytotoxic mono-tetrahydrofuran acetogenin, from the seeds of Annona reticulata and analyzed its biological effects. Herein, we have shown that annonacin caused significant cell death in various cancer cell lines. T24 bladder cancer cells at the S phase were more vulnerable to the cytotoxicity of annonacin. Furthermore, annonacin activated p21 in a p53-independent manner and arrested T24 cells at the G1 phase. It also induced Bax expression, enhanced caspase-3 activity, and caused apoptotic cell death in T24 cells. In summary, these results suggest that annonacin is potentially a promising anti-cancer compound. 相似文献
2.
Wagner D. Vital Heron F. V. Torquato Larissa de Oliveira Passos Jesus Wagner Alves de Souza Judice Maria Fátima das G. F. da Silva Tiago Rodrigues Giselle Zenker Justo Thiago A. M. Veiga Edgar J. Paredes-Gamero 《Journal of cellular biochemistry》2019,120(6):9608-9623
Several molecules extracted from natural products exhibit different biological activities, such as ion channel modulation, activation of signaling pathways, and anti-inflammatory or antitumor activity. In this study, we tested the antitumor ability of natural compounds extracted from the Raputia praetermissa plant. Among the compounds tested, an alkaloid, here called compound S4 (4-Deoxyraputindole C), showed antitumor effects against human tumor lineages. Compound S4 was the most active against Raji, a lymphoma lineage, promoting cell death with characteristics that including membrane permeabilization, dissipation of the mitochondrial potential, increased superoxide production, and lysosomal membrane permeabilization. The use of cell death inhibitors such as Z-VAD-FMK (caspase inhibitor), necrostatin-1 (receptor-interacting serine/threonine-protein kinase 1 inhibitor), E-64 (cysteine peptidases inhibitor), and N-acetyl- L -cysteine (antioxidant) did not decrease compound S4-dependent cell death. Additionally, we tested the effect of cellular activity on adherent human tumor cells. The highest reduction of cellular activity was observed in A549 cells, a lung carcinoma lineage. In this lineage, the effect on the reduction of the cellular activity was due to cell cycle arrest, without plasma membrane permeabilization, loss of the mitochondrial potential or lysosomal membrane permeabilization. Compound S4 was able to inhibit cathepsin B and L by a nonlinear competitive (negative co-operativity) and simple-linear competitive inhibitions, respectively. The potency of inhibition was higher against cathepsin L. Compound S4 promoted cell cycle arrest at G 0 and G 2 phase, and increase the expression of p16 and p21 proteins. In conclusion, compound S4 is an interesting molecule against cancer, promoting cell death in the human lymphoma lineage Raji and cell cycle arrest in the human lung carcinoma lineage A549. 相似文献
3.
Hou Q Jin J Zhou H Novgorodov SA Bielawska A Szulc ZM Hannun YA Obeid LM Hsu YT 《Journal of lipid research》2011,52(2):278-288
C(6)-pyridinium (D-erythro-2-N-[6'-(1'-pyridinium)-hexanoyl]sphingosine bromide [LCL29]) is a cationic mitochondrion-targeting ceramide analog that promotes mitochondrial permeabilization and cancer cell death. In this study, we compared the biological effects of that compound with those of D-erythro-C(6)-ceramide, its non-mitochondrion-targeting analog. In MCF7 cells it was found that C(6)-pyridinium ceramide preferentially promoted autophagosome formation and retarded cell growth more extensively than its uncharged analog. This preferential inhibition of cell growth was also observed in breast epithelial cells and other breast cancer cells. In addition, this compound could promote Bax translocation to mitochondria. This redistribution of Bax in MCF7 cells could be blocked by the pan-caspase inhibitor zVAD-fmk but via a Bid-independent signaling pathway. Moreover, C(6)-pyridinium ceramide-induced translocation of Bax to mitochondria led to mitochondrial permeabilization and cell death. Overall, we show that mitochondrial targeting of C(6)-pyridinium ceramide significantly enhances cellular response to this compound. 相似文献
4.
Park HS Huh SH Kim Y Shim J Lee SH Park IS Jung YK Kim IY Choi EJ 《The Journal of biological chemistry》2000,275(12):8487-8491
Selenium, an essential biological trace element, exerts its modulatory effects in a variety of cellular events including cell survival and death. In our study we observed that selenite protects HEK293 cells from cell death induced by ultraviolet B radiation (UVB). Exposure of HEK293 cells to UVB radiation resulted in the activation of caspase-3-like protease activity, and pretreatment of the cells with z-DEVD-fmk (N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone), a caspase-3 inhibitor, prevented UVB-induced cell death. Interestingly, enzymatic activity of caspase-3-like protease in cell lysates of UVB-exposed cells was repressed in vitro by the presence of selenite. Selenite also inhibited the in vitro activity of purified recombinant caspase-3 in cleaving Ac-DEVD-pNA (N-acetyl-Asp-Glu-Asp-p-nitroanilide) or ICAD(L) (inhibitor of a caspase-activated deoxyribonuclease) and in the induction of DNA fragmentation. The inhibitory action of selenite on a recombinant active caspase-3 could be reversed by sulfhydryl reducing agents, such as dithiothreitol and beta-mercaptoethanol. Furthermore, pretreatment of cells with selenite suppressed the stimulation of the caspase-3-like protease activity in UVB-exposed cells, whereas dithiothreitol and beta-mercaptoethanol reversed this suppression of the enzymatic activity. Taken together, our data suggest that selenite inhibits caspase-3-like protease activity through a redox mechanism and that inhibition of caspase-3-like protease activity may be the mechanism by which selenite exerts its protective effect against UVB-induced cell death. 相似文献
5.
《Bioorganic & medicinal chemistry letters》2014,24(11):2512-2516
A virtual screening strategy, through molecular docking, for the elaboration of an electronic library of Pontin inhibitors has resulted in the identification of two original scaffolds. The chemical synthesis of four candidates allowed extensive biological evaluations for their anticancer activity. Two compounds displayed an effect on Pontin ATPase activity, and one of them also exhibited a noticeable effect on cell growth. Further biological studies revealed that the most active compound induced apoptotic cell death together with necrosis, this latter effect being likely related to the cellular balance of ATP regulation. 相似文献
6.
Tuba Kul Kprülü Salih
kten aban Tekin Osman akmak 《Journal of biochemical and molecular toxicology》2019,33(3)
Due to a great deal of biological activities, quinoline derivatives have drawn attention for synthesis and biological activities in the search for new anticancer drug development. In this work, a variety of substituted (phenyl, nitro, cyano, N‐oxide, and methoxy) quinoline derivatives ( 3 ‐ 13 ) were tested in vitro for their biological activity against cancer cell lines, including rat glioblastoma (C6), human cervical cancer cells (HeLa), and human adenocarcinoma (HT29). 6‐Bromo‐5‐nitroquinoline ( 4 ), and 6,8‐diphenylquinoline (compound 13 ) showed the greatest antiproliferative activity as compared with the reference drug, 5‐fluorouracil (5‐FU), while the other compounds showed low antiproliferative activity. 6‐Bromo‐5‐nitroquinoline ( 4 ) possesses lower cytotoxic activity than 5‐FU in HT29 cell line. Due to its the apoptotic activity 6‐Bromo‐5‐nitroquinoline ( 4 ) has the potential to cause cancer cell death. 相似文献
7.
Melis Debreli Coskun Ferda Ari Arzu Yilmaztepe Oral Mehmet Sarimahmut Hatice M. Kutlu Veysel T. Yilmaz Engin Ulukaya 《Bioorganic & medicinal chemistry》2013,21(15):4698-4705
Fibrosarcoma is one of the fatal cancer types and there is still not satisfactory success in its treatment despite new drugs. Therefore, the search for a new compound has been going on. It is currently known that some palladium-based anti-cancer compounds seem to have powerful apoptosis-inducing effects in cancer cells. For this purpose, a palladium(II)-saccharinate complex containing terpyridine which was synthesized by our research group was investigated in terms of its anti-tumor effects against mouse embryonic fibroblast NIH/3T3 (normal cell line) and rat embryonic fibroblast 5RP7 (H-ras transformed cell line) in vitro. The MTT and ATP viability assays were used to determine anti-growth/cytotoxic effects. Cytotoxic activity was confirmed by real time cytotoxicity analysis system. Flow cytometry analysis was further used to determine the mode of cell death (apoptosis/necrosis). Apoptosis was confirmed by triple-staining the cells with Hoechst 33342/PI/Calcein-AM triple and evaluated with fluorescence microscopy. It was found that the compound showed significant anti-growth activity by inducing apoptosis in a dose dependent manner. In conclusion, taking into account the cytotoxic activity of the compound at even relatively lower doses, in vivo experiments to elucidate its potential use for the treatment of fibrosarcoma are warranted. 相似文献
8.
Tumor necrosis factor (TNF) is a key mediator in the inflammatory response which is implicated in the onset of a number of diseases. Research on TNF led to the characterization of the largest family of cytokines known until now, the TNF superfamily, which exert their biological effects through the interaction with transmembrane receptors of the TNFR superfamily. TNF itself exerts its biological effects interacting with two different receptors: TNFR1 and TNFR2. TNFR1 presents a death domain on its intracellular region. In contrast to TNFR1, TNFR2 does not have a death domain. Activation of TNFR1 implies the consecutive formation of two different TNF receptor signalling complexes. Complex I controls the expression of antiapoptotic proteins that prevent the triggering of cell death processes, whereas Complex II triggers cell death processes. TNFR2 only signals for antiapoptotic reactions. However, recent evidence indicates that TNFR2 also signals to induce TRAF2 degradation. TRAF2 is a key mediator in signal transduction of both TNFR1 and TNFR2. Thus, this novel signalling pathway has two important implications: on one hand, it represents an auto regulatory loop for TNFR2; on the other hand, when this signal is triggered TNFR1 activity is modified so that antiapoptotic pathways are inhibited and apoptotic reactions are enhanced. 相似文献
9.
Ragione FD Cucciolla V Borriello A Pietra VD Pontoni G Racioppi L Manna C Galletti P Zappia V 《Biochemical and biophysical research communications》2000,278(3):733-739
2-(3,4-Dihydroxyphenyl)ethanol (DPE), a naturally occurring phenolic antioxidant molecule found in olive oil, has been reported to exert several biological and pharmacological activities. We studied the effect of this compound on the proliferation and survival of HL60 cell line. Concentrations from 50 to 100 microM DPE, comparable to its olive oil content, caused a complete arrest of HL60 cell proliferation and the induction of apoptosis. This was demonstrated by flow cytometric analyses, poly(ADP-ribose) polymerase cleavage, and caspase 3 activation. The apoptotic effect requires the presence of two ortho-hydroxyl groups on the phenyl ring, since tyrosol, 2-(4-hydroxyphenyl)ethanol, did not induce either cell growth arrest or apoptosis. DPE-dependent apoptosis is associated with an early release of cytochrome c from mitochondria which precedes caspase 8 activation, thus ruling out the engagement of cell death receptors in the apoptotic process. 2-(3,4-Dihydroxyphenyl)ethanol induced cell death in quiescent and differentiated HL60 cells, as well as in resting and activated peripheral blood lymphocytes, while did not cause cell death in two colorectal cell lines (HT-29 and CaCo2). These results suggest that DPE down-regulates the immunological response, thus explaining the well-known antinflammatory and chemopreventive effects of olive oil at the intestinal level. 相似文献
10.
de Souza AC Kodach L Gadelha FR Bos CL Cavagis AD Aoyama H Peppelenbosch MP Ferreira CV 《Apoptosis : an international journal on programmed cell death》2006,11(10):1761-1771
Besides having a pivotal biological function as a component of coenzymes, riboflavin appears a promissing antitumoral agent,
but the underlying molecular mechanism remains unclear. In this work, we demonstrate that irradiated riboflavin, when applied
at μM concentrations, induces an orderly sequence of signaling events finally leading to leukemia cell death. The molecular
mechanism involved is dependent on the activation of caspase 8 caused by overexpression of Fas and FasL and also on mitochondrial
amplification mechanisms, involving the stimulation of ceramide production by sphingomyelinase and ceramide synthase. The
activation of this cascade led to an inhibition of mitogen activated protein kinases: JNK, MEK and ERK and survival mediators
(PKB and IAP1), upregulation of the proapoptotic Bcl2 member Bax and downregulation of cell cycle progression regulators.
Importantly, induction of apoptosis by irradiated riboflavin was leukaemia cell specific, as normal human lymphocytes did
not respond to the compound with cell death. Our data indicate that riboflavin selectively activates Fas cascade and also
constitutes a death receptor-engaged drug without harmful side effects in normal cells, bolstering the case for using this
compound as a novel avenue for combating cancerous disease. 相似文献
11.
Marco Masi Ramesh Dasari Antonio Evidente Veronique Mathieu Alexander Kornienko 《Bioorganic & medicinal chemistry letters》2019,29(7):859-869
Ophiobolin A is a fungal secondary metabolite that was found to have significant activity against apoptosis-resistant glioblastoma cells through the induction of a non-apoptotic cell death, offering an innovative strategy to combat this aggressive cancer. The current article aims to make the bridge between the anti-cancer effects of ophiobolin A and its unique reaction with primary amines and suggests that pyrrolylation of lysine residues on its intracellular target protein(s) and/or phosphatidylethanolamine lipid is responsible for its biological effects. The article also discusses chemical derivatization of ophiobolin A to establish first synthetically generated structure-activity relationship. Finally, the reported total synthesis efforts toward the ophiobolin class of sesterterpenes are discussed and identified as a fertile area for improvement in pursuit of these molecules as anticancer agents. 相似文献
12.
《Bioorganic & medicinal chemistry》2020,28(13):115557
Parthenolide is an important sesquiterpene lactone with potent anticancer activities. In order to further improve its biological activity, a series of parthenolide semicarbazone or thiosemicarbazone derivatives was synthesized and evaluated for their anticancer activity. Derivatives were tested in vitro against 5 human tumor cell lines, and many of these showed higher cytotoxicity than parthenolide. Five compounds were further studied for their antitumor activity in mice. The in vivo result indicated that compound 4d showed both promising antitumor activity against mice colon tumor and small side effects on immune systems. The cell apoptosis and cell cycle distribution of compound 4d were also studied. Molecular docking studies revealed multiple interactions between 4d and NF-κB. Our findings demonstrate the potential of semicarbazones as a promising type of compounds with anticancer activity. 相似文献
13.
《Journal of lipid research》2023,64(7):100396
Geranylgeranoic acid (GGA) was first reported in 1983 as one of the mevalonic acid metabolites, but its biological significance was not studied for a long time. Our research on the antitumor effects of retinoids led us to GGA, one of the acyclic retinoids that induce cell death in human hepatoma-derived cell lines. We were able to demonstrate the presence of endogenous GGA in various tissues of male rats, including the liver, testis, and cerebrum, by LC-MS/MS. Furthermore, the biosynthesis of GGA from mevalonic acid in mammals including humans was confirmed by isotopomer spectral analysis using 13C-labeled mevalonolactone and cultured hepatoma cells, and the involvement of hepatic monoamine oxidase B in the biosynthesis of GGA was also demonstrated. The biological activity of GGA was analyzed from the retinoid (differentiation induction) and nonretinoid (cell death induction) aspects, and in particular, the nonretinoid mechanism by which GGA induces cell death in hepatoma cells was found to involve pyroptosis via ER stress responses initiated by TLR4 signaling. In addition to these effects of GGA, we also describe the in vivo effects of GGA on reproduction. In this review, based mainly on our published papers, we have shown that hepatic monoamine oxidase B is involved in the biosynthesis of GGA and that GGA induces cell death in human hepatoma-derived cell lines by noncanonical pyroptosis, one of the mechanisms of sterile inflammatory cell death. 相似文献
14.
Platycodin D (PD) is a major active component of the roots of Platycodon grandiflorum (Jacq.) A.DC. and possesses multiple biological and pharmacological properties, including anti-cancer activity. The aim of this study was to characterize PD-induced cytoplasmic vacuolation in human cancer cells and investigate the underlying mechanisms. PD-induced cancer cell death was associated with cytoplasmic pinocytic and autophagic vacuolation. Cellular energy levels were decreased by this compound, leading to the activation of AMP-activated protein kinase (AMPK). Additionally, compound C, an inhibitor of AMPK, completely prevented PD-induced vacuolation. These results suggest that PD induces cancer cell death, associated with excessive vacuolation through AMPK activation when cellular energy levels are low. Therefore, our findings provide a mechanistic rationale for a novel combinatorial approach using PD to treat cancer. 相似文献
15.
Abbas Khojasteh Mohammad Hossein Mirjalili Diego Hidalgo Purificación Corchete Javier Palazon 《Biotechnology letters》2014,36(12):2393-2406
Rosmarinic acid (RA), an ester of caffeic acid and 3,4-dihydroxyphenyl lactic acid, is widely distributed in the plant kingdom. Interest in it is growing due to its promising biological activities, including cognitive-enhancing effects and slowing the development of Alzheimer’s disease, cancer chemoprotection or anti-inflammatory activity, among others. In order to meet the increasing demand for this compound, several biotechnological approaches to its production based on plant cell and hairy root cultures have been developed. Empirical strategies are currently being combined with metabolic engineering tools to increase RA production in plant cell platforms in a more rational way. Discussed here are the latest advances in the field, together with recent trends in plant biotechnology, such as the application of single use technology and the use of biosensors in downstream processes. 相似文献
16.
de Mier-Vinué J Lorenzo J Montaña AM Moreno V Avilés FX 《Journal of inorganic biochemistry》2008,102(4):973-987
A series of platinum compounds with an analogue structure to cisplatin have been synthesized and their biological activity against HL-60 cancer cell line has been studied. The interaction with DNA was evaluated by circular dichroism (CD), electrophoresis and atomic force microscopy (AFM) techniques showing slight but significant structure-dependent differences among the evaluated complexes. The cytotoxicity assays afforded interesting relationships between the structure and the biological activity, thus, a better antiproliferative activity was observed for the complexes with higher hydrophobicity: the methoxylated complexes showed better activity than the hydroxylated ones (17versus20 and 19versus21). Especially compound 22 having a fatty acid subunit presented a promising cytotoxic activity. On the other hand, dichloro complexes 12 and 13 had better activities than the diiodo complexes, probably due to their better metabolic stability. Between both dichloro complexes the aromatic one showed much higher activity, which could be rationalized on the basis of the intercalating ability of the benzene ring. The flow cytometry assays indicated that most of the complexes induced the cell death by apoptosis except for aromatic compound 12 and the lipophilic compound 22 that induced preferably a mechanism of necrosis. 相似文献
17.
Oh JH Ban JO Cho MC Jo M Jung JK Ahn B Yoon DY Han SB Hong JT 《The Journal of nutritional biochemistry》2012,23(7):706-715
Biphenolic components in the Magnolia family have shown several pharmacological activities such as antitumor effects. This study investigated the effects of 4-O-methylhonokiol (MH), a constituent of Magnolia officinalis, on human colon cancer cell growth and its action mechanism. 4-O-methylhonokiol (0–30 μM) decreased constitutive activated nuclear factor (NF)-κB DNA binding activity and inhibited growth of human colon (SW620 and HCT116) cancer cells. It also caused G0–G1 phase cell cycle arrest followed by an induction of apoptotic cell death. However, knockdown with small interfering RNA (siRNA) of p21 or transfection with cyclin D1/Cdk4 binding site-mutated p21 abrogated MH-induced cell growth inhibition, inhibition of NF-κB activity as well as expression of cyclin D1 and Cdk4. Conversely, inhibition of NF-κB with specific inhibitor or siRNA augmented MH-induced apoptotic cell death. 4-O-methylhonokiol inhibited tumor growth, NF-κB activity and expression of antiapoptotic proteins; however, it increased the expression of apoptotic proteins as well as p21 in xenograft nude mice bearing SW620 cancer cells. The present study reveals that MH causes p21-mediated human colon cancer cell growth inhibition through suppression of NF-κB and indicates that this compound by itself or in combination with other anticancer agents could be useful for the treatment of cancer. 相似文献
18.
F Di Nicuolo S Serini A Boninsegna P Palozza G Calviello 《Free radical biology & medicine》2001,31(11):1424-1431
Pyrrolidine dithiocarbamate (PDTC) is a synthetic compound largely used in cell biological studies and known to exert either antioxidant or pro-oxidant effects. Recently, its antitumoral activity has been proposed on the basis of its antioxidant and proapoptotic effects. In the present study, we evaluated the effect of increasing i.p. doses of PDTC on the growth of a strain of highly malignant thymoma cells inoculated in the peritoneum of inbred Balb/c mice. PDTC treatment increased the number of thymoma cells in a dose-dependent manner, enhancing the percentage of proliferating tumor cells. PDTC exerted regulatory effects on cell cycle distribution, decreasing the expression of cell cycle inhibitors. Alterations in the production of intracellular reactive oxygen species, levels of oxidized glutathione, and intracellular levels of the redox-active metals iron and copper were also observed. The above results represent the first evidence that PDTC may induce in vivo cell proliferation in a murine thymoma cell model. In addition, we suggest that the ability of PDTC to bind and transport metals inside the cell and its pro-oxidant property may be factors underlying its effects on thymoma cell proliferation and cell cycle distribution. 相似文献
19.
Lignan compounds and 4,4'-dihydroxybiphenyl protect C2C12 cells against damage from oxidative stress
Yoshikawa A Saito Y Maruyama K 《Biochemical and biophysical research communications》2006,344(1):394-399
Lignan compounds are known to have various biological activities, especially antioxidative effects. We investigated whether lignan compounds show antioxidative activity in myoblast C2C12 cells. Among 14 lignan compounds investigated, two lignans containing two phenolic functional groups, namely Gomisin J and GR-12, prevented hydrogen peroxide (H(2)O(2))-induced cell death. A simple compound, 4,4'-dihydroxybiphenyl, which was found to be a common component of Gomisin J and GR-12, also largely prevented H(2)O(2)-induced cell death and almost completely prevented H(2)O(2)-induced increases in p38 MAPK phosphorylation. Our present results provide a useful in vitro system for clarifying the molecular mechanisms of lignan-mediated antioxidative effects and evaluating lead molecules toward the development of therapeutic drugs. 相似文献
20.
Filomeni G Aquilano K Civitareale P Rotilio G Ciriolo MR 《Free radical biology & medicine》2005,39(3):345-354
Changes in intracellular redox status are crucial events that trigger downstream proliferation or death responses through activation of specific signaling pathways. Moreover, cell responses to oxidative challenge may depend on the pattern of redox-sensitive molecular factors. The stress-activated protein kinases c-Jun-N-terminal kinase (JNK) and p38 MAP kinase (p38MAPK) are implicated in different forms of apoptotic neuronal cell death. Here, we investigated the effects, on neuroblastoma cells, of the prooxidant molecule GSSG, which we previously demonstrated to be an efficient proapoptotic compound able to activate the p38MAPK death pathway in promonocytic cells. We found that neuroblastoma cells are not prone to GSSG-induced apoptosis, although the treatment slightly induced growth arrest through the accumulation of p53 and its downstream target gene, p21. However, GSSG treatment became cytotoxic when cells were previously depleted of intracellular GSH content. Under this condition, apoptosis was triggered by an increased production of superoxide that led to a specific activation of the JNK-dependent pathway. The involvement of superoxide and JNK was demonstrated by cell death inhibition in experiments carried out in the presence of Cu,Zn superoxide dismutase or with specific inhibitors of JNK activity. Our data give support to the studies that indicate preferential requirements for the involvement of stress-activated kinases in apoptotic neuronal cells. 相似文献