Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.5.3 (complex I)
8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

4-Methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione (oltipraz), a prototype drug candidate containing a 1,2-dithiole-3-thione moiety, has been widely studied as a cancer chemopreventive agent. Oltipraz and other novel 1,2-dithiole-3-thione congeners have the capability to prevent insulin resistance via AMP-activated protein kinase (AMPK) activation. Arachidonic acid (AA, a proinflammatory fatty acid) exerts a deleterious effect on mitochondria and promotes reactive oxygen species (ROS) production. This study investigated whether AA alone or in combination with iron (catalyst of autooxidation) causes ROS-mediated mitochondrial impairment, and if so, whether oltipraz and synthetic 1,2-dithiole-3-thiones protect mitochondria and cells against excess ROS produced by AA + iron. Oltipraz treatment effectively inhibited mitochondrial permeability transition promoted by AA + iron in HepG2 cells, thereby protecting cells from ROS-induced apoptosis. Oltipraz was found to attenuate apoptosis induced by rotenone (complex I inhibitor), but not that by antimycin A (complex III inhibitor), suggesting that the inhibition of AA-induced apoptosis by oltipraz might be associated with the electron transport system. AMPK activation by oltipraz contributed to cell survival, which was supported by the reversal of oltipraz's restoration of mitochondrial membrane potential by concomitant treatment of compound C. By the same token, an AMPK activator inhibited AA + iron-induced mitochondrial permeability transition with an increase in cell viability. Moreover, new 1,2-dithiole-3-thiones with the capability of AMPK activation protected cells from mitochondrial permeability transition and ROS overproduction induced by AA + iron. Our results demonstrate that oltipraz and new 1,2-dithiole-3-thiones are capable of protecting cells from AA + iron-induced ROS production and mitochondrial dysfunction, which may be associated with AMPK activation.
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PMID:Inhibition of arachidonic acid and iron-induced mitochondrial dysfunction and apoptosis by oltipraz and novel 1,2-dithiole-3-thione congeners. 1894 20

Acetogenins from Annonaceae (ACG) are potent inhibitors of the mitochondrial complex I, they present cytotoxic activity on neoplasic lines, including those with multiresistance to drugs. In vivo antitumor activities of some ACG have been reported; however, no information is available regarding the relationship between their cytotoxic activity in cell cultures and their antiproliferative action in vivo. Laherradurin and cherimolin-2 acetogenins were isolated from Annona diversifolia seeds, and their inhibitory potential was analysed in vitro on HeLa and SW-480 cells. Doses containing 1, 10, 100 and 500 times the IC50 obtained from the proliferation assays and multiplied by the weight of the animal, were injected once daily into athymic mice bearing these cancer cell lines; their effect upon tumor growth was measured over a period of 20 days. Laherradurin was more active than cherimolin-2, and it showed in in vitro proliferation assays a similar IC50 in both neoplasic lines. In athymic mice, laherradurin administered in 10x, 100x and 500x doses, reduced the size of HeLa tumors, and with 100x and 500x doses, affected the SW-480 tumor development. These doses were similar to results found with the control drug doxorubicin (p < or = 0.05). On the other hand, cherimolin-2 had an effect on HeLa tumors cells at 100x and 500x doses (p < or = 0.05).
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PMID:In vitro and in vivo antiproliferative activity of laherradurin and cherimolin-2 of Annona diversifolia Saff. 1917 Jan 40

Mitochondrial alteration has been long proposed to play a major role in tumorigenesis. Recently, mitochondrial DNA (mtDNA) mutations have been found in a variety of cancer cells. In this study, we examined the contribution of mtDNA mutation and mitochondrial dysfunction in tumorigenesis first using human cell lines carrying a frame-shift at NADH dehydrogenase (respiratory complex I) subunit 5 gene (ND5); the same homoplasmic mutation was also identified in a human colorectal cancer cell line earlier. With increasing mutant ND5 mtDNA content, respiratory function including oxygen consumption and ATP generation through oxidative phosphorylation declined progressively, while lactate production and dependence on glucose increased. Interestingly, the reactive oxygen species (ROS) levels and apoptosis exhibited antagonistic pleiotropy associated with mitochondrial defects. Furthermore, the anchorage-dependence phenotype and tumor-forming capacity of cells carrying wild-type and mutant mtDNA were tested by growth assay in soft agar and subcutaneous implantation of the cells in nude mice. Surprisingly, the cell line carrying the heteroplasmic ND5 mtDNA mutation showed significantly enhanced tumor growth, while cells with homoplasmic form of the same mutation inhibited tumor formation. Similar results were obtained from the analysis of a series of mouse cell lines carrying a nonsense mutation at ND5 gene. Our results indicate that the mtDNA mutations might play an important role in the early stage of cancer development, possibly through alteration of ROS generation and apoptosis.
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PMID:A heteroplasmic, not homoplasmic, mitochondrial DNA mutation promotes tumorigenesis via alteration in reactive oxygen species generation and apoptosis. 1920 52

NF-kappaB transcription factors marshal innate and adaptive immunity and inflammation. NF-kappaB also counters programmed cell death (PCD) induced by the proinflammatory cytokine tumor necrosis factor (TNF)alpha, and this activity of NF-kappaB is crucial for organismal physiology, chronic inflammation, and tumorigenesis. Indeed, whereas NF-kappaB contributes to many aspects of oncogenesis, it is now clear that its suppressive action on PCD is central to this process. Notably, recent studies indicate that NF-kappaB represents a crucial link in the well-established association between inflammation and carcinogenesis. In this link, NF-kappaB promotes synthesis of inflammatory mediators (e.g. TNFalpha) that stimulate growth of cancer cells, and upregulates genes that protect these cells against PCD induced by inflammatory signals. Elevated NF-kappaB activity also hampers tumor-cell killing inflicted by radiation and chemotherapeutic drugs, and in so doing, promotes resistance to anticancer therapy. Accordingly, NF-kappaB-targeting drugs are increasingly being used for treatment of human malignancies. Owing to the ubiquitous nature of the NF-kappaB pathway, however, these drugs have serious side effects, which limit their clinical use. Thus, a preferable approach would be to block, rather than NF-kappaB itself, its critical downstream targets that mediate discrete functions in cancer, such as prosurvival functions. Recent discoveries unraveling tissue specificity in the NF-kappaB-inducible mechanism(s) for control of PCD and identifying putative effectors of this control clearly validate this therapeutic approach. Given the emerging role of TNFkappa-induced signals of NF-kappaB activation in cancer and the potential of these signals for yielding new anticancer therapies, we focus herein on the methods most commonly used for analysis of the molecular steps leading from the triggering of TNF-Receptor (TNF-R)1 - the primary receptor of TNFalpha - to the induction of NF-kappaB. Specifically, we review the methods used for analysis of TNF-R1 trafficking, assembly of so-called TNF-R1 complex I, formation and activation of the IkappaB kinase (IKK) complex, phosphorylation and proteolysis of inhibitory IkappaB proteins, post-translational modifications and nuclear translocation of NF-kappaB dimers, induction of NF-kappaB transcriptional activity and binding to specific promoters, and upregulation of NF-kappaB target genes. The analysis of these events in cancerous cells may not only provide a better understanding of the basis for the role of NF-kappaB in carcinogenesis, but also potential new targets for selective anticancer therapy.
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PMID:The NF-kappaB transcription factor pathway as a therapeutic target in cancer: methods for detection of NF-kappaB activity. 1934 78

Oncocytic tumours are characterised by hyperproliferation of mitochondria. We immunohistochemically analysed all enzymes of the oxidative phosphorylation system in 19 oncocytic thyroid tumours. A specific lack of complex I was detected, which was expressed at <5% of the level determined in surrounding non-cancerous tissue.
Br J Cancer 2009 May 05
PMID:Lack of complex I is associated with oncocytic thyroid tumours. 1935 85

Avocados have a high content of phytochemicals with potential chemopreventive activity. Previously we reported that phytochemicals extracted from avocado meat into a chloroform partition (D003) selectively induced apoptosis in cancer but not normal, human oral epithelial cell lines. In the present study, we observed that treatment of human oral cancer cell lines containing high levels of reactive oxygen (ROS) with D003 increased ROS levels twofold to threefold and induced apoptosis. In contrast, ROS levels increased only 1.3-fold, and apoptosis was not induced in the normal cell lines containing much lower levels of basal ROS. When cellular ROS levels in the malignant cell lines were reduced by N-acetyl-l-cysteine (NAC), cells were resistant to D003 induced apoptosis. NAC also delayed the induction of apoptosis in dominant negative FADD-expressing malignant cell lines. D003 increased ROS levels via mitochondrial complex I in the electron transport chain to induce apoptosis. Normal human oral epithelial cell lines transformed with HPV16 E6 or E7 expressed higher basal levels of ROS and became sensitive to D003. These data suggest that perturbing the ROS levels in human oral cancer cell lines may be a key factor in selective apoptosis and molecular targeting for chemoprevention by phytochemicals.
Nutr Cancer 2009
PMID:Selective induction of apoptosis of human oral cancer cell lines by avocado extracts via a ROS-mediated mechanism. 1937 8

Impaired mitochondrial activity has been linked to increased risk for clinical complications after injury. Furthermore, variant mitochondrial alleles have been identified and are thought to result in decreased mitochondrial activity. These include a nonsynonymous mitochondrial polymorphism (T4216C) in the nicotinamide adenine dinucleotide dehydrogenase 1 gene (ND1), encoding a key member of complex I within the electron transport chain, which is found almost exclusively among Caucasians. We hypothesized that burn patients carrying ND1 4216C are less able to generate the cellular energy necessary for an effective immune response and are at increased risk for infectious complications. The association between 4216C and outcome after burn injury was evaluated in a cohort of 175 Caucasian patients admitted to the Parkland Hospital with burns covering greater than or equal to 15% of their total body surface area or greater than or equal to 5% full-thickness burns under an institutional review board-approved protocol. To remove confounding unrelated to burn injury, individuals were excluded if they presented with significant non-burn-related trauma (Injury Severity Score > or =16), traumatic or anoxic brain injury, spinal cord injury, were HIV/AIDS positive, had active malignancy, or survived less than 48 h postadmission. Within this cohort of patients, carriage of the 4216C allele was significantly associated by unadjusted analysis with increased risk for sepsis-related organ dysfunction or septic shock (P = 0.011). After adjustment for full-thickness burn size, inhalation injury, age, and sex, carriage of the 4216C allele was associated with complicated sepsis (adjusted odds ratio = 3.7; 95% confidence interval, 1.5-9.1; P = 0.005), relative to carriers of the T allele.
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PMID:Association of mitochondrial allele 4216C with increased risk for sepsis-related organ dysfunction and shock after burn injury. 1948 83

Complex II (succinate-ubiquinone reductase; SQR) is a mitochondrial respiratory chain enzyme that is directly involved in the TCA cycle. Complex II exerts a reverse reaction, fumarate reductase (FRD) activity, in various species such as bacteria, parasitic helminths and shellfish, but the existence of FRD activity in humans has not been previously reported. Here, we describe the detection of FRD activity in human cancer cells. The activity level was low, but distinct, and it increased significantly when the cells were cultured under hypoxic and glucose-deprived conditions. Treatment with phosphatase caused the dephosphorylation of flavoprotein subunit (Fp) with a concomitant increase in SQR activity, whereas FRD activity decreased. On the other hand, treatment with protein kinase caused an increase in FRD activity and a decrease in SQR activity. These data suggest that modification of the Fp subunit regulates both the SQR and FRD activities of complex II and that the phosphorylation of Fp might be important for maintaining mitochondrial energy metabolism within the tumor microenvironment.
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PMID:Regulation of succinate-ubiquinone reductase and fumarate reductase activities in human complex II by phosphorylation of its flavoprotein subunit. 1964 26

Rotenone is an inhibitor of the mitochondrial electron transport chain complex I, resulting in the generation of reactive oxygen species (ROS). Rotenone has been shown to display anticancer activity through the induction of apoptosis in various cancer cells. However, the underlying mechanism is still not fully understood. Here, rotenone showed a strong growth inhibitory effect against human breast cancer MCF-7 cells. DNA flow cytometric analysis, chromatin condensation, and poly (ADP-ribose) polymerase (PARP) cleavage indicated rotenone actively induced apoptosis in MCF-7 cells. The antiapoptotic protein, Bcl-2, was decreased, whereas the apoptotic protein, Bax, was increased in a time-dependent manner in rotenone-induced apoptosis. Moreover, the treatment of rotenone in MCF-7 cells caused the activation of c-jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (MAPKs), and the inactivation of extracellular signal-regulated protein kinase 1/2 (ERK1/2). The pharmacological inhibition of JNK and p38 MAPK revealed significant protection against rotenone-induced apoptosis. Taken together, these results indicate rotenone may induce apoptosis through ROS and JNK/p38 MAPKs activation in MCF-7 cells.
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PMID:Rotenone induces apoptosis in MCF-7 human breast cancer cell-mediated ROS through JNK and p38 signaling. 1977 65

2-Methoxyestradiol (2ME2) is an anticancer agent with antiproliferative, antiangiogenic, and proapoptotic effects. A major proposed mechanism of drug action is the disruption of the microtubule skeleton, leading to the induction of cell cycle arrest and apoptosis. In addition, other mechanisms of action have been proposed, including the generation of reactive oxygen species (ROS), inhibition of hypoxia-inducible factor (HIF), and interference with mitochondrial function. In this study, we used a selection of 2ME2 analogues to conduct structure activity analysis and correlated the antiproliferative and proapoptotic activity of the various analogues with their effects on different drug targets. A good correlation was observed between drug activity and effects on microtubule function. In contrast, our results indicate that effects on ROS, HIF, and mitochondria are unlikely to contribute significantly to the cellular activity of 2ME2. Thus, our data indicate that the structural requirements for inducing ROS and inhibition of complex I of the mitochondrial electron transport chain were different from those required for proapoptotic drug activity. Furthermore, antioxidant treatment or overexpression of catalase did not inhibit the cellular activity of 2ME2 in epithelial cancer cells. Inhibition of HIF required much higher concentrations of 2ME2 analogues compared with concentrations that inhibited cell proliferation and induced apoptosis. Our results thus provide a better insight into the mechanism of action of 2ME2 and reveal structural requirements that confer high cellular activity, which may aid future drug development.
Mol Cancer Ther 2010 Jan
PMID:Structure activity analysis of 2-methoxyestradiol analogues reveals targeting of microtubules as the major mechanism of antiproliferative and proapoptotic activity. 2005 69


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