An epigrammatic (abridged) recounting of the myriad tales of astonishing deeds and dire consequences pertaining to nitric oxide and reactive oxygen species in mitochondria with an ancillary missive concerning the origins of apoptosis

Heck, Diane E.; Kagan, Valerian E.; Shvedova, Anna A.; Laskin, Jeffrey D.

doi:10.1016/j.tox.2004.11.027

Cited by 29 publications

(25 citation statements)

References 107 publications

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“…An additional point is equally clear: a significant fraction of cell signalling pathways modulated by these agents is RONS dependent or RONS responsive; activation of such pathways culminates to the death of the relevant cell through either apoptosis or its variants or through necrosis (Heck et al, 2005). That the chemopreventive agents discussed here work by increasing RONS levels suggests that modulation of redox biochemistry represents a fruitful approach to cancer prevention.…”

Section: Discussionmentioning

confidence: 91%

Induction of oxidative stress as a mechanism of action of chemopreventive agents against cancer

Rigas

Sun

2008

Br J Cancer

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Prevention is a promising option for the control of cancer. Cellular redox changes have emerged as a pivotal and proximal event in cancer. In this review, we provide a brief background on redox biochemistry, discuss the important distinction between redox signalling and oxidative stress, and outline the 'multiple biological personalities' of reactive oxygen and nitrogen species: at low concentrations they protect the cell; at higher concentrations they can damage many biological molecules, such as DNA, proteins, and lipids; and, as we argue here, they may also prevent cancer by initiating the death of the transformed cell. Nitric oxide-donating aspirin is discussed as an instructive example: it generates a state of oxidative stress through which it affects several redox-sensitive signalling pathways, leading ultimately to the elimination of the neoplastic cell via apoptosis or necrosis. As additional examples, we discuss the chemopreventive n -3 polyunsaturated fatty acids and conventional nonsteroidal anti-inflammatory drugs, which induce cell death through redox changes. We conclude that modulation of redox biochemistry represents a fruitful approach to cancer prevention.

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Section: Discussionmentioning

confidence: 91%

Induction of oxidative stress as a mechanism of action of chemopreventive agents against cancer

Rigas

Sun

2008

Br J Cancer

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“…Catalase transfection led to a decrease in AEO 2 2 , which suggested at least two possibilities. Either the superoxide measured is produced from H 2 O 2 metabolism, a normal process in cells, 40 induction, but virtually completely blocked apoptosis (Fig. 4c), as measured by Annexin-V (Anx V)-binding.…”

Section: Ros Blockade Blocks Manumycin-a Actionmentioning

confidence: 96%

“…40 Casp9 then activates caspase 3 (Casp3) and other effector caspases, which proceed to cleave and inactivate the DNA repair enzyme PARP (poly ADP ribose polymerase 12 ). Hence, PARP cleavage is used as a classic readout for upstream effector caspase activity.…”

Section: Ros Induction Is Upstream Of Caspase Activationmentioning

confidence: 99%

Reactive oxygen species‐dependent destruction of MEK and Akt in Manumycin stimulated death of lymphoid tumor and myeloma cell lines

Sears

Daino

Carey

2008

Intl Journal of Cancer

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Manumycin-A (Man-A) is a farnesyltransferase inhibitor (FTI), which was originally identified as an effective tumoricide against several cancers, especially ones harboring constitutively active Ras. However, it is becoming apparent that Man-A can stimulate tumor death independently of FTases. Antioxidant treatment blocked Man-A-stimulated DNA damage and reversed Man-Ainhibited tumor growth. However, the precise molecular details of how these reactive oxygen species (ROS) influence cell signaling modules are poorly understood. We examined how ROS may modulate death and survival pathways in a panel of tumor cells. Man-A treatment resulted in a massive induction of superoxide anion (AEO 2 2 ) only in Man-A-sensitive tumors. Within 1 hr, Man-A caused the ROS-dependent activation of caspases 9 and 3. In this time-frame, the Ras-Raf target, MEK, and the survival protein Akt were dephosphorylated in ROS-dependent fashions and then cleaved in ROS and caspase-dependent manners. Pretreatment with ROS scavengers blocked the adverse effects of Man-A, including the processing of caspases and the cleavage of MEK and Akt. These events were noted before any losses in Ras activity or changes in its maturation could be detected. Finally, transfection with cDNAs encoding the antioxidant enzymes catalase, superoxide dismutase and thioredoxin reductase inhibited superoxide induction and apoptosis. Together, our data suggest that the elimination of tumors by Man-A can be independent of the inhibiting of Ras. However, one universal feature observed is the generation of death-triggering intracellular oxidants that appear to directly participate in the select targeting of growth and survival proteins that then either augment or ensure tumor cell death. ' 2007 Wiley-Liss, Inc.Key words: Manumycin; farnesyltransferase inhibitor; MEK; Akt; reactive oxygen species; cleavage; caspase; Ras Ras is a small, 21 kDa, guanosine triphosphate (GTP)-binding protein, which controls numerous cellular functions including growth and proliferation as well as providing scaffolding for other signaling enzymes. Ras regulates the PI3K/Akt and PI3K/mTOR/ p70 S6K signaling modules, which drive cell proliferation, cell growth and survival. 1 Furthermore, the canonical Ras signaling network (Ras/Raf/MEK/ERK) regulates anabolism, induces growth-enhancing genes through transcription factors such as Elk-1 and it also suppresses the activities of proapoptotic proteins. 2 Hence, it is not surprising that 30% of known human tumors and 90% of pancreatic carcinomas, one of the most aggressive and morbid types of cancer, harbor mutated or dysfunctional Ras. [3][4][5] Together these features make Ras an attractive target for cancer therapy.Ras maturation requires the post-translational transfer of a farnesyl hydrocarbon group to its C-terminal cysteine in a process termed prenylation, 6-8 which is essential for the subsequent localization of Ras at the plasma membrane where receptor signals regulate its on and off state. 9 Because prenylation is also required for subsequen...

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“…npg with caspase-9 and Apaf-1, forming the apoptosome and beginning the intrinsic apoptotic process [41,42]. Recently, Eldering et al demonstrated that anti-IgM-mediated apoptosis of Ramos cells invoked a type-2 pathway which was closely associated with the collapse of the mitochondrial membrane potential (DYm), a bona fide measure of overall mitochondrial health [38,40].…”

Section: Il-4 Protects Ch31 From Apoptosis By Akt 948mentioning

confidence: 99%

IL-4 protects the B-cell lymphoma cell line CH31 from anti-IgM-induced growth arrest and apoptosis: contribution of the PI-3 kinase/AKT pathway

Carey

Семенова

et al. 2007

Cell Res

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Interleukin-4 (IL-4) promotes lymphocyte survival and protects primary lymphomas from apoptosis. Previous studies reported differential requirements for the signal transducer and activator of transcription 6 (STAT6) and IRS2/phosphatidylinositol 3 kinase (PI-3K) signaling pathways in mediating the IL-4-induced protection from Fas-mediated apoptosis. In this study, we characterized IL-4-activated signals that suppress anti-IgM-mediated apoptosis and growth arrest of CH31, a model B-cell lymphoma line. In CH31, anti-IgM treatment leads to the loss of mitochondrial membrane potential, phospho-Akt, phospho-CDK2, and c-myc protein. These losses are followed by massive induction of p27 Kip1 protein expression, cell cycle arrest, and apoptosis. Strikingly, IL-4 treatment prevented or reversed these changes. Furthermore, IL-4 suppressed the activation of caspases 9 and 3, and, in contrast to previous reports, induced the phosphorylation (deactivation) of BAD. IL-4 treatment also induced expression of BclxL, a STAT6-dependent gene. Pharmacologic inhibitors and dominant inhibitory forms of PI-3K and Akt abrogated the anti-apoptotic function of IL-4. These results suggest that the IL-4 receptor activates several signaling pathways, with the Akt pathway playing a major role in suppression of the apoptotic program activated by anti-IgM.

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An epigrammatic (abridged) recounting of the myriad tales of astonishing deeds and dire consequences pertaining to nitric oxide and reactive oxygen species in mitochondria with an ancillary missive concerning the origins of apoptosis

Cited by 29 publications

References 107 publications

Induction of oxidative stress as a mechanism of action of chemopreventive agents against cancer

Induction of oxidative stress as a mechanism of action of chemopreventive agents against cancer

Reactive oxygen species‐dependent destruction of MEK and Akt in Manumycin stimulated death of lymphoid tumor and myeloma cell lines

IL-4 protects the B-cell lymphoma cell line CH31 from anti-IgM-induced growth arrest and apoptosis: contribution of the PI-3 kinase/AKT pathway

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