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ROS
ROS
ROS(15) ROS(12)

ROS, chemically reactive molecules containing oxygen, are formed as a natural byproduct of the normal metabolism of oxygen, and have important roles in cell signaling and homeostasis. During times of environmental stress, ROS levels can increase dramatically. Effects of ROS include not only roles in apoptosis, but also induction of host defense genes and mobilization of ion transport systems. Platelets involved in wound repair and blood homeostasis release ROS to recruit additional platelets to sites of injury. Harmful effects of ROS on the cell include damage of DNA, oxidation of polyunsaturated fatty acids, oxidations of amino acids, inactivate specific enzymes by oxidation of co-factors.(1) After growth factor stimulation of RTKs, ROS can trigger activation of signaling pathways involved in cell migration and invasion such as members of the MAPK family - ERK, JNK, and p38 MAPK. ROS can also promote migration by augmenting phosphorylation of the FAK p130Cas and paxilin.(1, 2) A role for ROS in antiviral defense mechanisms has been demonstrated via Rig-like helicase-1 and mitochondiral antiviral signaling protein. Increased levels of ROS potentiate signaling through this mitochondia-associated antiviral receptor to activate IRF-3, IRF-7, and NF&kapp;B, resulting in an antiviral state. If too much damage is present in mitochondria, a cell undergoes apoptosis. Bcl-2 proteins layered on the surface of the mitochondria, detect damage and activate Bax, which punch holes in the mitochondrial membrane, causing Cytc to leak out. This Cytc binds to Apaf-1, or apoptotic protease activating factor-1. Apaf-1 and Cytc bind together to form apoptosomes, which bind to and activate caspase-9. The caspase-9 then cleaves the proteins of the mitochondrial membrane, causing it to break down and start a chain reaction of protein denaturation and eventually phagocytosis of the cell.(1)
Cells defend themselves against ROS damage with enzymes such as α-1-microglobulin, SoDs, catalases, lactoperoxidases, glutathione peroxidases, and peroxiredoxins.(1) SoDs are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. SOD1 is located primarily in the cytoplasm, SOD2 in the mitochondria, and SOD3 is extracellular. SOD1 is a dimer, while the others are tetramers. SOD1 and SOD3 contain copper and zinc ions, while SOD2 has a manganese ion in its reactive center. The genes are located on chromosomes 21, 6, and 4, respectively. Catalase, concentrated in peroxisomes next to mitochondria, reacts with the hydrogen peroxide to catalyze the formation of water and oxygen. Glutathione peroxidase reduces hydrogen peroxide by transferring the energy of the reactive peroxides to a sulfur-containing protein called glutathione.
Although ROS can promote tumor cell proliferation, a great increase in ROS has been associated with reduced cancer cell proliferation by induction of G2/M cell cycle arrest; increased phosphorylation of ataxia telangiectasia mutated (ATM), Chk 1, Chk 2; and reduced cell division cycle 25 homolog c (CDC25). At low levels, ROS facilitates cancer cell survival since cell-cycle progression driven by growth factors and RTKs require ROS for activation and chronic inflammation, a major mediator of cancer, is regulated by ROS.(3) In the extrinsic pathway of apoptosis, ROS are generated by Fas ligand as an upstream event for Fas activation via phosphorylation, which is necessary for subsequent recruitment of Fas-associated protein with death domain and caspase 8 as well as apoptosis induction. In the intrinsic pathway, ROS function to facilitate Cytc release by activating pore-stabilizing proteins (Bcl-2 and Bcl-xL) as well as inhibiting pore-destabilizing proteins (Bcl-2-associated X protein, Bcl-2 homologous antagonist/killer).(4) Cells counterbalance the detrimental effects of ROS by producing antioxidant molecules, such as reduced glutathione (GSH) and thioredoxin (TRX).(1, 5)
Cancer cells exhibit greater ROS stress than normal cells do.(6) Most of the chemotherapeutic and radiotherapeutic agents kill cancer cells by augmenting ROS stress.(7) At lower levels, ROS can activate various transcription factors such as NF-κB, AP-1, HIF-1α, and STAT3, leading to expression of proteins that control inflammation, cellular transformation, tumor cell survival, tumor cell proliferation, invasion, agiogenesis, and metastasis. ROS controls the expression of tumor suppressor genes such as p53, Rb, and PTEN. ROS-related oxidation of DNA is one of the main causes of mutations. The resulting genomic instability directly contributes to carcinogenesis. ROS induces transcription factors and modulate signaling molecules involved in angiogenesis (MMP, VEGF) and metastasis (upregulation of AP-1, CXCR4, AKT and downregulation of PTEN). ROS induces chronic inflammation by the induction of COX-2, inflammatory cytokines (TNFα, IL-1, and IL-6), chemokines (IL-8, CXCR4), and pro-inflammatory transcription factors (NF-κB). These chemokines and chemokine receptors, in turn, promote invasion and metastasis of various tumor types.(1)
ROS-elevating drugs increase cellular ROS stress level, either by direct ROS-generation (e.g. motexafin gadolinium, elesclomol) or by agents that abrogate the inherent antioxidant system such as SOD inhibitor (e.g. ATN-224, 2-methoxyestradiol) and GSH inhibitor (e.g. PEITC, buthionine sulfoximine). The result is an overall increase in endogenous ROS, which when above a cellular tolerability threshold, may induce cell death.(8) On the other hand, normal cells appear to have, under lower basal stress and reserve, a higher capacity to cope with additional ROS-generating insults than cancer cells do.(1, 9)
tNOX is a membrane-bound enzyme complex, found in the plasma membrane and the membranes of phagosomes. Normally, the complex is latent in neutrophils, and is activated to assemble in the membranes during respiratory burst. tNOX generates superoxide by transferring electrons from NADPH which are then coupled to oxygen. In a phagosome, superoxide can spontaneously form hydrogen peroxide that will undergo further reactions to generate ROS.(10) tNOX is found in two types: one in white blood cells and the other in vascular cells, differing in biochemical structure and functions.(11, 12) tNOX is made up of six subunits: a Rho GTPase, e.g. Rac1 or Rac2, and five phox units.(10) Vascular tNOXs are regulated by a variety of hormones and factors known to be important players in vascular remodeling and disease, including thrombin, PDGF, TNFa, lactosylceramide, IL-1, and oxidized LDL.(12, 13) tNOX can be inhibited by apocynin and diphenylene iodonium. Apocynin prevents the assembly of the NADPH oxidase subunits.(10, 14)

Drugs/Indications
Trial Drugs/Indications
Generic Code Old Code Brand Company Indication trials
glutathione NOV-002 Novelos P3: NSCLC; P2: ovarian, Leukemia, BC, MDS trials
darinaparsin SP-02L ZIO-101 Zinapar Solasia P2: HCC, MM, hem, bone, NHL; P1: lymphoma, solid trials
ezatiostat TLK199 Telintra P2: NSCLC, MDS trials
artesunate Dafra P1: BC, HCC, solid trials
ME-143 MEI P1: solid trials
Failed Drugs
Generic Code Old Code Brand Company Indication trials
ranpirnase Onconase Alfacell Last new trial started in 2004; P3: mesothelioma; P2: HNN, NSCLC trials
daporinad APO866 FK866 TopoTarget Last trial started in 2007; P2: lymphoma, melanoma; P1/2: CLL trials
NM-3 Genzyme (Sanofi) Last new trial started in 2001; P1: solid trials


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References

1. Reactive_oxygen_species. Available from: http://en.wikipedia.org/wiki/Reactive_oxygen_species.

2. Tochhawng L, Deng S, Pervaiz S, Yap CT. Redox regulation of cancer cell migration and invasion. Mitochondrion. 2013;13(3):246-53.

3. Irani K, Xia Y, Zweier JL, Sollott SJ, Der CJ, Fearon ER, Sundaresan M, Finkel T, Goldschmidt-Clermont PJ. Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts. Science. 1997;275(5306):1649-52.

4. Martindale JL, Holbrook NJ. Cellular response to oxidative stress: Signaling for suicide and survival*. Journal of Cellular Physiology. 2002;192(1):1-15.

5. Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nature Reviews Cancer. 2011;11(2):85-95.

6. Ramsey MR, Sharpless NE. ROS as a tumour suppressor? Nature Cell Biology. 2006;8(11):1213-5.

7. Renschler MF. The emerging role of reactive oxygen species in cancer therapy. European journal of cancer. 2004;40(13):1934-40.

8. Schumacker PT. Reactive oxygen species in cancer cells: live by the sword, die by the sword. Cancer cell. 2006;10(3):175-6.

9. Trachootham D, Alexandre J, Huang P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nature Reviews Drug Discovery. 2009;8(7):579-91.

10. NADPH_oxidase. Available from: http://en.wikipedia.org/wiki/NADPH_oxidase.

11. Dusting GJ, Selemidis S, Jiang F. Mechanisms for suppressing NADPH oxidase in the vascular wall. Memrias do Instituto Oswaldo Cruz. 2005;100:97-103.

12. NAD(P)H_oxidase. Available from: http://en.wikipedia.org/wiki/NAD(P)H_oxidase.

13. Griendling KK, Sorescu D, Ushio-Fukai M. NAD (P) H oxidase role in cardiovascular biology and disease. Circulation research. 2000;86(5):494-501.

14. Vlahos R, Stambas J, Bozinovski S, Broughton BR, Drummond GR, Selemidis S. Inhibition of Nox2 oxidase activity ameliorates influenza A virus-induced lung inflammation. PLoS pathogens. 2011;7(2):e1001271.

15. Novo E, Parola M. Redox mechanisms in hepatic chronic wound healing and fibrogenesis. Fibrogenesis & tissue repair. 2008;1(1):5.



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Wednesday, September 21, 2016 4:18 AM|Elsevier|JournalTOCs API - Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (50 articles)|Labels: ROS

The Anticancer Agent, Di-2-Pyridylketone 4,4-Dimethyl-3-Thiosemicarbazone (Dp44mT), Up-Regulates the AMPK-Dependent Energy Homeostasis Pathway in Cancer Cells

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Vol. , No. (2016) pp. -
Publication date: Available online 15 September 2016 Source:Biochimica et Biophysica Acta (BBA) - Molecular Cell Research Author(s): Sukriti Krishan, Des R. Richardson, Sumit Sahni Adenosine monophosphate-activated protein kinase (AMPK) is a cellular energy sensor that monitors ATP levels. There is also evidence that AMPK has onco-suppressive properties. Iron plays a crucial role in cellular energy transducing pathways and tumor cell proliferation. Therefore, metals (e.g., iron) could play an important role in the regulation of AMPK-dependent pathways. Hence, this investigation examined the effect of the iron and copper chelator and potent anti-cancer agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), on the AMPK-mediated pathway. These studies demonstrated that Dp44mT, which forms intracellular redox-active complexes with iron and copper, significantly activated AMPK (i.e., p-AMPK/AMPK ratio) in 5 different tumor cell-types. Furthermore, examination of the Dp44mT-metal complexes demonstrated that the effect of Dp44mT on AMPK was due to a dual mechanism: (1) its ability to chelate metal ions; and (2) the generation of reactive oxygen species (ROS). The activation of the AMPK-pathway by Dp44mT was mediated by the upstream kinase, liver kinase B1 (LKB1) that is a known tumor suppressor. Moreover, using AMPKα1-selective silencing, we demonstrated that Dp44mT activated AMPK, resulting in inhibition of acetyl CoA carboxylase 1 (ACC1) and raptor, and activation of Unc-51 like kinase (ULK1). These effects are vital for inhibition of fatty acid synthesis, suppression of protein synthesis and autophagic activation, respectively. Together, this AMPK-mediated repair response aims to rescue the loss of metal ions via chelation and the induction of cytotoxic damage mediated by redox cycling of the Dp44mT-metal ion complex. In conclusion, this study demonstrates for the first time that chelators target the AMPK-dependent pathway.

Friday, September 16, 2016 4:27 PM|Huai-Qiang Ju, Yun-Xin Lu, Dong-Liang Chen, Tian Tian, Hai-Yu Mo, Xiao-Li Wei, Jian-Wei Liao, Feng Wang, Zhao-Lei Zeng, Helene Pelicano, Mitzi Aguilar, Wei-Hua Jia, Rui-Hua Xu|Theranostics|Labels: ROS, CRC

Colorectal cancer (CRC) is a common neoplastic disease and a frequent cause of death. Drug resistance is a major challenge to CRC treatment and stem-like side-population (SP) cells may play a key role in this resistance. Although it has been recognized that cancer stem cells may be affected by redox status, the underlying mechanisms for this effect and the roles of celllular redox adaptation and antioxidant capacity in CRC remain elusive. Our study shows that CRC SP cells are highly dependent on cellular GSH to maintain ROS levels below those of non-SP cells. Exposing CRC cells to H2O2 produced a significant decrease in the percentage of SP cells, which was rescued by adding N-acetylcysteine. Mechanistically, CD44v interacts with and stabilizes xCT and thereby promotes the uptake of cysteine for GSH synthesis and stimulates SP cell enrichment. Additionally, miR-1297 levels were inversely correlated with the expression of xCT; thus, reduced miR-1297 contributes to SP cell enrichment in CRC tumors, which results in tumor aggressiveness and poor clinical outcomes. Importantly, redox modification by PEITC significantly reduces CRC SP cells in vitro and impairs tumors growth in vivo. The combination of 5FU and PEITC led to synergistic cytotoxic effects against CRC cells in vitro and in vivo. Taken together, our data suggest that a GSH-mediated reduction in cellular ROS levels is an essential regulator of CRC SP cells mediated by the CD44v-xCT axis, and disrupting the redox status may eliminate the chemotherapy-resistant CRC SP cells with potentially significant benefits for cancer treatment.

Wednesday, September 14, 2016 10:11 PM|Maria V. Yusenko, Dmitry Zubakov, Gyula Kovacs|International Journal of Biological Sciences|Labels: ROS, kidney cancer, biomarker diagnostic

Due to overlapping morphology, malignant chromophobe renal cell carcinomas (RCC) and benign renal oncocytomas (RO) may pose a diagnostic problem. In the present study, we have applied different algorithms to evaluate the data sets obtained by hybridisation of pooled and also individual samples of renal cell tumours (RCT) onto two different gene expression platforms. The two approaches revealed high similarities in the gene expression profiles of chromophobe RCCs and ROs but also some differences. After identifying the differentially expressed genes by statistic analyses, the candidate genes were further selected by a real time and normal RT-PCR and their products were analysed by immunohistochemistry. We have identified CD82 and S100A1 as valuable markers for chromophobe RCC as well as AQP6 for ROs. However, these genes are expressed at the protein level in other types of RCTs as well albeit at a low frequency and low intensity. As none of the selected genes marks exclusively one type of RCTs, for the differential diagnosis of chromophobe RCCs and ROs, a set of markers such as CD82, S100A1 and AQP6 as well as some others would be an option in routine histological laboratories.

Wednesday, September 14, 2016 4:42 PM|P03 : Last 10 articles|Labels: ROS
Background/Aims: The bis-indole alkaloid Fascaplysin is effective against malignancy, an effect at least partially due to stimulation of tumor cell apoptosis. Similar to apoptosis of nucleated cells, erythrocytes could enter suicidal erythrocyte death or eryptosis, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i), oxidative stress and ceramide. The present study explored, whether Fascaplysin induces eryptosis and, if so, to shed light on the cellular mechanisms involved. Methods: Flow cytometry was employed to estimate phosphatidylserine exposure at the cell surface from annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, ROS formation from DCFDA dependent fluorescence, and ceramide abundance utilizing specific antibodies. Hemolysis was quantified from the hemoglobin concentration in the supernatant. Results: A 48 hours exposure of human erythrocytes to Fascaplysin (≥ 5 µM) significantly increased the percentage of annexin-V-binding cells, significantly decreased forward scatter, and significantly increased Fluo3-fluorescence, DCFDA fluorescence as well as ceramide abundance. The effect of Fascaplysin on annexin-V-binding and forward scatter was significantly blunted but not abolished by removal of extracellular Ca2+. Conclusions: Fascaplysin triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part due to Ca2+ entry, oxidative stress and ceramide.
Cell Physiol Biochem 2016;39:1638-1647
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: ALK, ROS
This is an open-label, multicenter, global Phase 2 basket study of entrectinib (RXDX-101) for the treatment of patients with solid tumors that harbor an NTRK1/2/3, ROS1, or ALK gene rearrangement. Patients will be assigned to different baskets according to tumor type and gene rearrangement. NSCLC and mCRC will be the main patient populations of interest
Tuesday, September 13, 2016 11:38 PM|Miroslav Genov, Birgit Kreiseder, Michael Nagl, Elisabeth Drucker, Martina Wiederstein, Barbara Muellauer, Julia Krebs, Teresa Grohmann, Dagmar Pretsch, Karl Baumann, Markus Bacher, Alexander Pretsch, Christoph Wiesner|Journal of Cancer|Labels: NFKb, P53, ROS, melanoma

Background: Malignant melanoma is an aggressive type of skin cancer with high risk for metastasis and chemoresistance. Disruption of tightly regulated processes such as cell cycle, cell adhesion, cell differentiation and cell death are predominant in melanoma development. So far, conventional treatment options have been insufficient to treat metastatic melanoma and survival rates are poor. Anthraquinone compounds have been reported to have anti-tumorigenic potential by DNA-interaction, promotion of apoptosis and suppression of proliferation in various cancer cells.

Methods: In the current study, the racemic tetrahydroanthraquinone derivative (±)-4-deoxyaustrocortilutein (4-DACL) was synthesized and the cytotoxic activity against melanoma cells and melanoma spheroids determined by CellTiter-Blue viability Assay and phase contrast microscopy. Generation of reactive oxygen species (ROS) was determined with CellROX Green and Deep Red Reagent kit and microplate-based fluorometry. Luciferase reporter gene assays for nuclear factor kappa B (NF-κB) and p53 activities and western blotting analysis were carried out to detect the expression of anti-proliferative or pro-apoptotic (p53, p21, p27, MDM2, and GADD45M) and anti-apoptotic (p65, IκB-α, IKK) proteins. Cell cycle distribution and apoptosis rate were detected by flow cytometry, the morphological changes visualized by fluorescence microscopy and the activation of different caspase cascades distinguished by Caspase Glo 3/7, 8 and 9 Assays.

Results: We demonstrated that 4-DACL displayed high activity against different malignant melanoma cells and melanoma spheroids and only low toxicity to melanocytes and other primary cells. In particular, 4-DACL treatment induced mitochondrial ROS, reduced NF-κB signaling activity and increased up-regulation of the cell cycle inhibitors cyclin-dependent kinase inhibitor p21 (p21WAF1/Cip1) and the tumor suppressor protein p53 in a dose-dependent manner, which was accompanied by decreased cell proliferation and apoptosis via the intrinsic pathway.

Conclusion: According to these results, we suggest that 4-DACL may be a promising therapeutic agent for the treatment of malignant melanoma.

Tuesday, September 13, 2016 11:38 PM|Laura H. Engelke, Alexandra Hamacher, Peter Proksch, Matthias U. Kassack|Journal of Cancer|Labels: EGFR, ROS, ovarian cancer

Purpose. Several studies have shown that natural compounds like resveratrol or ellagic acid have anticancer and antioxidant properties and can stimulate apoptosis in many cancer cell lines. The aim of this study was to elucidate if resveratrol or ellagic acid, respectively, could improve the efficacy of cisplatin in ovarian cancer.

Methods. As a cellular resistance model, the epithelial ovarian cancer cell line A2780 and its cisplatin-resistant subclone A2780CisR were used. A2780CisR was obtained by intermittent treatment of A2780 with cisplatin for 26 weekly cycles and showed a 4-6-fold increased resistance towards cisplatin compared to A2780.

Results. Pretreatment with resveratrol or ellagic acid 48 h prior to treatment with cisplatin showed a moderate enhancement of cisplatin cytotoxicity in A2780CisR cells (shift factors were 1.6 for ellagic acid and 2.5 for resveratrol). However, intermittent treatment of A2780 with cisplatin for 26 weekly cycles in permanent presence of resveratrol or ellagic acid, respectively, completely prevented the development of cisplatin resistance. The generated cell lines named A2780Resv and A2780Ellag displayed functional characteristics (migration, proliferation, apoptosis, activation of ErbB3, ROS generation) similar to the parental cell line A2780.

Conclusion. In conclusion, weekly intermittent treatment cycles of cisplatin-sensitive ovarian cancer cells with cisplatin retain cisplatin chemosensitivity in permanent presence of ellagic acid or resveratrol, respectively, whereas clinically relevant cisplatin chemoresistance develops in the absence of ellagic acid or resveratrol. Use of natural phenolic compounds may thus be a promising approach to prevent cisplatin resistance in ovarian cancer.

Monday, September 12, 2016 6:00 PM|Donatella Tramontano|International Journal of Molecular Sciences|Labels: ROS, prostate cancer
Resveratrol, a dietary polyphenol, is under consideration as chemopreventive and chemotherapeutic agent for several diseases, including cancer. However, its mechanisms of action and its effects on non-tumor cells, fundamental to understand its real efficacy as chemopreventive agent, remain largely unknown. Proline-rich tyrosine kinase 2 (PYK2), a non-receptor tyrosine kinase acting as signaling mediator of different stimuli, behaves as tumor-suppressor in prostate. Since, PYK2 and RSV share several fields of interaction, including oxidative stress, we have investigated their functional relationship in human non-transformed prostate EPN cells and in their tumor-prone counterpart EPN-PKM, expressing a PYK2 dead-kinase mutant. We show that RSV has a strong biological activity in both cell lines, decreasing ROS production, inducing morphological changes and reversible growth arrest, and activating autophagy but not apoptosis. Interestingly, the PYK2 mutant increases basal ROS and autophagy levels, and modulates the intensity of RSV effects. In particular, the anti-oxidant effect of RSV is more potent in EPN than in EPN-PKM, whereas its anti-proliferative and pro-autophagic effects are more significant in EPN-PKM. Consistently, PYK2 depletion by RNAi replicates the effects of the PKM mutant. Taken together, our results reveal that PYK2 and RSV act on common cellular pathways and suggest that RSV effects on prostate cells may depend on mutational-state or expression levels of PYK2 that emerges as a possible mediator of RSV mechanisms of action. Moreover, the observation that resveratrol effects are reversible and not associated to apoptosis in tumor-prone EPN-PKM cells suggests caution for its use in humans.
Tuesday, September 6, 2016 6:00 PM|Chih-Hsin Tang|International Journal of Molecular Sciences|Labels: electron transport, ROS, childhood cancer
Chondrosarcoma is a highly malignant cartilage-forming bone tumor that has the capacity to invade locally and cause distant metastasis. Moreover, chondrosarcoma is intrinsically resistant to conventional chemotherapy or radiotherapy. The novel benzofuran derivative, BL-038 (2-amino-3-(2,6-dichlorophenyl)-6-(4-methoxyphenyl)benzofuran-4-yl acetate), has been evaluated for its anticancer effects in human chondrosarcoma cells. BL-038 caused cell apoptosis in two human chondrosarcoma cell lines, JJ012 and SW1353, but not in primary chondrocytes. Treatment of chondrosarcoma with BL-038 also induced reactive oxygen species (ROS) production. Furthermore, BL-038 decreased mitochondrial membrane potential (MMP) and changed mitochondrial-related apoptosis, by downregulating the anti-apoptotic activity members (Bcl-2, Bcl-xL) and upregulating pro-apoptotic members (Bax, Bak) of the B-cell lymphoma 2 (Bcl-2) family of proteins, key regulators of the apoptotic machinery in cells. These results demonstrate that in human chondrosarcoma cells, the apoptotic and cytotoxic effects of BL-038 are mediated by the intrinsic mitochondria-mediated apoptotic pathway, which in turn causes the release of cytochrome c, the activation of caspase-9 and caspase-3, and the cleavage of poly (ADP-ribose) polymerase (PARP), to elicit apoptosis response. Our results show that the benzofuran derivative BL-038 induces apoptosis in chondrosarcoma cells.
Wednesday, August 31, 2016 10:05 PM|Cheng, C.-T., Kuo, C.-Y., Ouyang, C., Li, C.-F., Chung, Y., Chan, D. C., Kung, H.-J., Ann, D. K.|Cancer Research current issue|Labels: electron transport, ROS, breast cancer
Mitochondrial dynamics during nutrient starvation of cancer cells likely exert profound effects on their capability for metastatic progression. Here, we report that KAP1 (TRIM28), a transcriptional coadaptor protein implicated in metastatic progression in breast cancer, is a pivotal regulator of mitochondrial fusion in glucose-starved cancer cells. Diverse metabolic stresses induced Ser473 phosphorylation of KAP1 (pS473-KAP1) in a ROS- and p38-dependent manner. Results from live-cell imaging and molecular studies revealed that during the first 6 to 8 hours of glucose starvation, mitochondria initially underwent extensive fusion, but then subsequently fragmented in a pS473-KAP1-dependent manner. Mechanistic investigations using phosphorylation-defective mutants revealed that KAP1 Ser473 phosphorylation limited mitochondrial hyperfusion in glucose-starved breast cancer cells, as driven by downregulation of the mitofusin protein MFN2, leading to reduced oxidative phosphorylation and ROS production. In clinical specimens of breast cancer, reduced expression of MFN2 corresponded to poor prognosis in patients. In a mouse xenograft model of human breast cancer, there was an association in the core region of tumors between MFN2 downregulation and the presence of highly fragmented mitochondria. Collectively, our results suggest that KAP1 Ser473 phosphorylation acts through MFN2 reduction to restrict mitochondrial hyperfusion, thereby contributing to cancer cell survival under conditions of sustained metabolic stress. Cancer Res; 76(17); 5006–18. ©2016 AACR.
Saturday, August 20, 2016 6:00 PM|Krishna S. Tummala, Filippos Kottakis, Nabeel Bardeesy|Trends in Molecular Medicine|Labels: ROS, pancreatic cancer
Cancer requires mechanisms to mitigate reactive oxygen species (ROS) generated during rapid growth, such as induction of the antioxidant transcription factor, Nrf2. However, the targets of ROS-mediated cytotoxicity are unclear. Recent studies in pancreatic cancer show that redox control by Nrf2 prevents cysteine oxidation of the mRNA translational machinery, thereby supporting efficient protein synthesis.
Sunday, August 14, 2016 10:05 PM|Farge, T.|Clinical Cancer Research recent issues|Labels: ROS, AML

The major therapeutic barrier in acute myeloid leukemia (AML) is chemotherapy resistance. AML cells resistant to conventional chemotherapy targeting DNA synthesis are thought to be enriched in quiescent leukemic stem cells (LSCs). In order to better understand chemotherapy resistance in AML, we analyzed the response to cytarabine (AraC) through patient-derived xenograft (PDX) models with 20 primary AML patient specimens from two clinical sites and in the context of a French "Innovative models initiative" (IMODI) program. After confirming AML engraftment, highly immunodeficient NOD/LtSz-scid IL2Rc null (NSG) mice were treated with AraC administered IP for 5 days as a single agent at 60 mg/kg daily, which correlates with human dosing. In all mice treated with this regimen, there was a significant but variable cytoreductive effect (4- to 46-fold reduction of tumor cell burden; 2- to 13-fold induction of apoptosis) at 3 days post-treatment. This in vivo AraC response in PDX models has been compared to clinicobiological data of their matched patients (including overall survival, FAB classification, and age at diagnosis). Furthermore, residual leukemic cells (RLCs), surviving after in vivo AraC treatment, have been characterized for their cell surface phenotype, stem cell frequency, cell cycle and metabolic status. Gene expression of RLCs from three different PDX models showed an enrichment of genes involved in inflammatory, immune and stress/ROS responses. When tested in three independent cohorts of AML patients (Verhaak et al. 2009; TGCA. 2011; Metzeler et al. 2011), the down-regulated gene signature is associated with an unfavorable prognosis in patients treated with intensive chemotherapy. Altogether, these results suggest a novel model of AraC chemotherapy resistance uncovering the control of the oxidative and mitochondrial energy metabolism in vivo and the relevance of PDX models for clinical investigations and new preclinical drug assessment. Further studies of the role of immune and stromal microenvironment will be assessed in this model to extend our findings in a more relevant setting.

Citation Format: Thomas Farge{Authors}. Studying cytarabine resistance through PDX models in acute myeloid leukemia. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B06.

Monday, August 1, 2016 10:05 PM|Unknown Author|Cancer Discovery recent issues|Labels: ALK, ROS, lung cancer, clinical trial

Data from a phase I study indicate that the investigational ALK inhibitor lorlatinib is active in patients with ALK- or ROS1-positive non–small cell lung cancer, including those with brain metastases. Objective responses were seen among patients with known ALK resistance mutations who had relapsed following treatment with other tyrosine kinase inhibitors.

Monday, August 1, 2016 3:09 PM|Sumitomo, Y., Koya, J., Nakazaki, K., Kataoka, K., Tsuruta-Kishino, T., Morita, K., Sato, T., Kurokawa, M.|BLOOD First Edition Papers|Labels: ROS, AML

Despite advances in the treatment of acute myeloid leukemia (AML), relapse and drug resistance frequently occur. Therefore, detailed mechanisms of refractoriness, including leukemia-initiating cell (LIC) biology, should be elucidated to treat AML. The self-degradative property of cytosolic macromolecules is central to autophagy and can contribute to homeostasis and stress response. Recent reports suggest the importance of autophagy in hematopoietic stem cells and various tumors. Thus, this study investigated the functional role of autophagy in AML maintenance and drug resistance using tamoxifen-inducible conditional knockout mice of Atg5 or Atg7, which are essential genes for autophagy, combined with an MLL-ENL-induced murine AML model. Inactivation of autophagy by deletion of Atg5 or Atg7 prolonged survival in leukemic mice and reduced functional LICs. Atg7-deficient LICs displayed enhanced mitochondrial activity and ROS production together with increased cell death. In addition, Atg7 deletion markedly decreased peripheral blood leukemia cells, concurrent with increased apoptosis, suggesting a higher dependency on autophagy compared to bone marrow leukemia cells. Finally, cytarabine (AraC) treatment activated autophagy in LICs, and Atg7 deletion potentiated the therapeutic effects of AraC, which included decreased LICs and prolonged survival, suggesting that autophagy contributes to AraC resistance. Our results highlight the intratumoral heterogeneity related to autophagy in AML and the unique role of autophagy in leukemia development and drug resistance.

Thursday, July 28, 2016 7:56 AM|Hanley, C. J., Mellone, M., Thomas, G. J.|Cancer Research recent issues|Labels: ROS
Purpose: Smooth muscle actin (SMA)-positive myofibroblasts (cancer-associated fibroblasts), within the tumor microenvironment, promote many of the hallmarks of malignancy and correlate with poor prognosis in multiple cancer types. The purpose of this study was to investigate the mechanisms regulating myofibroblast differentiation in solid tumors in order to therapeutically target this cell population.Experimental procedures:Clinical Samples: Human tumor samples were analyzed by immunohistochemistry and RNA sequencing followed by bioinformatics analyses.In vitro: Myofibroblast differentiation was analyzed in Human fetal foreskin fibroblasts (HFFF2), adult primary fibroblasts and cancer associated fibroblasts (CAFs) by Western blotting for α-SMA; immunofluorescence for α-SMA stress fiber formation; collagen gel contraction assays and analysis of gene expression by RNA sequencing/PCR. Intracellular Reactive Oxygen Species (ROS) generation was measured using FACS analysis of DCFH-DA fluorescence.In vivo: To monitor tumor growth in vivo, a xenograft model of Head 5PT) co-injected with HFFF2s in B6.129S7-Rag1tm1Mom/J mice; and an isograft model (K2) in C57BL/6-Tg(TRAMP)8247Ng/J mice was used. Lymph node (LN) metastases were assayed in the 5PT model using the LI-COR IRDye® 800CW 2-DG Optical Probe. Myofibroblast accumulation was assessed by immunohistochemistry for α-SMA and collagen deposition by Masson's trichrome staining.Results: Using TGF-β1 treatment to model fibroblast-to-myofibroblast differentiation in vitro, we found that a delayed phase of intracellular ROS generation, beginning 24/48 hours post-treatment was required to induce differentiation in HFFF2s and adult primary fibroblasts.RNA-Sequencing of fibroblasts treated with TGF-β1 showed that NOX4 was the most significantly up-regulated ROS-producing enzyme. NOX4 was also found to be up-regulated in the stroma of multiple solid tumors, co-localized with α-SMA, and correlating with a myofibroblast gene signature.Genetic (si/shRNA) and pharmacological (GKT137831) inhibition of NOX4 abrogated multiple processes associated with myofibroblast differentiation, down-stream of TGF-β1: suppressing ROS generation; α-SMA expression; collagen gel contraction and expression of genes associated with ECM deposition (COL1A1, COL3A1, FN1 and CTGF). Furthermore, NOX4 inhibition reversed the myofibroblast phenotype in Cancer Associated Fibroblasts (CAFs) isolated from HNSCC and esophageal adenocarcinoma.Genetic and pharmacological inhibition of NOX4 in fibroblasts significantly slowed tumor growth and myofibroblast accumulation in the 5PT and K2, in vivo, model systems. Notably, LN metastases in the 5PT model were significantly reduced following shRNA mediated NOX4 knockdown in HFFF2s.Conclusions: NOX4 is a critical regulator of myofibroblast accumulation in multiple tumor types. Fibroblast-specific inhibition of this enzyme suppresses tumor growth and metastatic spread, suggesting that NOX4 is a promising therapeutic target for preventing myofibroblast differentiation within the tumor microenvironment.Citation Format: Christopher J. Hanley, Massimiliano Mellone, Gareth J. Thomas. Targeting NOX4 in the tumor microenvironment inhibits myofibroblast differentiation and suppresses tumor progression. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B15.
Thursday, July 28, 2016 7:56 AM|Tseng, H.-Y., Chen, Y.-A., Chen, Y.-R., Hsu, H.-L.|Cancer Research recent issues|Labels: electron transport, ROS
The underlying mechanism of oncogene activation that induces reactive oxygen species (ROS) generation and promotes tumor progression and metastasis is still ambiguous. We now demonstrate that the oncogenic MCT-1 activation protects cells from oxidative damage via increase of YY1 and subsequently enhances EGFR expression and activation. Overexpressing MCT-1 induces cell invasion, intracellular ROS generation and MnSOD expression in mitochondria via YY1 pathway, thus targeting YY1 suppresses cancer cell invasion and blocks EGFR-MnSOD signaling function enhanced by MCT-1. Recapitulating in vitro outcomes, MCT-1 increment promotes tumor angiogenesis, necrosis and metastasis with oxidative metabolism deregulation and malignant microenvironment development in xenograft mice. Clinical data also confirms that MCT-1 enrichment connects to poor survival and prognosis coincident with YY1, EGFR and MnSOD upregulation in patients with lung cancer. Collectively, MCT-1 is a key inducer of YY1-EGFR-MnSOD axis involving the redox mechanism in the process of carcinogenesis.Citation Format: Hong-Yu Tseng, Yen-An Chen, Yi-Rong Chen, Hsin-Ling Hsu. Oncogene MCT-1 deregulates oxidative metabolism and promotes tumor metastasis via YY1 signaling network. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B02.
Wednesday, July 13, 2016 6:00 PM|Xu Dong Zhang|JournalTOCs API - Journal of Investigative Dermatology (875 articles)|Labels: ROS, melanoma

Reactive oxygen species dictate the apoptotic response of melanoma cells to TH588
Jia Yu Wang Lei Jin, Xu Guang Yan, Simonne Sherwin, Margaret Farrelly, Yuan Yuan Zhang, Fen Liu, Chun Yan Wang, Su Tang Guo, Hamed Yari, Ting La, Jennifer McFarlane, Fu Xi Lei, Hessam Tabatabaee, Jie Zhong Chen, Amanda Croft, Chen Chen Jiang, Xu Dong Zhang
Journal of Investigative Dermatology, Vol. , No. (2016) pp. -
The effect of MTH1 inhibition on cancer cell survival has been elusive. Here we report that while silencing of MTH1 does not affect survival of melanoma cell, TH588, one of the first-in-class MTH1 inhibitors, kills melanoma cells through apoptosis independently of its inhibitory effect on MTH1. Induction of apoptosis by TH588 was not alleviated by MTH1 overexpression or introduction of the bacterial homologue of MTH1 that has 8-oxodGTPase activity but can not be inhibited by TH588, indicating that MTH1 inhibition is not the cause of TH588-induced killing of melanoma cells.

Monday, June 27, 2016 10:52 AM|SHIMAMURA, Y., TAMATANI, D., KUNIYASU, S., MIZUKI, Y., SUZUKI, T., KATSURA, H., YAMADA, H., ENDO, Y., OSAKI, T., ISHIZUKA, M., TANAKA, T., YAMANAKA, N., KURAHASHI, T., UTO, Y.|Anticancer Research recent issues|Labels: electron transport, ROS, breast cancer

Background/Aim: 5-Aminolevulinic acid (5-ALA), a precursor of protoporphyrin IX (PpIX), is now used for photodynamic therapy (PDT) of pre-cancers of the skin and photodynamic diagnosis (PDD) of brain tumors. Sonodynamic therapy (SDT) of cancers with ultrasound has been studied using 5-ALA as a sonosensitizer. In this article, we evaluated the sonosensitizing activity and mode of action of 5-ALA/PpIX by using mouse mammary tumor EMT6 cells. Results: 5-ALA-SDT showed significant antitumor effects toward EMT6 cells in vitro and in vivo. The fluorescence of MitoSOX Red, an indicator specific for mitochondrial superoxide, was significantly increased by 5-ALA-SDT. Moreover, the fluorescence derived from JC-1, an indicator of mitochondrial membrane potential, was also significantly increased by 5-ALA-SDT. These findings suggest that mitochondria are one of the target organelles of 5-ALA-SDT. PpIX enhanced reactive oxygen species (ROS) production from tert-butyl hydroperoxide (tBHP), suggesting that PpIX might stabilize or promote ROS generation from tBHP. Conclusion: 5-ALA-SDT showed an antitumor effect in mouse mammary tumor EMT6 cells through oxidation of the mitochondrial membrane via ROS production.

Tuesday, June 7, 2016 8:29 AM|Gina M. DeNicola et al.|Department of Surgery Faculty Papers|Labels: RAS, ROS

Reactive oxygen species (ROS) are mutagenic and may thereby promote cancer. Normally, ROS levels are tightly controlled by an inducible antioxidant program that responds to cellular stressors and is predominantly regulated by the transcription factor Nrf2 (also known as Nfe2l2) and its repressor protein Keap1 (refs 2-5). In contrast to the acute physiological regulation of Nrf2, in neoplasia there is evidence for increased basal activation of Nrf2. Indeed, somatic mutations that disrupt the Nrf2-Keap1 interaction to stabilize Nrf2 and increase the constitutive transcription of Nrf2 target genes were recently identified, indicating that enhanced ROS detoxification and additional Nrf2 functions may in fact be pro-tumorigenic. Here, we investigated ROS metabolism in primary murine cells following the expression of endogenous oncogenic alleles of Kras, Braf and Myc, and found that ROS are actively suppressed by these oncogenes. K-Ras(G12D), B-Raf(V619E) and Myc(ERT2) each increased the transcription of Nrf2 to stably elevate the basal Nrf2 antioxidant program and thereby lower intracellular ROS and confer a more reduced intracellular environment. Oncogene-directed increased expression of Nrf2 is a new mechanism for the activation of the Nrf2 antioxidant program, and is evident in primary cells and tissues of mice expressing K-Ras(G12D) and B-Raf(V619E), and in human pancreatic cancer. Furthermore, genetic targeting of the Nrf2 pathway impairs K-Ras(G12D)-induced proliferation and tumorigenesis in vivo. Thus, the Nrf2 antioxidant and cellular detoxification program represents a previously unappreciated mediator of oncogenesis.

Thursday, March 24, 2016 6:00 PM|Wang Min|Cancers|Labels: electron transport, ROS
Cancer cell can reprogram their energy production by switching mitochondrial oxidative phosphorylation to glycolysis. However, mitochondria play multiple roles in cancer cells, including redox regulation, reactive oxygen species (ROS) generation, and apoptotic signaling. Moreover, these mitochondrial roles are integrated via multiple interconnected metabolic and redox sensitive pathways. Interestingly, mitochondrial redox proteins biphasically regulate tumor progression depending on cellular ROS levels. Low level of ROS functions as signaling messengers promoting cancer cell proliferation and cancer invasion. However, anti-cancer drug-initiated stress signaling could induce excessive ROS, which is detrimental to cancer cells. Mitochondrial redox proteins could scavenger basal ROS and function as “tumor suppressors” or prevent excessive ROS to act as “tumor promoter”. Paradoxically, excessive ROS often also induce DNA mutations and/or promotes tumor metastasis at various stages of cancer progression. Targeting redox-sensitive pathways and transcriptional factors in the appropriate context offers great promise for cancer prevention and therapy. However, the therapeutics should be cancer-type and stage-dependent.
Tuesday, March 22, 2016 4:00 PM|Cell Biology International|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: caspase, ROS, lung cancer
In this study, using non-small cell lung cancer cell A549 to screen against a structurally novel and diverse synthetic small molecule library of 2,400 compounds, we identified a molecule named rosline that has strong anti-proliferation activity on A549 cells with a 50% cell growth inhibitory concentration (IC50 ) of 2.87 ± 0.39µM. We showed that rosline treatment increased the number of Annexin V-positive staining cell, as well as G2/M arrest in their cell cycle progression. Further, we have demonstrated that rosline induces a decrease of mitochondrial membrane potential (Δϕm) and an increase of caspase 3/7 and caspase 9 activities in A549 cells, while having no effect on the activity of caspase 8. Moreover, we found that rosline could induce the production of reactive oxygen speci...

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Sunday, March 20, 2016 4:00 PM|Free Radical Biology and Medicine|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ROS, lung cancer
In this study, we found LZ-106, an analogue of enoxacin, exhibiting potent inhibitory effects on NSCLC in both cultured cells and xenograft mouse model. We identified apoptosis-inducing action of LZ-106 in NSCLC cells through the mitochondrial and endoplasmic reticulum (ER)-stress apoptotic pathways via Annexin-V/PI double-staining assay, membrane potential detection, calcium level detection and the expression analysis of the key apoptotic proteins. Through comet assay, reactive oxygen species (ROS) detection, the expression analysis of DNA damage response (DDR) marker γ-H2AX and other DDR-related proteins, we also demonstrated that LZ-106 notably induced ROS overproduction and DDR. Interestingly, additional evidence in our findings revealed that DDR and apoptosis could be alleviated in t...
Saturday, March 19, 2016 9:00 PM|Chinese Journal of Lung Cancer|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, ROS, lung cancer
Conclusion The clinical features, efficacy, and adverse events of crizotinib in the treatment of the 40 patients with ALK/ROS1-positive NSCLC are similar to the data from the previous reports. The most common site of progression was brain metastases. The treatment of crizotinib-resistant patients using 2nd/3rd generation ALK-TKI could delay progression. DOI: 10.3779/j.issn.1009-3419.2016.03.07 (Source: Chinese Journal of Lung Cancer)
Thursday, March 17, 2016 4:00 PM|Investigational New Drugs|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ROS, CRC
Abstract Sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] (NKP-1339) is a clinically investigated ruthenium-based metal complex, which shows promising results in solid tumors, such as non-small cell lung cancer, colorectal carcinoma, and most distinctively in gastrointestinal neuroendocrine tumors. In previous studies, fast binding to albumin as well as transferrin could be shown. The enhanced permeability and retention (EPR) effect, which is diversely being exploited for tumor targeting, could therefore be applicable for NKP-1339. Here we studied the serum dependence of its biological activity in various methods, influencing its cellular accumulation, cytotoxicity as well as the generation of reactive oxygen species (ROS). ROS lead to Nrf2 activation, which is known to ...
Monday, March 14, 2016 5:00 PM|Pharmaceutical Technology|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ROS, lung cancer, clinical trial
Pfizer has received approval from the US Food and Drug Administration (FDA) for a supplemental new drug application (sNDA) for Xalkori (crizotinib) to treat patients with ROS1-positive metastatic non-small cell lung cancer (NSCLC). (Source: Pharmaceutical Technology)
Monday, March 14, 2016 12:13 PM|American Cancer Society :: News and Features|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, ROS, lung cancer
By Stacy SimonThe US Food and Drug Administration (FDA) has approved the first treatment for people with advanced, ROS1-positive non-small cell lung cancer. These tumors have a mutation in the ROS1 gene that affects only about 1% of people with non-small cell lung cancer. Many people with this type of lung cancer tend to be younger than the average lung cancer patient and are less likely to have been smokers.The drug, Xalkori (crizotinib), was previously approved for patients with advanced non-small cell lung cancer that has a mutation in a gene called ALK. It’s a targeted therapy that works by blocking the changes in the lung cancer cells that help them grow.The FDA based its latest approval of Xalkori on a study of 50 people with ROS1-positive non-small cell lung cancer that had sp...
Friday, March 11, 2016 2:30 PM|Medscape Hematology-Oncology Headlines|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ROS, lung cancer, regulatory
The FDA has approved crizotinib for the treatment for patients with ROS-1-positive non-small cell lung cancer. FDA Approvals (Source: Medscape Hematology-Oncology Headlines)
Friday, February 19, 2016 4:00 PM|Apoptosis|MedWorm: Cancer Therapy|Comments|Labels: ROS, breast cancer
In this study we report that HAP induced activation and over expression of PAR-1 in breast cancer cells (EAC). Immunoprecipitation studies have shown that HAP specifically binds with PAR-1. HAP mediated activation of PAR-1 caused nuclear translocation of p50–p65 and the phosphorylation of p38 which triggered the activation of NFκB and MAP kinase signaling pathways. These signaling pathways enhanced the cellular ROS level in malignant cells that induced the intrinsic pathway of cell apoptosis. PAR-1 mediated apoptosis by HAP of malignant breast cells without effecting normal healthy cells in the same environment makes it a good therapeutic agent for treatment of cancer. (Source: Apoptosis)
Sunday, February 7, 2016 4:00 PM|Biochemical and Biophysical Research communications|MedWorm: Cancer Therapy|Comments|Labels: ROS, pancreatic cancer
Authors: Jeong SM, Hwang S, Seong RH Abstract The transferrin receptor (TfR1) is upregulated in malignant cells and its expression is associated with cancer progression. Because of its pre-eminent role in cell proliferation, TfR1 has been an important target for the development of cancer therapy. Although TfR1 is highly expressed in pancreatic cancers, what it carries out in these refractory cancers remains poorly understood. Here we report that TfR1 supports mitochondrial respiration and ROS production in human pancreatic ductal adenocarcinoma (PDAC) cells, which is required for their tumorigenic growth. Elevated TfR1 expression in PDAC cells contributes to oxidative phosphorylation, which allows for the generation of ROS. Importantly, mitochondrial-derived ROS are essential for P...
Tuesday, February 2, 2016 4:00 PM|Cancer Chemotherapy and Pharmacology|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, BRAF, EGFR, PI3K, RAS, ROS, lung cancer
Conclusion Combined analysis of these commonly studied genes may promote the individual treatment in NSCLC. RRM1 may be a prognostic and predictive biomarker for PFS in patients with NSCLC who received platinum-based adjuvant chemotherapy, and combining EGFR mutation and RRM1 expression or combining ERCC1 and RRM1 expression can enhance prognostic and predictive power for PFS. (Source: Cancer Chemotherapy and Pharmacology)
Friday, January 29, 2016 8:39 PM|Oncotarget|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: MapK, ROS, lung cancer
Authors: Xie D, Wu X, Lan L, Shangguan F, Lin X, Chen F, Xu S, Zhang Y, Chen Z, Huang K, Wang R, Wang L, Song X, Liu Y, Lu B Abstract Mitochondrial transcription factor A (TFAM) is essential for the replication, transcription and maintenance of mitochondrial DNA (mtDNA). The role of TFAM in non-small cell lung cancer (NSCLC) remains largely unknown. Herein, we report that downregulation of TFAM in NSCLC cells resulted in cell cycle arrest at G1 phase and significantly blocked NSCLC cell growth and migration through the activation of reactive oxygen species (ROS)-induced c-Jun amino-terminal kinase(JNK)/p38 MAPK signaling and decreased cellular bioenergetics. We further found that TFAM downregulation in NSCLC cells led to increased apoptotic cell death and enhanced the sensitivity o...
Tuesday, January 26, 2016 4:00 PM|Tumor Biology|MedWorm: Cancer Therapy|Comments|Labels: ROS, breast cancer
Abstract Reactive oxygen species (ROS) are produced by both enzymatic and non-enzymatic systems within eukaryotic cells and play important roles in cellular physiology and pathophysiology. Although physiological concentrations are crucial for ensuring cell survival, ROS overproduction is detrimental to cells, and considered key-factors for the development of several diseases, such as neurodegenerative diseases, cardiovascular disorders, and cancer. Cancer cells are usually submitted to higher ROS levels that further stimulate malignant phenotype through stimulus to sustained proliferation, death evasion, angiogenesis, invasiveness, and metastasis. The role of ROS on breast cancer etiology and progression is being progressively elucidated. However, less attention has been given to ...
Monday, January 25, 2016 12:39 PM|Oncotarget|MedWorm: Cancer Therapy|Comments|Labels: ALK, ROS, lung cancer
Authors: Ye M, Zhang X, Li N, Zhang Y, Jing P, Chang N, Wu J, Ren X, Zhang J Abstract During the past decade, more than 10 targetable oncogenic driver genes have been validated in non-small cell lung cancer (NSCLC). Anaplastic lymphoma kinase (ALK) and ROS1 kinase are two new driver genes implicated in ALK- and ROS1-rearranged NSCLC. Inhibition of ALK and ROS1 by crizotinib has been reported to be highly effective and well tolerated in these patients. However, resistance to crizotinib emerges years after treatment, and increasing efforts have been made to overcome this issue. Here, we review the biology of ALK and ROS1 and their roles in cancer progression. We also summarize the ongoing and completed clinical trials validating ALK and ROS1 as targets for cancer treatment. In the la...
Saturday, January 23, 2016 4:00 PM|Journal of Applied Biomedicine|MedWorm: Cancer Therapy|Comments|Labels: ROS, prostate cancer
Publication date: Available online 23 January 2016 Source:Journal of Applied Biomedicine Author(s): Valliappan Karuppiah, Kumarappan Alagappan, Kannan Sivakumar, Lakshmanan Kannan Phenazine-1-carboxylic acid has extensive pharmacological activity, including antibiotic and immunomodulatory, but the anticancer activity remains unknown. Treatment of prostate cancer cell line (DU145) with phenazine-1-carboxylic acid stimulated inhibition of cell proliferation in concentration- and time-dependent manner. Dual staining confirmed phenazine-1-carboxylic acid stimulated prostate cancer cell apoptosis in time-dependent manner. To investigate the exact mechanism, phenazine-1-carboxylic acid-stimulated oxidative stress and mitochondrial-related apoptotic pathway in human prostate cancer cells we...
Thursday, January 21, 2016 4:00 PM|Apoptosis|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ROS, lung cancer
Abstract It has been previously reported that cisplatin is a well-known anticancer drug being used against a wide range of malignancies including head and neck, ovarian and non-small cell lung carcinoma, and demonstrated its anticancer activity by reacting with DNA or changing cell structure, immune response, reactive oxygen species level (ROS). In this research we proved that cisplatin induced cell injuries and heme oxygenase-1 (HO-1) expression in laryngeal squamous cell cancer Hep-2 cells through ROS generation. The induction of HO-1 clearly protected Hep-2 cells from cisplatin-induced cell death and ROS reaction, and the inhibitor of HO-1 enhanced the cell death and ROS generation induced by cisplatin. Furthermore, the HO-1 expression induced by cisplatin was strongly inhibite...
Wednesday, January 20, 2016 4:00 PM|Tumor Biology|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: MapK, ROS, lung cancer
In this study, we investigated whether fisetin can induce endoplasmic reticulum (ER) stress-mediated apoptosis in NCI-H460 cells. Fisetin induced mitochondrial reactive oxygen species (ROS) and characteristic signs of ER stress: ER staining; mitochondrial Ca2+ overload; expression of ER stress-related proteins; glucose-regulated protein (GRP)-78, phosphorylation of protein kinase RNA (PKR)-like endoplasmic reticulum kinase (PERK) and phosphorylation of eukaryotic initiation factor-2 α subunit; cleavage of activating transcription factor-6; phosphorylation of inositol-requiring kinase-1 and splicing of X-box transcription factor-1; induction of C/EBP homologous protein and cleaved caspase-12. siRNA-mediated knockdown of CHOP and ATF-6 attenuated fisetin-induced apoptotic cell death. In add...
Thursday, January 14, 2016 4:00 PM|Molecular Cancer Research|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ROS, lung cancer
The fundamental role that NAD(P)H/quinone oxidoreductase 1 (NQO1) plays, in normal cells, as a cytoprotective enzyme guarding against stress induced by reactive oxygen species (ROS) is well documented. However, what is not known is whether the observed overexpression of NQO1 in neoplastic cells contributes to their survival. The current study discovered that depleting NQO1 expression in A549 and H292 lung adenocarcinoma cells caused an increase in ROS formation, inhibited anchorage-independent growth, increased anoikis sensitization, and decreased three-dimensional tumor spheroid invasion. These in vivo data further implicate tumor-NQO1 expression in a protumor survival role, because its depletion suppressed cell proliferation and decreased lung tumor xenograft growth. Finally, these data ...
Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, ROS, lung cancer
In this study we have extended the capability of this technology to plasma samples from donors previously diagnosed with NSCLC. Data generated during the development of this test involved extraction of RNA from cell lines and donor plasma, processing to cDNA, adaptor ligation and two-step anchored PCR with specificity for human ALK, RET and ROS1. Amplicons were sequenced on a MiSeq (v2 chemistry) and reads were mapped to the human genome and a fusion specific database in order to identify the specific fusion partner(s). Test turn-around time from RNA extraction to results averaged 72 hours. With this test system we evaluated known variant-positive cell lines for EML4-ALK, SLC34A2-ROS1 and CCDC6-RET, as well as remnant prospectively-collected plasma from NSCLC donors (females of less than 6...
Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, ROS
Conclusions: ALK and ROS-1 rearrangement was found in 4.1% and 2.7% of NSCLC, respectively, in keeping with literature data. In other solid tumors, the percentage of rearrangements is exceedingly low, but melanoma, neuroendocrine tumors, pancreatic and colon cancer may show significant CNV. We speculate that such aberrations of ALK and ROS-1 could act as potential therapy targets, but additional investigation by immunohistochemistry and next generation sequencing is clinically warranted.Citation Format: Maria Silvia Cona, matteo Duca, Adele Testi, Sara Cresta, Katia Fiorella Dotti, Alice Indini, Diego Signorelli, Giuseppe Pelosi, Filippo Guglielmo de Braud, Silvia Damian. ALK and ROS-1 status: A retrospective analysis in solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC Inter...

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