Editing Reactive oxygen species (section)

==Cancer==
ROS are constantly generated and eliminated in the biological system and are required to drive regulatory pathways.<ref>{{Cite journal |vauthors=Dickinson BC, Chang CJ |date=July 2011 |title=Chemistry and biology of reactive oxygen species in signaling or stress responses |journal=Nature Chemical Biology |volume=7 |issue=8 |pages=504–511 |doi=10.1038/nchembio.607 |pmc=3390228 |pmid=21769097}}</ref> Under normal physiological conditions, cells control ROS levels by balancing the generation of ROS with their elimination by scavenging systems. But under oxidative stress conditions, excessive ROS can damage cellular proteins, lipids and DNA, leading to fatal lesions in the cell that contribute to carcinogenesis.

Cancer cells exhibit greater ROS stress than normal cells do, partly due to oncogenic stimulation, increased metabolic activity and mitochondrial malfunction. ROS is a double-edged sword. On one hand, at low levels, ROS facilitates cancer cell survival since cell-cycle progression driven by growth factors and receptor tyrosine kinases (RTK) require ROS for activation<ref>{{Cite journal |display-authors=6 |vauthors=Irani K, Xia Y, Zweier JL, Sollott SJ, Der CJ, Fearon ER, Sundaresan M, Finkel T, Goldschmidt-Clermont PJ |date=March 1997 |title=Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts |journal=Science |volume=275 |issue=5306 |pages=1649–1652 |doi=10.1126/science.275.5306.1649 |pmid=9054359 |s2cid=19733670}}</ref> and chronic inflammation, a major mediator of cancer, is regulated by ROS. On the other hand, a high level of ROS can suppress tumor growth through the sustained activation of cell-cycle inhibitor<ref>{{Cite journal |vauthors=Ramsey MR, Sharpless NE |date=November 2006 |title=ROS as a tumour suppressor? |journal=Nature Cell Biology |volume=8 |issue=11 |pages=1213–1215 |doi=10.1038/ncb1106-1213 |pmid=17077852 |s2cid=21104991}}</ref><ref>{{Cite journal |display-authors=6 |vauthors=Takahashi A, Ohtani N, Yamakoshi K, Iida S, Tahara H, Nakayama K, Nakayama KI, Ide T, Saya H, Hara E |date=November 2006 |title=Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence |journal=Nature Cell Biology |volume=8 |issue=11 |pages=1291–1297 |doi=10.1038/ncb1491 |pmid=17028578 |s2cid=8686894}}</ref> and induction of cell death as well as senescence by damaging macromolecules. In fact, most of the chemotherapeutic and radiotherapeutic agents kill cancer cells by augmenting ROS stress.<ref>{{Cite journal |vauthors=Renschler MF |date=September 2004 |title=The emerging role of reactive oxygen species in cancer therapy |journal=European Journal of Cancer |volume=40 |issue=13 |pages=1934–1940 |doi=10.1016/j.ejca.2004.02.031 |pmid=15315800}}</ref><ref>{{Cite journal |vauthors=Toler SM, Noe D, Sharma A |date=December 2006 |title=Selective enhancement of cellular oxidative stress by chloroquine: implications for the treatment of glioblastoma multiforme |journal=Neurosurgical Focus |volume=21 |issue=6 |pages=1–4 |doi=10.3171/foc.2006.21.6.1 |pmid=17341043 |doi-access=free}}</ref> The ability of cancer cells to distinguish between ROS as a survival or apoptotic signal is controlled by the dosage, duration, type, and site of ROS production. Modest levels of ROS are required for cancer cells to survive, whereas excessive levels kill them.

Metabolic adaptation in tumours balances the cells' need for energy with equally important need for macromolecular building blocks and tighter control of redox balance. As a result, production of [[NADPH]] is greatly enhanced, which functions as a cofactor to provide reducing power in many enzymatic reactions for macromolecular biosynthesis and at the same time rescuing the cells from excessive ROS produced during rapid proliferation. Cells counterbalance the detrimental effects of ROS by producing antioxidant molecules, such as reduced glutathione (GSH) and thioredoxin (TRX), which rely on the reducing power of NADPH to maintain their activities.<ref>{{Cite journal |vauthors=Cairns RA, Harris IS, Mak TW |date=February 2011 |title=Regulation of cancer cell metabolism |journal=Nature Reviews. Cancer |volume=11 |issue=2 |pages=85–95 |doi=10.1038/nrc2981 |pmid=21258394 |s2cid=8891526}}</ref>

Most risk factors associated with cancer interact with cells through the generation of ROS. ROS then activate various transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), activator protein-1 (AP-1), hypoxia-inducible factor-1α and signal transducer and activator of transcription 3 (STAT3), leading to expression of proteins that control inflammation; cellular transformation; tumor cell survival; tumor cell proliferation; and invasion, angiogenesis as well as metastasis. And ROS also control the expression of various tumor suppressor genes such as p53, retinoblastoma gene (Rb), and phosphatase and tensin homolog (PTEN).<ref name="pmid22117137">{{Cite journal |vauthors=Gupta SC, Hevia D, Patchva S, Park B, Koh W, Aggarwal BB |date=June 2012 |title=Upsides and downsides of reactive oxygen species for cancer: the roles of reactive oxygen species in tumorigenesis, prevention, and therapy |journal=Antioxidants & Redox Signaling |volume=16 |issue=11 |pages=1295–1322 |doi=10.1089/ars.2011.4414 |pmc=3324815 |pmid=22117137}}</ref>

===Carcinogenesis===
ROS-related oxidation of DNA is one of the main causes of mutations, which can produce several types of DNA damage, including non-bulky (8-oxoguanine and formamidopyrimidine) and bulky (cyclopurine and etheno adducts) base modifications, abasic sites, non-conventional single-strand breaks, protein-DNA adducts, and intra/interstrand DNA crosslinks.<ref>{{Cite journal |vauthors=Waris G, Ahsan H |date=May 2006 |title=Reactive oxygen species: role in the development of cancer and various chronic conditions |journal=Journal of Carcinogenesis |volume=5 |pages=14 |doi=10.1186/1477-3163-5-14 |pmc=1479806 |pmid=16689993 |doi-access=free}}</ref> It has been estimated that endogenous ROS produced via normal cell metabolism modify approximately 20,000 bases of DNA per day in a single cell. 8-oxoguanine is the most abundant among various oxidized nitrogeneous bases observed. During DNA replication, DNA polymerase mispairs 8-oxoguanine with adenine, leading to a G→T transversion mutation. The resulting genomic instability directly contributes to carcinogenesis. Cellular transformation leads to cancer and interaction of atypical PKC-ζ isoform with p47phox controls ROS production and transformation from apoptotic cancer stem cells through [[blebbishield emergency program]].<ref>{{Cite journal |vauthors=Jinesh GG, Taoka R, Zhang Q, Gorantla S, Kamat AM |date=April 2016 |title=Novel PKC-ζ to p47 phox interaction is necessary for transformation from blebbishields |journal=Scientific Reports |volume=6 |pages=23965 |bibcode=2016NatSR...623965J |doi=10.1038/srep23965 |pmc=4819220 |pmid=27040869}}</ref><ref>Jinesh GG, Kamat AM. [http://www.nature.com/cdd/journal/vaop/ncurrent/full/cdd201626a.html Blebbishield emergency program: an apoptotic route to cellular transformation]. Cell Death Differ. 2016 In Press.</ref>

===Cell proliferation===
Uncontrolled proliferation is a hallmark of cancer cells. Both exogenous and endogenous ROS have been shown to enhance proliferation of cancer cells. The role of ROS in promoting tumor proliferation is further supported by the observation that agents with potential to inhibit ROS generation can also inhibit cancer cell proliferation.<ref name="pmid22117137" /> 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 [[aTM serine/threonine kinase|ataxia telangiectasia mutated]] (ATM), checkpoint kinase 1 (Chk 1), Chk 2; and reduced cell division cycle 25 homolog c (CDC25).<ref>{{Cite journal |vauthors=Ames BN |date=September 1983 |title=Dietary carcinogens and anticarcinogens. Oxygen radicals and degenerative diseases |journal=Science |volume=221 |issue=4617 |pages=1256–1264 |bibcode=1983Sci...221.1256A |doi=10.1126/science.6351251 |pmid=6351251}}</ref>

===Cell death===
A cancer cell can die in three ways: [[apoptosis]], [[necrosis]], and [[autophagy]]. Excessive ROS can induce apoptosis through both the extrinsic and intrinsic pathways.<ref>{{Cite journal |vauthors=Ozben T |date=September 2007 |title=Oxidative stress and apoptosis: impact on cancer therapy |journal=Journal of Pharmaceutical Sciences |volume=96 |issue=9 |pages=2181–2196 |doi=10.1002/jps.20874 |pmid=17593552}}</ref> 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.<ref name="pmid22117137" /> In the intrinsic pathway, ROS function to facilitate cytochrome c 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).<ref>{{Cite journal |vauthors=Martindale JL, Holbrook NJ |date=July 2002 |title=Cellular response to oxidative stress: signaling for suicide and survival |journal=Journal of Cellular Physiology |volume=192 |issue=1 |pages=1–15 |doi=10.1002/jcp.10119 |pmid=12115731 |doi-access=free}}</ref> The intrinsic pathway is also known as the caspase cascade and is induced through mitochondrial damage which triggers the release of cytochrome c. DNA damage, oxidative stress, and loss of mitochondrial membrane potential lead to the release of the pro-apoptotic proteins mentioned above stimulating apoptosis.<ref name="pmid17717517">{{Cite journal |vauthors=Maiuri MC, Zalckvar E, Kimchi A, Kroemer G |date=September 2007 |title=Self-eating and self-killing: crosstalk between autophagy and apoptosis |journal=Nature Reviews. Molecular Cell Biology |volume=8 |issue=9 |pages=741–752 |doi=10.1038/nrm2239 |pmid=17717517 |s2cid=3912801}}</ref> Mitochondrial damage is closely linked to apoptosis and since mitochondria are easily targeted there is potential for cancer therapy.<ref name="pmid20467424">{{Cite journal |vauthors=Fulda S, Galluzzi L, Kroemer G |date=June 2010 |title=Targeting mitochondria for cancer therapy |journal=Nature Reviews. Drug Discovery |volume=9 |issue=6 |pages=447–464 |doi=10.1038/nrd3137 |pmid=20467424 |s2cid=14643750 |doi-access=free}}</ref>

The cytotoxic nature of ROS is a driving force behind apoptosis, but in even higher amounts, ROS can result in both apoptosis and necrosis, a form of uncontrolled cell death, in cancer cells.<ref>{{Cite journal |vauthors=Hampton MB, Orrenius S |date=September 1997 |title=Dual regulation of caspase activity by hydrogen peroxide: implications for apoptosis |journal=FEBS Letters |volume=414 |issue=3 |pages=552–556 |bibcode=1997FEBSL.414..552H |doi=10.1016/s0014-5793(97)01068-5 |pmid=9323034 |s2cid=41952954 |doi-access=free}}</ref>

Numerous studies have shown the pathways and associations between ROS levels and apoptosis, but a newer line of study has connected ROS levels and autophagy.<ref>{{Cite journal |vauthors=Gibson SB |date=October 2010 |title=A matter of balance between life and death: targeting reactive oxygen species (ROS)-induced autophagy for cancer therapy |journal=Autophagy |volume=6 |issue=7 |pages=835–837 |doi=10.4161/auto.6.7.13335 |pmid=20818163 |doi-access=free}}</ref> ROS can also induce cell death through autophagy, which is a self-catabolic process involving sequestration of cytoplasmic contents (exhausted or damaged organelles and protein aggregates) for degradation in lysosomes.<ref>{{Cite journal |vauthors=Shrivastava A, Kuzontkoski PM, Groopman JE, Prasad A |date=July 2011 |title=Cannabidiol induces programmed cell death in breast cancer cells by coordinating the cross-talk between apoptosis and autophagy |journal=Molecular Cancer Therapeutics |volume=10 |issue=7 |pages=1161–1172 |doi=10.1158/1535-7163.MCT-10-1100 |pmid=21566064 |doi-access=free}}</ref> Therefore, autophagy can also regulate the cell's health in times of oxidative stress. Autophagy can be induced by ROS levels through many pathways in the cell in an attempt to dispose of harmful organelles and prevent damage, such as carcinogens, without inducing apoptosis.<ref name="sciencedirect.com">{{Cite journal |vauthors=Scherz-Shouval R, Elazar Z |date=September 2007 |title=ROS, mitochondria and the regulation of autophagy |journal=Trends in Cell Biology |volume=17 |issue=9 |pages=422–427 |doi=10.1016/j.tcb.2007.07.009 |pmid=17804237}}</ref> Autophagic cell death can be prompted by the over expression of autophagy where the cell digests too much of itself in an attempt to minimize the damage and can no longer survive. When this type of cell death occurs, an increase or loss of control of autophagy regulating genes is commonly co-observed.<ref>{{Cite journal |vauthors=Xie Z, Klionsky DJ |date=October 2007 |title=Autophagosome formation: core machinery and adaptations |journal=Nature Cell Biology |volume=9 |issue=10 |pages=1102–1109 |doi=10.1038/ncb1007-1102 |pmid=17909521 |s2cid=26402002}}</ref> Thus, once a more in-depth understanding of autophagic cell death is attained and its relation to ROS, this form of programmed cell death may serve as a future cancer therapy.
Autophagy and apoptosis are distinct mechanisms for cell death brought on by high levels of ROS. Aautophagy and apoptosis, however, rarely act through strictly independent pathways. There is a clear connection between ROS and autophagy and a correlation seen between excessive amounts of ROS leading to apoptosis.<ref name="sciencedirect.com" /> The depolarization of the mitochondrial membrane is also characteristic of the initiation of autophagy. When mitochondria are damaged and begin to release ROS, autophagy is initiated to dispose of the damaging organelle. If a drug targets mitochondria and creates ROS, autophagy may dispose of so many mitochondria and other damaged organelles that the cell is no longer viable. The extensive amount of ROS and mitochondrial damage may also signal for apoptosis. The balance of autophagy within the cell and the crosstalk between autophagy and apoptosis mediated by ROS is crucial for a cell's survival. This crosstalk and connection between autophagy and apoptosis could be a mechanism targeted by cancer therapies or used in combination therapies for highly resistant cancers.

===Tumor cell invasion, angiogenesis and metastasis===
After growth factor stimulation of RTKs, ROS can trigger activation of signaling pathways involved in cell migration and invasion such as members of the mitogen activated protein kinase (MAPK) family – extracellular regulated kinase (ERK), c-jun NH-2 terminal kinase (JNK) and p38 MAPK. ROS can also promote migration by augmenting phosphorylation of the focal adhesion kinase (FAK) p130Cas and paxilin.<ref>{{Cite journal |vauthors=Tochhawng L, Deng S, Pervaiz S, Yap CT |date=May 2013 |title=Redox regulation of cancer cell migration and invasion |journal=Mitochondrion |volume=13 |issue=3 |pages=246–253 |doi=10.1016/j.mito.2012.08.002 |pmid=22960576}}</ref>

Both in vitro and in vivo, ROS have been shown to induce transcription factors and modulate signaling molecules involved in angiogenesis (MMP, VEGF) and metastasis (upregulation of AP-1, CXCR4, AKT and downregulation of PTEN).<ref name="pmid22117137" />

===Chronic inflammation and cancer===
Experimental and epidemiologic research over the past several years has indicated close associations among ROS, chronic inflammation, and cancer.<ref name="pmid22117137" /> ROS induces chronic inflammation by the induction of COX-2, inflammatory cytokines (TNFα, interleukin 1 (IL-1), IL-6), chemokines (IL-8, CXCR4) and pro-inflammatory transcription factors (NF-κB).<ref name="pmid22117137" /> These chemokines and chemokine receptors, in turn, promote invasion and metastasis of various tumor types.

===Cancer therapy===
[[File:Open source and reduced expenditure ROS generation strategy.pdf|thumb|The scheme of fabrication process and therapeutic mechanism of thermo-responsive (MSNs@CaO2-ICG)@LA NPs for synergistic CDT/PDT with H2O2/O2 self-supply and GSH depletion]]

Both ROS-elevating and ROS-eliminating strategies have been developed with the former being predominantly used. Cancer cells with elevated ROS levels depend heavily on the antioxidant defense system. ROS-elevating drugs further 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 (BSO)). The result is an overall increase in endogenous ROS, which when above a cellular tolerability threshold, may induce cell death.<ref>{{Cite journal |vauthors=Schumacker PT |date=September 2006 |title=Reactive oxygen species in cancer cells: live by the sword, die by the sword |journal=Cancer Cell |volume=10 |issue=3 |pages=175–176 |doi=10.1016/j.ccr.2006.08.015 |pmid=16959608 |doi-access=free}}</ref> 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.<ref>{{Cite journal |vauthors=Trachootham D, Alexandre J, Huang P |date=July 2009 |title=Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? |journal=Nature Reviews. Drug Discovery |volume=8 |issue=7 |pages=579–591 |doi=10.1038/nrd2803 |pmid=19478820 |s2cid=20697221}}</ref> Therefore, the elevation of ROS in all cells can be used to achieve the selective killing of cancer cells.

Radiotherapy also relies on ROS toxicity to eradicate tumor cells. Radiotherapy uses X-rays, γ-rays as well as heavy particle radiation such as protons and neutrons to induce ROS-mediated cell death and mitotic failure.<ref name="pmid22117137" />

Due to the dual role of ROS, both prooxidant and antioxidant-based anticancer agents have been developed. However, modulation of ROS signaling alone seems not to be an ideal approach due to adaptation of cancer cells to ROS stress, redundant pathways for supporting cancer growth and toxicity from ROS-generating anticancer drugs. Combinations of ROS-generating drugs with pharmaceuticals that can break the redox adaptation could be a better strategy for enhancing cancer cell cytotoxicity.<ref name="pmid22117137" />

[[James Watson]]<ref>{{Cite journal |vauthors=Watson JD |date=March 2014 |title=Type 2 diabetes as a redox disease |journal=Lancet |volume=383 |issue=9919 |pages=841–843 |doi=10.1016/s0140-6736(13)62365-x |pmid=24581668 |s2cid=1076963}}</ref> and others<ref name="ReferenceA">{{Cite journal |vauthors=Molenaar RJ, van Noorden CJ |date=September 2014 |title=Type 2 diabetes and cancer as redox diseases? |journal=Lancet |volume=384 |issue=9946 |pages=853 |doi=10.1016/s0140-6736(14)61485-9 |pmid=25209484 |s2cid=28902284 |doi-access=free}}</ref> have proposed that lack of intracellular ROS due to a lack of physical exercise may contribute to the malignant progression of cancer, because spikes of ROS are needed to correctly fold proteins in the endoplasmatic reticulum and low ROS levels may thus aspecifically hamper the formation of tumor suppressor proteins.<ref name="ReferenceA" /> Since physical exercise induces temporary spikes of ROS, this may explain why physical exercise is beneficial for cancer patient prognosis.<ref>{{Cite journal |display-authors=6 |vauthors=Irwin ML, Smith AW, McTiernan A, Ballard-Barbash R, Cronin K, Gilliland FD, Baumgartner RN, Baumgartner KB, Bernstein L |date=August 2008 |title=Influence of pre- and postdiagnosis physical activity on mortality in breast cancer survivors: the health, eating, activity, and lifestyle study |journal=Journal of Clinical Oncology |volume=26 |issue=24 |pages=3958–3964 |doi=10.1200/jco.2007.15.9822 |pmc=2654316 |pmid=18711185}}</ref> Moreover, high inducers of ROS such as 2-deoxy-D-glucose and carbohydrate-based inducers of cellular stress induce cancer cell death more potently because they exploit the cancer cell's high avidity for sugars.<ref>{{Cite journal |vauthors=Ndombera FT, VanHecke GC, Nagi S, Ahn YH |date=March 2016 |title=Carbohydrate-based inducers of cellular stress for targeting cancer cells |journal=Bioorganic & Medicinal Chemistry Letters |volume=26 |issue=5 |pages=1452–1456 |doi=10.1016/j.bmcl.2016.01.063 |pmid=26832785}}</ref>
<references group="Carbohydrate-based inducers of cellular stress for targeting cancer cells Fidelis T. Ndombera, Garrett C. VanHecke, Shima Nagi, Young-Hoon Ahn"/><!--====ROS-directed cancer chemotherapeutics====
Recent research demonstrates that redox dysregulation originating from metabolic alterations and dependence on [[mitogenic]] and survival signaling through ROS represents a specific vulnerability of malignant cells that can be selectively targeted by pro- and antioxidant redox chemotherapeutics.<ref>{{Cite journal |vauthors=Wondrak GT |date=December 2009 |title=Redox-directed cancer therapeutics: molecular mechanisms and opportunities |journal=Antioxidants & Redox Signaling |volume=11 |issue=12 |pages=3013–69 |doi=10.1089/ARS.2009.2541 |pmc=2824519 |pmid=19496700}}</ref> -->