Editing Reactive oxygen species (section)

===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.