Editing Metabolic pathway (section)

==Clinical applications in targeting metabolic pathways==

===Targeting oxidative phosphorylation===
Metabolic pathways can be targeted for clinically therapeutic uses. Within the mitochondrial metabolic network, for instance, there are various pathways that can be targeted by compounds to prevent cancer cell proliferation.<ref name="Frattaruolo">{{cite journal | vauthors = Frattaruolo L, Brindisi M, Curcio R, Marra F, Dolce V, Cappello AR | title = Targeting the Mitochondrial Metabolic Network: A Promising Strategy in Cancer Treatment | journal = International Journal of Molecular Sciences | volume = 21 | issue = 17 | pages = 2–11 | date = August 2020 | pmid = 32825551 | pmc = 7503725 | doi = 10.3390/ijms21176014 | doi-access = free }}</ref> One such pathway is [[oxidative phosphorylation]] (OXPHOS) within the [[electron transport chain]] (ETC). Various inhibitors can downregulate the electrochemical reactions that take place at Complex I, II, III, and IV, thereby preventing the formation of an electrochemical gradient and downregulating the movement of electrons through the ETC. The substrate-level phosphorylation that occurs at ATP synthase can also be directly inhibited, preventing the formation of ATP that is necessary to supply energy for cancer cell proliferation.<ref>{{cite journal | vauthors = Yadav N, Kumar S, Marlowe T, Chaudhary AK, Kumar R, Wang J, O'Malley J, Boland PM, Jayanthi S, Kumar TK, Yadava N, Chandra D | display-authors = 6 | title = Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents | journal = Cell Death & Disease | volume = 6 | issue = 11 | pages = e1969 | date = November 2015 | pmid = 26539916 | pmc = 4670921 | doi = 10.1038/cddis.2015.305 }}</ref> Some of these inhibitors, such as [[lonidamine]] and [[atovaquone]],<ref name="Frattaruolo"/> which inhibit Complex II and Complex III, respectively, are currently undergoing clinical trials for [[Food and Drug Administration|FDA]] approval. Other non-FDA-approved inhibitors have still shown experimental success in vitro.

===Targeting Heme===

[[Heme]], an important prosthetic group present in Complexes I, II, and IV can also be targeted, since heme biosynthesis and uptake have been correlated with increased cancer progression.<ref>{{cite journal | vauthors = Hooda J, Cadinu D, Alam MM, Shah A, Cao TM, Sullivan LA, Brekken R, Zhang L | display-authors = 6 | title = Enhanced heme function and mitochondrial respiration promote the progression of lung cancer cells | journal = PLOS ONE | volume = 8 | issue = 5 | pages = e63402 | date = 2013 | pmid = 23704904 | pmc = 3660535 | doi = 10.1371/journal.pone.0063402 | doi-access = free | bibcode = 2013PLoSO...863402H }}</ref> Various molecules can inhibit heme via different mechanisms. For instance, [[succinylacetone]] has been shown to decrease heme concentrations by inhibiting δ-aminolevulinic acid in murine erythroleukemia cells.<ref>{{cite journal | vauthors = Ebert PS, Hess RA, Frykholm BC, Tschudy DP | title = Succinylacetone, a potent inhibitor of heme biosynthesis: effect on cell growth, heme content and delta-aminolevulinic acid dehydratase activity of malignant murine erythroleukemia cells | journal = Biochemical and Biophysical Research Communications | volume = 88 | issue = 4 | pages = 1382–1390 | date = June 1979 | pmid = 289386 | doi = 10.1016/0006-291x(79)91133-1 }}</ref> The primary structure of heme-sequestering peptides, such as HSP1 and HSP2, can be modified to downregulate heme concentrations and reduce proliferation of non-small lung cancer cells.<ref>{{cite journal | vauthors = Sohoni S, Ghosh P, Wang T, Kalainayakan SP, Vidal C, Dey S, Konduri PC, Zhang L | display-authors = 6 | title = Elevated Heme Synthesis and Uptake Underpin Intensified Oxidative Metabolism and Tumorigenic Functions in Non-Small Cell Lung Cancer Cells | journal = Cancer Research | volume = 79 | issue = 10 | pages = 2511–2525 | date = May 2019 | pmid = 30902795 | doi = 10.1158/0008-5472.CAN-18-2156 | s2cid = 85456667 }}</ref>

===Targeting the tricarboxylic acid cycle and glutaminolysis===
The [[tricarboxylic acid cycle]] (TCA) and [[glutaminolysis]] can also be targeted for cancer treatment, since they are essential for the survival and proliferation of cancer cells. [[Ivosidenib]] and [[enasidenib]], two FDA-approved cancer treatments, can arrest the TCA cycle of cancer cells by inhibiting isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2), respectively.<ref name="Frattaruolo"/>  Ivosidenib is specific to acute myeloid leukemia (AML) and cholangiocarcinoma, whereas enasidenib is specific to just acute myeloid leukemia (AML).

In a clinical trial consisting of 185 adult patients with cholangiocarcinoma and an IDH-1 mutation, there was a statistically significant improvement (p<0.0001; HR: 0.37) in patients randomized to ivosidenib. Still, some of the adverse side effects in these patients included fatigue, nausea, diarrhea, decreased appetite, ascites, and anemia.<ref>{{cite web |title=FDA approves Ivosidenib for advanced or metastatic cholangiocarcinoma |url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ivosidenib-advanced-or-metastatic-cholangiocarcinoma |website=U.S. Food & Drug Administration|date=26 August 2021 }}</ref> In a clinical trial consisting of 199 adult patients with AML and an IDH2 mutation, 23% of patients experienced complete response (CR) or complete response with partial hematologic recovery (CRh) lasting a median of 8.2 months while on enasidenib. Of the 157 patients who required transfusion at the beginning of the trial, 34% no longer required transfusions during the 56-day time period on enasidenib. Of the 42% of patients who did not require transfusions at the beginning of the trial, 76% still did not require a transfusion by the end of the trial.  Side effects of enasidenib included nausea, diarrhea, elevated bilirubin and, most notably, differentiation syndrome.<ref>{{cite web |title=FDA granted regular approval to enasidenib for the treatment of relapsed or refractory AML |url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-granted-regular-approval-enasidenib-treatment-relapsed-or-refractory-aml |website=U.S. Food & Drug Administration|date=9 February 2019 }}</ref>

[[Glutaminase]] (GLS), the enzyme responsible for converting glutamine to glutamate via hydrolytic deamidation during the first reaction of glutaminolysis, can also be targeted. In recent years, many small molecules, such as azaserine, acivicin, and CB-839 have been shown to inhibit glutaminase, thus reducing cancer cell viability and inducing apoptosis in cancer cells.<ref>{{cite journal | vauthors = Matés JM, Di Paola FJ, Campos-Sandoval JA, Mazurek S, Márquez J | title = Therapeutic targeting of glutaminolysis as an essential strategy to combat cancer | journal = Seminars in Cell & Developmental Biology | volume = 98 | pages = 34–43 | date = February 2020 | pmid = 31100352 | doi = 10.1016/j.semcdb.2019.05.012 | s2cid = 157067127 | doi-access = free | hdl = 10630/32822 | hdl-access = free }}</ref> Due to its effective antitumor ability in several cancer types such as ovarian, breast and lung cancers, CB-839 is the only GLS inhibitor currently undergoing clinical studies for FDA-approval.