Reactive oxygen species (ROS) are small reactive molecules produced by cellular metabolism and regulate various physiological and pathological functions. Many studies have shown that ROS plays an essential role in the proliferation and inhibition of tumor cells. Different concentrations of ROS can have a "double-edged sword" effect on the occurrence and development of tumors. A certain concentration of ROS can activate growth-promoting signals, enhance the proliferation and invasion of tumor cells, and cause damage to biomacromolecules such as proteins and nucleic acids. However, ROS can enhance the body's antitumor signal at higher levels by initiating oxidative stress-induced apoptosis and autophagy in tumor cells. This review analyzes ROS's unique bidirectional regulation mechanism on tumor cells, focusing on the key signaling pathways and regulatory factors that ROS affect the occurrence and development of tumors and providing ideas for an in-depth understanding of the mechanism of ROS action and its clinical application.

Key Laboratory of Medical Microecology Fujian Province University School of Pharmacy and Medical Technology Putian University Putian China

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Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72:7–33. doi: 10.3322/caac.21708. PubMed DOI

Aggarwal V, Tuli HS, Varol A, Thakral F, Yerer MB, Sak K, Varol M, Jain A, Khan MA, Sethi G. Role of reactive oxygen species in cancer progression: molecular mechanisms and recent advancements. Biomolecules. 2019;9:735. doi: 10.3390/biom9110735. PubMed DOI PMC

Rincheval V, Bergeaud M, Mathieu L, Leroy J, Guillaume A, Mignotte B, Le Floch N, Vayssière JL. Differential effects of Bcl-2 and caspases on mitochondrial permeabilization during endogenous or exogenous reactive oxygen species-induced cell death: a comparative study of H2O2, paraquat t-BHP, etoposide, TNF-α-induced cell death. Cell Biol Toxicol. 2012;28:239–253. doi: 10.1007/s10565-012-9219-9. PubMed DOI

Sies H, Jones DP. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol. 2020;21:363–383. doi: 10.1038/s41580-020-0230-3. PubMed DOI

Moloney JN, Cotter TG. ROS signalling in the biology of cancer. Semin Cell Dev Biol. 2018;80:50–64. doi: 10.1016/j.semcdb.2017.05.023. PubMed DOI

Jaganjac M, Milkovic L, Sunjic SB, Zarkovic N. The NRF2, thioredoxin, and glutathione system in tumorigenesis and anticancer therapies. Antioxidants (Basel) 2020;9:1151. doi: 10.3390/antiox9111151. PubMed DOI PMC

Sang J, Li W, Diao HJ, Fan RZ, Huang JL, Gan L, Zou MF, Tang GH, Yin S. Jolkinolide B targets thioredoxin and glutathione systems to induce ROS-mediated paraptosis and apoptosis in bladder cancer cells. Cancer Lett. 2021;509:13–25. doi: 10.1016/j.canlet.2021.03.030. PubMed DOI

Hussain SP, Harris CC. Inflammation and cancer: an ancient link with novel potentials. Int J Cancer. 2007;121:2373–2380. doi: 10.1002/ijc.23173. PubMed DOI

Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med. 2010;49:1603–1616. doi: 10.1016/j.freeradbiomed.2010.09.006. PubMed DOI PMC

Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA. Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res. 2014;2014:149185. doi: 10.1155/2014/149185. PubMed DOI PMC

Forrester SJ, Kikuchi DS, Hernandes MS, Xu Q, Griendling KK. Reactive oxygen species in metabolic and inflammatory signaling. Circ Res. 2018;122:877–902. doi: 10.1161/CIRCRESAHA.117.311401. PubMed DOI PMC

Qi S, Xin Y, Guo Y, Diao Y, Kou X, Luo L, Yin Z. Ampelopsin reduces endotoxic inflammation via repressing ROS-mediated activation of PI3K/Akt/NF-κB signaling pathways. Int Immunopharmacol. 2012;12:278–287. doi: 10.1016/j.intimp.2011.12.001. PubMed DOI

Azad N, Rojanasakul Y, Vallyathan V. Inflammation and lung cancer: roles of reactive oxygen/nitrogen species. J Toxicol Environ Health B Crit Rev. 2008;11:1–15. doi: 10.1080/10937400701436460. PubMed DOI

Rajaram P, Chandra P, Ticku S, Pallavi BK, Rudresh KB, Mansabdar P. Epidermal growth factor receptor: Role in human cancer. Indian J Dent Res. 2017;28:687–694. doi: 10.4103/ijdr.IJDR_534_16. PubMed DOI

Goldmann E. The growth of malignant disease in man and the lower animals, with special reference to the vascular system. Proc R Soc Med. 1908;1:1–13. doi: 10.1177/003591570800101201. PubMed DOI PMC

Dewhirst MW, Cao Y, Moeller B. Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer. 2008;8:425–437. doi: 10.1038/nrc2397. PubMed DOI PMC

Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182–1186. doi: 10.1056/NEJM197111182852108. PubMed DOI

Sarmiento-Salinas FL, Perez-Gonzalez A, Acosta-Casique A, Ix-Ballote A, Diaz A, Treviño S, Rosas-Murrieta NH, Millán-Perez-Peña L, Maycotte P. Reactive oxygen species: Role in carcinogenesis, cancer cell signaling and tumor progression. Life Sci. 2021;284:119942. doi: 10.1016/j.lfs.2021.119942. PubMed DOI

Karar J, Maity A. PI3K/AKT/mTOR pathway in angiogenesis. Front Mol Neurosci. 2011;4:51. doi: 10.3389/fnmol.2011.00051. PubMed DOI PMC

Park KR, Nam D, Yun HM, Lee SG, Jang HJ, Sethi G, Cho SK, Ahn KS. β-Caryophyllene oxide inhibits growth and induces apoptosis through the suppression of PI3K/AKT/mTOR/S6K1 pathways and ROS-mediated MAPKs activation. Cancer Lett. 2011;312:178–188. doi: 10.1016/j.canlet.2011.08.001. PubMed DOI

Ray PD, Huang BW, Tsuji Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal. 2012;24:981–990. doi: 10.1016/j.cellsig.2012.01.008. PubMed DOI PMC

Ersahin T, Tuncbag N, Cetin-Atalay R. The PI3K/AKT/mTOR interactive pathway. Mol Biosyst. 2015;11:1946–1954. doi: 10.1039/C5MB00101C. PubMed DOI

Han X, Sun S, Zhao M, Cheng X, Chen G, Lin S, Guan Y, Yu X. Celastrol stimulates hypoxia-inducible factor-1 activity in tumor cells by initiating the ROS/Akt/p70S6K signaling pathway and enhancing hypoxia-inducible factor-1α protein synthesis. PLoS One. 2014;9:e112470. doi: 10.1371/journal.pone.0112470. PubMed DOI PMC

Santoro MM. Fashioning blood vessels by ROS signalling and metabolism. Semin Cell Dev Biol. 2018;80:35–42. doi: 10.1016/j.semcdb.2017.08.002. PubMed DOI

Ushio-Fukai M, Alexander RW. Reactive oxygen species as mediators of angiogenesis signaling: role of NAD(P)H oxidase. Mol Cell Biochem. 2004;264:85–97. doi: 10.1023/B:MCBI.0000044378.09409.b5. PubMed DOI

Seyfried TN, Huysentruyt LC. On the origin of cancer metastasis. Crit Rev Oncog. 2013;18:43–73. doi: 10.1615/CritRevOncog.v18.i1-2.40. PubMed DOI PMC

Zhou Z, Apte SS, Soininen R, Cao R, Baaklini GY, Rauser RW, Wang J, Cao Y, Tryggvason K. Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I. Proc Natl Acad Sci U S A. 2000;97:4052–4057. doi: 10.1073/pnas.060037197. PubMed DOI PMC

Gào X, Schöttker B. Reduction-oxidation pathways involved in cancer development: a systematic review of literature reviews. Oncotarget. 2017;8:51888–51906. doi: 10.18632/oncotarget.17128. PubMed DOI PMC

Kashyap D, Tuli HS, Sak K, Garg VK, Goel N, Punia S, Chaudhary A. Role of reactive oxygen species in cancer progression. Curr Pharmacol Rep. 2019;5:79–86. doi: 10.1007/s40495-019-00171-y. DOI

Kamiya T, Goto A, Kurokawa E, Hara H, Adachi T. Cross talk mechanism among EMT, ROS, and histone acetylation in phorbol ester-treated human breast cancer MCF-7 cells. Oxid Med Cell Longev. 2016;2016:1284372. doi: 10.1155/2016/1284372. PubMed DOI PMC

Cai H, Chen X, Zhang J, Wang J. 18β-glycyrrhetinic acid inhibits migration and invasion of human gastric cancer cells via the ROS/PKC-α/ERK pathway. J Nat Med. 2018;72:252–259. doi: 10.1007/s11418-017-1145-y. PubMed DOI

Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19:1423–1437. doi: 10.1038/nm.3394. PubMed DOI PMC

Liao Z, Chua D, Tan NS. Reactive oxygen species: a volatile driver of field cancerization and metastasis. Mol Cancer. 2019;18:65. doi: 10.1186/s12943-019-0961-y. PubMed DOI PMC

Tobar N, Villar V, Santibanez JF. ROS-NFkappaB mediates TGF-beta1-induced expression of urokinase-type plasminogen activator, matrix metalloproteinase-9 and cell invasion. Mol Cell Biochem. 2010;340:195–202. doi: 10.1007/s11010-010-0418-5. PubMed DOI

Orrenius S, Gogvadze V, Zhivotovsky B. Calcium and mitochondria in the regulation of cell death. Biochem Biophys Res Commun. 2015;460:72–81. doi: 10.1016/j.bbrc.2015.01.137. PubMed DOI

Shalini S, Dorstyn L, Dawar S, Kumar S. Old, new and emerging functions of caspases. Cell Death Differ. 2015;22:526–539. doi: 10.1038/cdd.2014.216. PubMed DOI PMC

Kalpage HA, Bazylianska V, Recanati MA, Fite A, Liu J, Wan J, Mantena N, et al. Tissue-specific regulation of cytochrome c by post-translational modifications: respiration, the mitochondrial membrane potential, ROS, and apoptosis. FASEB J. 2019;33:1540–1553. doi: 10.1096/fj.201801417R. PubMed DOI PMC

Redza-Dutordoir M, Averill-Bates DA. Activation of apoptosis signalling pathways by reactive oxygen species. Biochim Biophys Acta. 2016;1863:2977–2992. doi: 10.1016/j.bbamcr.2016.09.012. PubMed DOI

Arfin S, Jha NK, Jha SK, Kesari KK, Ruokolainen J, Roychoudhury S, Rathi B, Kumar D. Oxidative stress in cancer cell metabolism. Antioxidants (Basel) 2021;10:642. doi: 10.3390/antiox10050642. PubMed DOI PMC

Zhang L, Wang K, Lei Y, Li Q, Nice EC, Huang C. Redox signaling: potential arbitrator of autophagy and apoptosis in therapeutic response. Free Radic Biol Med. 2015;89:452–465. doi: 10.1016/j.freeradbiomed.2015.08.030. PubMed DOI

Yang Y, Duan W, Liang Z, Yi W, Yan J, Wang N, Li Y, Chen W, Yu S, Jin Z, Yi D. Curcumin attenuates endothelial cell oxidative stress injury through Notch signaling inhibition. Cell Signal. 2013;25:615–629. doi: 10.1016/j.cellsig.2012.11.025. PubMed DOI

Glory A, Bettaieb A, Averill-Bates DA. Mild thermotolerance induced at 40 °C protects cells against hyperthermia-induced pro-apoptotic changes in Bcl-2 family proteins. Int J Hyperthermia. 2014;30:502–512. doi: 10.3109/02656736.2014.968641. PubMed DOI

Ola MS, Nawaz M, Ahsan H. Role of Bcl-2 family proteins and caspases in the regulation of apoptosis. Mol Cell Biochem. 2011;351:41–58. doi: 10.1007/s11010-010-0709-x. PubMed DOI

Happo L, Strasser A, Cory S. BH3-only proteins in apoptosis at a glance. J Cell Sci. 2012;125:1081–1087. doi: 10.1242/jcs.090514. PubMed DOI PMC

Kaminskyy VO, Zhivotovsky B. Free radicals in cross talk between autophagy and apoptosis. Antioxid Redox Signal. 2014;21:86–102. doi: 10.1089/ars.2013.5746. PubMed DOI

Pallepati P, Averill-Bates D. Mild thermotolerance induced at 40 degrees C increases antioxidants and protects HeLa cells against mitochondrial apoptosis induced by hydrogen peroxide: Role of p53. Arch Biochem Biophys. 2010;495:97–111. doi: 10.1016/j.abb.2009.12.014. PubMed DOI

Edlich F. BCL-2 proteins and apoptosis: Recent insights and unknowns. Biochem Biophys Res Commun. 2018;500:26–34. doi: 10.1016/j.bbrc.2017.06.190. PubMed DOI

Brentnall M, Rodriguez-Menocal L, De Guevara RL, Cepero E, Boise LH. Caspase-9, caspase-3 and caspase-7 have distinct roles during intrinsic apoptosis. BMC Cell Biol. 2013;14:32. doi: 10.1186/1471-2121-14-32. PubMed DOI PMC

Amini MA, Talebi SS, Karimi J. Reactive Oxygen Species Modulator 1 (ROMO1), a new potential target for cancer diagnosis and treatment. Chonnam Med J. 2019;55:136–143. doi: 10.4068/cmj.2019.55.3.136. PubMed DOI PMC

Kaufmann T, Strasser A, Jost PJ. Fas death receptor signalling: roles of Bid and XIAP. Cell Death Differ. 2012;19:42–50. doi: 10.1038/cdd.2011.121. PubMed DOI PMC

Circu ML, Aw TY. Glutathione and modulation of cell apoptosis. Biochim Biophys Acta. 2012;1823:1767–1777. doi: 10.1016/j.bbamcr.2012.06.019. PubMed DOI PMC

Blaser H, Dostert C, Mak TW, Brenner D. TNF and ROS crosstalk in inflammation. Trends Cell Biol. 2016;26:249–261. doi: 10.1016/j.tcb.2015.12.002. PubMed DOI

D'Arcy MS. Cell death: a review of the major forms of apoptosis, necrosis and autophagy. Cell Biol Int. 2019;43:582–592. doi: 10.1002/cbin.11137. PubMed DOI

Poillet-Perez L, Despouy G, Delage-Mourroux R, Boyer-Guittaut M. Interplay between ROS and autophagy in cancer cells, from tumor initiation to cancer therapy. Redox Biol. 2015;4:184–192. doi: 10.1016/j.redox.2014.12.003. PubMed DOI PMC

Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008;30:214–226. doi: 10.1016/j.molcel.2008.03.003. PubMed DOI PMC

Choi SL, Kim SJ, Lee KT, Kim J, Mu J, Birnbaum MJ, Soo Kim S, Ha J. The regulation of AMP-activated protein kinase by H(2)O(2) Biochem Biophys Res Commun. 2001;287:92–97. doi: 10.1006/bbrc.2001.5544. PubMed DOI

Ciccarone F, Castelli S, Ciriolo MR. Oxidative stress-driven autophagy acROSs onset and therapeutic outcome in hepatocellular carcinoma. Oxid Med Cell Longev. 2019;2019:6050123. doi: 10.1155/2019/6050123. PubMed DOI PMC

Lin Q, Li S, Jiang N, Shao X, Zhang M, Jin H, Zhang Z, et al. PINK1-parkin pathway of mitophagy protects against contrast-induced acute kidney injury via decreasing mitochondrial ROS and NLRP3 inflammasome activation. Redox Biol. 2019;26:101254. doi: 10.1016/j.redox.2019.101254. PubMed DOI PMC

Taguchi K, Fujikawa N, Komatsu M, Ishii T, Unno M, Akaike T, Motohashi H, Yamamoto M. Keap1 degradation by autophagy for the maintenance of redox homeostasis. Proc Natl Acad Sci U S A. 2012;109:13561–13566. doi: 10.1073/pnas.1121572109. PubMed DOI PMC

Chen Y, Luo G, Yuan J, Wang Y, Yang X, Wang X, Li G, Liu Z, Zhong N. Vitamin C mitigates oxidative stress and tumor necrosis factor-alpha in severe community-acquired pneumonia and LPS-induced macrophages. Mediators Inflamm. 2014;2014:426740. doi: 10.1155/2014/426740. PubMed DOI PMC

Lv H, Wang C, Fang T, Li T, Lv G, Han Q, Yang W, Wang H. Vitamin C preferentially kills cancer stem cells in hepatocellular carcinoma via SVCT-2. NPJ Precis Oncol. 2018;2:1. doi: 10.1038/s41698-017-0044-8. PubMed DOI PMC

Sayin VI, Ibrahim MX, Larsson E, Nilsson JA, Lindahl P, Bergo MO. Antioxidants accelerate lung cancer progression in mice. Sci Transl Med. 2014;6:221ra215. doi: 10.1126/scitranslmed.3007653. PubMed DOI

Nathan CF, Cohn ZA. Antitumor effects of hydrogen peroxide in vivo. J Exp Med. 1981;154:1539–1553. doi: 10.1084/jem.154.5.1539. PubMed DOI PMC

Waters MD, Stack HF. The short-term test activity profile for procarbazine hydrochloride. Mutagenesis. 1988;3:89–94. doi: 10.1093/mutage/3.2.89. PubMed DOI

Panchuk RR, Skorokhyd NR, Kozak YS, Lehka LV, Moiseenok AG, Stoika RS. Tissue-protective activity of selenomethionine and D-panthetine in B16 melanoma-bearing mice under doxorubicin treatment is not connected with their ROS scavenging potential. Croat Med J. 2017;58:171–184. doi: 10.3325/cmj.2017.58.171. PubMed DOI PMC

Megías-Vericat JE, Montesinos P, Herrero MJ, Moscardó F, Bosó V, Rojas L, Martínez-Cuadrón D, et al. Impact of NADPH oxidase functional polymorphisms in acute myeloid leukemia induction chemotherapy. Pharmacogenomics J. 2018;18:301–307. doi: 10.1038/tpj.2017.19. PubMed DOI

Karki K, Hedrick E, Kasiappan R, Jin UH, Safe S. Piperlongumine induces reactive oxygen species (ROS)-dependent downregulation of specificity protein transcription factors. Cancer Prev Res (Phila) 2017;10:467–477. doi: 10.1158/1940-6207.CAPR-17-0053. PubMed DOI PMC

Upadhyaya B, Liu Y, Dey M. Phenethyl isothiocyanate exposure promotes oxidative stress and suppresses Sp1 transcription factor in cancer stem cells. Int J Mol Sci. 2019;20:5. doi: 10.3390/ijms20051027. PubMed DOI PMC

Chikara S, Nagaprashantha LD, Singhal J, Horne D, Awasthi S, Singhal SS. Oxidative stress and dietary phytochemicals: Role in cancer chemoprevention and treatment. Cancer Lett. 2018;413:122–134. doi: 10.1016/j.canlet.2017.11.002. PubMed DOI

Kirshner JR, He S, Balasubramanyam V, Kepros J, Yang CY, Zhang M, Du Z, Barsoum J, Bertin J. Elesclomol induces cancer cell apoptosis through oxidative stress. Mol Cancer Ther. 2008;7:2319–2327. doi: 10.1158/1535-7163.MCT-08-0298. PubMed DOI

Kin T, Ohtani S, Maeda R, Ueno A, Fujihara M, Takamatsu Y, Kajiwara Y, Ito M, Kawasaki K, Abe K, Sakata Y, Hiraki K. Nab-Paclitaxel Followed by 5-Fluorouracil, Epirubicin and Cyclophosphamide in Neoadjuvant Chemotherapy for Resectable Breast Cancer: A Phase II Trial. World J Oncol. 2020;11:197–203. doi: 10.14740/wjon1333. PubMed DOI PMC

El-Hussein A, Manoto SL, Ombinda-Lemboumba S, Alrowaili ZA, Mthunzi-Kufa P. A review of chemotherapy and photodynamic therapy for lung cancer treatment. Anticancer Agents Med Chem. 2021;21:149–161. doi: 10.2174/18715206MTA1uNjQp3. PubMed DOI

Binder S, Hosikova B, Mala Z, Zarska L, Kolarova H. Effect of ClAlPcS(2) photodynamic and sonodynamic therapy on HeLa cells. Physiol Res. 2019;68(Suppl 4):S467–S474. doi: 10.33549/physiolres.934374. PubMed DOI

Brown E, Yedjou CG, Tchounwou PB. Cytotoxicity and oxidative stress in human liver carcinoma cells exposed to arsenic trioxide (HepG(2)) Met Ions Biol Med. 2008;10:583–587. PubMed PMC

Smith DM, Patel S, Raffoul F, Haller E, Mills GB, Nanjundan M. Arsenic trioxide induces a beclin-1-independent autophagic pathway via modulation of SnoN/SkiL expression in ovarian carcinoma cells. Cell Death Differ. 2010;17:1867–1881. doi: 10.1038/cdd.2010.53. PubMed DOI PMC

Sumi D, Shinkai Y, Kumagai Y. Signal transduction pathways and transcription factors triggered by arsenic trioxide in leukemia cells. Toxicol Appl Pharmacol. 2010;244:385–392. doi: 10.1016/j.taap.2010.02.012. PubMed DOI

Kato I, Kasukabe T, Kumakura S. Menin-MLL inhibitors induce ferroptosis and enhance the anti-proliferative activity of auranofin in several types of cancer cells. Int J Oncol. 2020;57:1057–1071. doi: 10.3892/ijo.2020.5116. PubMed DOI

Lippmann J, Petri K, Fulda S, Liese J. Redox modulation and induction of ferroptosis as a new therapeutic strategy in hepatocellular carcinoma. Transl Oncol. 2020;13:100785. doi: 10.1016/j.tranon.2020.100785. PubMed DOI PMC

Sehrawat A, Singh SV. Short-form RON overexpression augments benzyl isothiocyanate-induced apoptosis in human breast cancer cells. Mol Carcinog. 2016;55:473–485. doi: 10.1002/mc.22295. PubMed DOI PMC

Kasiappan R, Jutooru I, Karki K, Hedrick E, Safe S. Benzyl isothiocyanate (BITC) induces reactive oxygen species-dependent repression of STAT3 protein by down-regulation of specificity proteins in pancreatic cancer. J Biol Chem. 2016;291:27122–27133. doi: 10.1074/jbc.M116.746339. PubMed DOI PMC

Huang YP, Jiang YW, Chen HY, Hsiao YT, Peng SF, Chou YC, Yang JL, Hsia TC, Chung JG. Benzyl isothiocyanate induces apoptotic cell death through mitochondria-dependent pathway in gefitinib-resistant NCI-H460 human lung cancer cells in vitro. Anticancer Res. 2018;38:5165–5176. doi: 10.21873/anticanres.12839. PubMed DOI

Yang H, Villani RM, Wang H, Simpson MJ, Roberts MS, Tang M, Liang X. The role of cellular reactive oxygen species in cancer chemotherapy. J Exp Clin Cancer Res. 2018;37:266. doi: 10.1186/s13046-018-0909-x. PubMed DOI PMC

Li Y, Zhou Q, Shen J, Zhu L. Down-regulation of PSMD4 can attenuate autophagy, enhance the accumulation of intracellular ROS, and increase the sensitivity of epithelial ovarian cancer to carboplatin by inhibiting the NF-κB pathway. Transl Cancer Res. 2021;10:4756–4772. doi: 10.21037/tcr-21-1389. PubMed DOI PMC

Xie Y, Hou W, Song X, Yu Y, Huang J, Sun X, Kang R, Tang D. Ferroptosis: process and function. Cell Death Differ. 2016;23:369–379. doi: 10.1038/cdd.2015.158. PubMed DOI PMC

Guo J, Xu B, Han Q, Zhou H, Xia Y, Gong C, Dai X, Li Z, Wu G. Ferroptosis: a novel antitumor action for cisplatin. Cancer Res Treat. 2018;50:445–460. doi: 10.4143/crt.2016.572. PubMed DOI PMC

Mikuła-Pietrasik J, Witucka A, Pakuła M, Uruski P, Begier-Krasińska B, Niklas A, Tykarski A, Książek K. Comprehensive review on how platinum- and taxane-based chemotherapy of ovarian cancer affects biology of normal cells. Cell Mol Life Sci. 2019;76:681–697. doi: 10.1007/s00018-018-2954-1. PubMed DOI PMC

Montero AJ, Diaz-Montero CM, Deutsch YE, Hurley J, Koniaris LG, Rumboldt T, Yasir S, et al. Phase 2 study of neoadjuvant treatment with NOV-002 in combination with doxorubicin and cyclophosphamide followed by docetaxel in patients with HER-2 negative clinical stage II–IIIc breast cancer. Breast Cancer Res Treat. 2012;132:215–223. doi: 10.1007/s10549-011-1889-0. PubMed DOI PMC

Garg M, Kanojia D, Mayakonda A, Ganesan TS, Sadhanandhan B, Suresh S, SS, et al. Selinexor (KPT-330) has antitumor activity against anaplastic thyroid carcinoma in vitro and in vivo and enhances sensitivity to doxorubicin. Sci Rep. 2017;7:9749. doi: 10.1038/s41598-017-10325-x. PubMed DOI PMC

Stein EM, DiNardo CD, Pollyea DA, Fathi AT, Roboz GJ, Altman JK, Stone RM, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130:722–731. doi: 10.1182/blood-2017-04-779405. PubMed DOI PMC

Nassereddine S, Lap CJ, Tabbara IA. Evaluating ivosidenib for the treatment of relapsed/refractory AML: design, development, and place in therapy. Onco Targets Ther. 2019;12:303–308. doi: 10.2147/OTT.S182443. PubMed DOI PMC

Tejera D, Kushnirsky M, Gultekin SH, Lu M, Steelman L, de la Fuente MI. Ivosidenib, an IDH1 inhibitor, in a patient with recurrent, IDH1-mutant glioblastoma: a case report from a Phase I study. CNS Oncol. 2020;9:Cns62. doi: 10.2217/cns-2020-0014. PubMed DOI PMC

Li KW, Wen TF, Li GD. Hepatic mucormycosis mimicking hilar cholangiocarcinoma: a case report and literature review. World J Gastroenterol. 2010;16:1039–1042. doi: 10.3748/wjg.v16.i8.1039. PubMed DOI PMC

Shaw AT, Winslow MM, Magendantz M, Ouyang C, Dowdle J, Subramanian A, Lewis TA, Maglathin RL, Tolliday N, Jacks T. Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress. Proc Natl Acad Sci U S A. 2011;108:8773–8778. doi: 10.1073/pnas.1105941108. PubMed DOI PMC

Zhou X, Chen J, Yi G, Deng M, Liu H, Liang M, Shi B, Fu X, Chen Y, Chen L, He Z, Wang J, Liu J. Metformin suppresses hypoxia-induced stabilization of HIF-1α through reprogramming of oxygen metabolism in hepatocellular carcinoma. Oncotarget. 2016;7:873–884. doi: 10.18632/oncotarget.6418. PubMed DOI PMC

Scharping NE, Menk AV, Whetstone RD, Zeng X, Delgoffe GM. Efficacy of PD-1 blockade is potentiated by metformin-induced reduction of tumor hypoxia. Cancer Immunol Res. 2017;5:9–16. doi: 10.1158/2326-6066.CIR-16-0103. PubMed DOI PMC

Kunisada Y, Eikawa S, Tomonobu N, Domae S, Uehara T, Hori S, Furusawa Y, Hase K, Sasaki A, Udono H. Attenuation of CD4(+)CD25(+) regulatory T cells in the tumor microenvironment by metformin, a type 2 diabetes drug. EBioMedicine. 2017;25:154–164. doi: 10.1016/j.ebiom.2017.10.009. PubMed DOI PMC

Chen YX, Xie X, Zhou CY, Xu CH. Methotrexate-induced apoptosis of JAR cells of choriocarcinoma and expression of its related proteins (Article in Chinese) Zhonghua Fu Chan Ke Za Zhi. 2004;39:558–559. PubMed

Luo GJ, Wang L, Hu GF, Li CB, Liu HX, Peng MT. Clinical application of the simultaneous detection of methotrexate and 7-hydroxymethotrexate in the delayed elimination for pediatric acute lymphoblastic leukemia (Article in Chinese) Zhonghua Yi Xue Za Zhi. 2020;100:1973–1978. doi: 10.3760/cma.j.cn112137-20200424-01305. PubMed DOI

Su WP, Lo YC, Yan JJ, Liao IC, Tsai PJ, Wang HC, Yeh HH, Lin CC, Chen HH, Lai WW, Su WC. Mitochondrial uncoupling protein 2 regulates the effects of paclitaxel on Stat3 activation and cellular survival in lung cancer cells. Carcinogenesis. 2012;33:2065–2075. doi: 10.1093/carcin/bgs253. PubMed DOI

Sonoda H, Shimizu T, Mekata E, Endo Y, Ishida M, Tani T. A complete response to mFOLFOX6 and panitumumab chemotherapy in advanced stage rectal adenocarcinoma: a case report. World J Surg Oncol. 2014;12:63. doi: 10.1186/1477-7819-12-63. PubMed DOI PMC

Duan C, Zhang B, Deng C, Cao Y, Zhou F, Wu L, Chen M, et al. Piperlongumine induces gastric cancer cell apoptosis and G2/M cell cycle arrest both in vitro and in vivo. Tumour Biol. 2016;37:10793–10804. doi: 10.1007/s13277-016-4792-9. PubMed DOI

Zheng J, Son DJ, Gu SM, Woo JR, Ham YW, Lee HP, Kim WJ, Jung JK, Hong JT. Piperlongumine inhibits lung tumor growth via inhibition of nuclear factor kappa B signaling pathway. Sci Rep. 2016;6:26357. doi: 10.1038/srep26357. PubMed DOI PMC

Gao F, Zhou L, Li M, Liu W, Yang S, Li W. Inhibition of ERKs/Akt-mediated c-Fos expression is required for piperlongumine-induced cyclin D1 downregulation and tumor suppression in colorectal cancer cells. Onco Targets Ther. 2020;13:5591–5603. doi: 10.2147/OTT.S251295. PubMed DOI PMC

Lachaier E, Louandre C, Godin C, Saidak Z, Baert M, Diouf M, Chauffert B, Galmiche A. Sorafenib induces ferroptosis in human cancer cell lines originating from different solid tumors. Anticancer Res. 2014;34:6417–6422. PubMed

Stockwell BR. A powerful cell-protection system prevents cell death by ferroptosis. Nature. 2019;575:597–598. doi: 10.1038/d41586-019-03145-8. PubMed DOI PMC

Buccarelli M, Marconi M, Pacioni S, De Pascalis I, D'Alessandris QG, Martini M, Ascione B, et al. Inhibition of autophagy increases susceptibility of glioblastoma stem cells to temozolomide by igniting ferroptosis. Cell Death Dis. 2018;9:841. doi: 10.1038/s41419-018-0864-7. PubMed DOI PMC

Salerni BL, Bates DJ, Albershardt TC, Lowrey CH, Eastman A. Vinblastine induces acute, cell cycle phase-independent apoptosis in some leukemias and lymphomas and can induce acute apoptosis in others when Mcl-1 is suppressed. Mol Cancer Ther. 2010;9:791–802. doi: 10.1158/1535-7163.MCT-10-0028. PubMed DOI PMC

Wang J, Xu L, Ye JM, Zhao JX, Duan XN, Liu YH. Effects of vinorelbine plus cisplatin as second-line neoadjuvant chemotherapy regimen in the treatment of breast cancer (Article in Chinese) Zhonghua Yi Xue Za Zhi. 2013;93:93–95. PubMed

Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3:330–338. doi: 10.1038/nrc1074. PubMed DOI