The antimalarial drug artemisinin and its derivatives have been explored as potential anticancer agents, but their underlying mechanisms are controversial. In this study, we found that artemisinin compounds can sensitize cancer cells to ferroptosis, a new form of programmed cell death driven by iron-dependent lipid peroxidation. Mechanistically, dihydroartemisinin (DAT) can induce lysosomal degradation of ferritin in an autophagy-independent manner, increasing the cellular free iron level and causing cells to become more sensitive to ferroptosis. Further, by associating with cellular free iron and thus stimulating the binding of iron-regulatory proteins (IRPs) with mRNA molecules containing iron-responsive element (IRE) sequences, DAT impinges on IRP/IRE-controlled iron homeostasis to further increase cellular free iron. Importantly, in both in vitro and a mouse xenograft model in which ferroptosis was triggered in cancer cells by the inducible knockout of GPX4, we found that DAT can augment GPX4 inhibition-induced ferroptosis in a cohort of cancer cells that are otherwise highly resistant to ferroptosis. Collectively, artemisinin compounds can sensitize cells to ferroptosis by regulating cellular iron homeostasis. Our findings can be exploited clinically to enhance the effect of future ferroptosis-inducing cancer therapies.
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Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007;35:495–516.
Ashkenazi A, Salvesen G. Regulated cell death: signaling and mechanisms. Annu Rev Cell Dev Biol. 2014;30:337–56.
Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018;25:486–541.
Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.
Gao M, Monian P, Quadri N, Ramasamy R, Jiang XJ. Glutaminolysis and transferrin regulate ferroptosis. Mol Cell. 2015;59:298–308.
Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171:273–85.
Conrad M, Angeli JP, Vandenabeele P, Stockwell BR. Regulated necrosis: disease relevance and therapeutic opportunities. Nat Rev Drug Discov. 2016;15:348–66.
Toyokuni S, Ito F, Yamashita K, Okazaki Y, Akatsuka S. Iron and thiol redox signaling in cancer: An exquisite balance to escape ferroptosis. Free Radic Biol Med. 2017;108:610–26.
Tonnus W, Linkermann A. The in vivo evidence for regulated necrosis. Immunol Rev. 2017;277:128–49.
Wang SJ, Li D, Ou Y, Jiang L, Chen Y, Zhao Y, et al. Acetylation Is Crucial for p53-Mediated Ferroptosis and Tumor Suppression. Cell Rep. 2016;17:366–73.
Zhang Y, Shi J, Liu X, Feng L, Gong Z, Koppula P, et al. BAP1 links metabolic regulation of ferroptosis to tumour suppression. Nat Cell Biol. 2018;20:1181–92.
Gao M, Yi J, Zhu J, Minikes AM, Monian P, Thompson CB, et al. Role of mitochondria in ferroptosis. Mol Cell. 2018;72:354–63.
Viswanathan VS, Ryan MJ, Dhruv HD, Gill S, Eichhoff OM, Seashore-Ludlow B, et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature. 2017;547:453–7.
Klayman DL. Qinghaosu (artemisinin): an antimalarial drug from China. Science. 1985;228:1049–55.
Balint GA. Artemisinin and its derivatives: an important new class of antimalarial agents. Pharm Ther. 2001;90:261–5.
O’Neill PM, Barton VE, Ward SA. The molecular mechanism of action of artemisinin–the debate continues. Molecules. 2010;15:1705–21.
Cui L, Su XZ. Discovery, mechanisms of action and combination therapy of artemisinin. Expert Rev Anti Infect Ther. 2009;7:999–1013.
Krishna S, Uhlemann AC, Haynes RK. Artemisinins: mechanisms of action and potential for resistance. Drug Resist Updat. 2004;7:233–44.
Asawamahasakda W, Ittarat I, Pu YM, Ziffer H, Meshnick SR. Reaction of antimalarial endoperoxides with specific parasite proteins. Antimicrob Agents Chemother. 1994;38:1854–8.
Meshnick SR. The mode of action of antimalarial endoperoxides. Trans R Soc Trop Med Hyg. 1994;88(Suppl 1):S31–2.
Zhang F, Gosser DK Jr., Meshnick SR. Hemin-catalyzed decomposition of artemisinin (qinghaosu). Biochem Pharmacol. 1992;43:1805–9.
Efferth T. Molecular pharmacology and pharmacogenomics of artemisinin and its derivatives in cancer cells. Curr Drug Targets. 2006;7:407–21.
Chaturvedi D, Goswami A, Saikia PP, Barua NC, Rao PG. Artemisinin and its derivatives: a novel class of anti-malarial and anti-cancer agents. Chem Soc Rev. 2010;39:435–54.
Konstat-Korzenny E, Ascencio-Aragon JA, Niezen-Lugo S, Vazquez-Lopez R. Artemisinin and its synthetic derivatives as a possible therapy for cancer. Med Sci. 2018;6:19.
Berdelle N, Nikolova T, Quiros S, Efferth T, Kaina B. Artesunate induces oxidative DNA damage, sustained DNA double-strand breaks, and the ATM/ATR damage response in cancer cells. Mol Cancer Ther. 2011;10:2224–33.
Li PC, Lam E, Roos WP, Zdzienicka MZ, Kaina B, Efferth T. Artesunate derived from traditional Chinese medicine induces DNA damage and repair. Cancer Res. 2008;68:4347–51.
Wang Z, Hu W, Zhang JL, Wu XH, Zhou HJ. Dihydroartemisinin induces autophagy and inhibits the growth of iron-loaded human myeloid leukemia K562 cells via ROS toxicity. FEBS Open Bio. 2012;2:103–12.
Singh NP, Lai HC. Artemisinin induces apoptosis in human cancer cells. Anticancer Res. 2004;24:2277–80.
Ooko E, Saeed ME, Kadioglu O, Sarvi S, Colak M, Elmasaoudi K, et al. Artemisinin derivatives induce iron-dependent cell death (ferroptosis) in tumor cells. Phytomedicine. 2015;22:1045–54.
Gaschler MM, Andia AA, Liu H, Csuka JM, Hurlocker B, Vaiana CA, et al. FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation. Nat Chem Biol. 2018;14:507–15.
Chen G, Gong R, Shi X, Yang D, Zhang G, Lu A, et al. Halofuginone and artemisinin synergistically arrest cancer cells at the G1/G0 phase by upregulating p21Cip1 and p27Kip1. Oncotarget. 2016;7:50302–14.
Chen T, Li M, Zhang R, Wang H. Dihydroartemisinin induces apoptosis and sensitizes human ovarian cancer cells to carboplatin therapy. J Cell Mol Med. 2009;13:1358–70.
Rouault TA. The role of iron regulatory proteins in mammalian iron homeostasis and disease. Nat Chem Biol. 2006;2:406–14.
Prus E, Fibach E. Flow cytometry measurement of the labile iron pool in human hematopoietic cells. Cytom A. 2008;73:22–7.
Esterbauer H, Cheeseman KH. Determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hydroxynonenal. Methods Enzym. 1990;186:407–21.
De la Cruz JP, Olveira C, Gonzalez-Correa JA, Benitez A, Sanchez, de la Cuesta F. Inhibition of ferrous-induced lipid peroxidation by dipyridamole, RA-642 and mopidamol in human lung tissue. Gen Pharmacol. 1996;27:855–9.
Li JY, Ram G, Gast K, Chen X, Barasch K, Mori K, et al. Detection of intracellular iron by its regulatory effect. Am J Physiol Cell Physiol. 2004;287:C1547–59.
Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156:317–31.
Hou W, Xie Y, Song X, Sun X, Lotze MT, Zeh HJ 3rd, et al. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy. 2016;12:1425–8.
Gao M, Monian P, Pan Q, Zhang W, Xiang J, Jiang X. Ferroptosis is an autophagic cell death process. Cell Res. 2016;26:1021–32.
Zhang Z, Yao Z, Zhao S, Shao J, Chen A, Zhang F, et al. Interaction between autophagy and senescence is required for dihydroartemisinin to alleviate liver fibrosis. Cell Death Dis. 2017;8:e2886.
Wang J, Pantopoulos K. Regulation of cellular iron metabolism. Biochem J. 2011;434:365–81.
Asano T, Komatsu M, Yamaguchi-Iwai Y, Ishikawa F, Mizushima N, Iwai K. Distinct mechanisms of ferritin delivery to lysosomes in iron-depleted and iron-replete cells. Mol Cell Biol. 2011;31:2040–52.
Kurz T, Eaton JW, Brunk UT. The role of lysosomes in iron metabolism and recycling. Int J Biochem. Cell B. 2011;43:1686–97.
Radisky DC, Kaplan J. Iron in cytosolic ferritin can be recycled through lysosomal degradation in human fibroblasts. Biochem J. 1998;336:201–5.
Mancias JD, Wang X, Gygi SP, Harper JW, Kimmelman AC. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature. 2014;509:105–9.
Dice JF. Chaperone-mediated autophagy. Autophagy. 2007;3:295–9.
Sibmooh N, Udomsangpetch R, Kujoa A, Chantharaksri U, Mankhetkorn S. Redox reaction of artemisinin with ferrous and ferric ions in aqueous buffer. Chem Pharm Bull. 2001;49:1541–6.
Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol. 2014;16:1180–91.
Eckstein-Ludwig U, Webb RJ, Van Goethem ID, East JM, Lee AG, Kimura M, et al. Artemisinins target the SERCA of Plasmodium falciparum. Nature. 2003;424:957–61.
Eichhorn T, Winter D, Buchele B, Dirdjaja N, Frank M, Lehmann WD, et al. Molecular interaction of artemisinin with translationally controlled tumor protein (TCTP) of Plasmodium falciparum. Biochem Pharm. 2013;85:38–45.
Willoughby JA, Sundar SN, Cheung M, Tin AS, Modiano J, Firestone GL. Artemisinin blocks prostate cancer growth and cell cycle progression by disrupting Sp1 interactions with the cyclin-dependent kinase-4 (CDK4) promoter and inhibiting CDK4 gene expression. J Biol Chem. 2009;284:2203–13.
Hong YL, Yang YZ, Meshnick SR. The interaction of artemisinin with malarial hemozoin. Mol Biochem Parasitol. 1994;63:121–8.
Wang SJ, Gao Y, Chen H, Kong R, Jiang HC, Pan SH, et al. Dihydroartemisinin inactivates NF-kappaB and potentiates the anti-tumor effect of gemcitabine on pancreatic cancer both in vitro and in vivo. Cancer Lett. 2010;293:99–108.
Chen H, Sun B, Pan S, Jiang H, Sun X. Dihydroartemisinin inhibits growth of pancreatic cancer cells in vitro and in vivo. Anticancer Drugs. 2009;20:131–40.
Yang ND, Tan SH, Ng S, Shi Y, Zhou J, Tan KS, et al. Artesunate induces cell death in human cancer cells via enhancing lysosomal function and lysosomal degradation of ferritin. J Biol Chem. 2014;289:33425–41.
Button RW, Lin F, Ercolano E, Vincent JH, Hu B, Hanemann CO, et al. Artesunate induces necrotic cell death in schwannoma cells. Cell Death Dis. 2014;5:e1466.
Dowdle WE, Nyfeler B, Nagel J, Elling RA, Liu S, Triantafellow E, et al. Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo. Nat Cell Biol. 2014;16:1069–79.
Huang J, Jones D, Luo B, Sanderson M, Soto J, Abel ED, et al. Iron overload and diabetes risk: a shift from glucose to Fatty Acid oxidation and increased hepatic glucose production in a mouse model of hereditary hemochromatosis. Diabetes. 2011;60:80–7.
Dabbagh AJ, Shwaery GT, Keaney JF Jr., Frei B. Effect of iron overload and iron deficiency on atherosclerosis in the hypercholesterolemic rabbit. Arterioscler Thromb Vasc Biol. 1997;17:2638–45.
Hare D, Ayton S, Bush A, Lei P. A delicate balance: Iron metabolism and diseases of the brain. Front Aging Neurosci. 2013;5:34.
Gammella E, Recalcati S, Rybinska I, Buratti P, Cairo G. Iron-induced damage in cardiomyopathy: oxidative-dependent and independent mechanisms. Oxid Med Cell Longev. 2015;2015:230182.
The authors thank members of the Jiang and Bian labs for advice, technical assistance and for critically reading the manuscript. This work is supported by NIH grants R01CA204232 & R01GM113013 (X.J.), Geoffrey Beene Cancer Research fund (X.J.), NCI Cancer Center Core Grant P30CA008748 for Memorial Sloan-Kettering Cancer Center, China Scholarship Council Fellowship 201603170375 (J.W.), and HKRGC GRF grant 12104415 (Z-X.B.).