The Role of Reactive Oxygen Species in Tumor Treatment and its Impact on Bone Marrow Hematopoiesis

Yongfeng       Chen; Xingjing       Luo; Zhenyou       Zou; Yong       Liang
Abstract

Reactive oxygen species (ROS), an important molecule inducing oxidative stress in organisms, play a key role in tumorigenesis, tumor progression and recurrence. Recent findings on ROS have shown that ROS can be used to treat cancer as they accelerate the death of tumor cells. At present, pro-oxidant drugs that are intended to increase ROS levels of the tumor cells have been widely used in the clinic. However, ROS are a double-edged sword in the treatment of tumors. High levels of ROS induce not only the death of tumor cells but also oxidative damage to normal cells, especially bone marrow hemopoietic cells, which leads to bone marrow suppression and (or) other side effects, weak efficacy of tumor treatment and even threatening patients’ life. How to enhance the killing effect of ROS on tumor cells while avoiding oxidative damage to the normal cells has become an urgent issue. This study is a review of the latest progress in the role of ROS-mediated programmed death in tumor treatment and prevention and treatment of oxidative damage in bone marrow induced by ROS.
Keywords: ROS, programmed cell death, bone marrow protection, chemotherapy, tumor, hematopoiesis.
Graphical Abstract

[1] 
Yarosz EL, Chang CH. The role of reactive oxygen species in regulating t cell-mediated immunity and disease. Immune Netw  2018; 18(1)e14
[http://dx.doi.org/10.4110/in.2018.18.e14] [PMID:  29503744] 
[2] 
Zou Z, Cai J, Zhong A, et al. Using the synthesized peptide HAYED (5) to protect the brain against iron catalyzed radical attack in a naturally senescence Kunming mouse model. Free Radic Biol Med  2019; 130: 458-70.
[http://dx.doi.org/10.1016/j.freeradbiomed.2018.11.014] [PMID:  30448512] 
[3] 
Little AC, Sulovari A, Danyal K, Heppner DE, Seward DJ, van der Vliet A. Paradoxical roles of dual oxidases in cancer biology. Free Radic Biol Med  2017; 110: 117-32.
[http://dx.doi.org/10.1016/j.freeradbiomed.2017.05.024] [PMID:  28578013] 
[4] 
Zou Z, Shen Q, Pang Y, et al. The synthesized transporter K16APoE enabled the therapeutic HAYED peptide to cross the blood-brain barrier and remove excess iron and radicals in the brain, thus easing Alzheimer’s disease. Drug Deliv Transl Res  2019; 9(1): 394-403.
[http://dx.doi.org/10.1007/s13346-018-0579-4] [PMID:  30136122] 
[5] 
Dharmaraja AT. Role of reactive oxygen species (ROS) in therapeutics and drug resistance in cancer and bacteria. J Med Chem  2017; 60(8): 3221-40.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01243] [PMID:  28135088] 
[6] 
Chen Y, Zou Z, Wu Z, et al. TNF-α-induced programmed cell death in the pathogenesis of acquired aplastic anemia. Expert Rev Hematol  2015; 8(4): 515-26.
[http://dx.doi.org/10.1586/17474086.2015.1049593] [PMID:  26149913] 
[7] 
Kim J, Kim J, Bae JS. ROS homeostasis and metabolism: a critical liaison for cancer therapy. Exp Mol Med  2016; 48(11)e269
[http://dx.doi.org/10.1038/emm.2016.119] [PMID:  27811934] 
[8] 
Xiao H, Xiong L, Song X, et al. Angelica sinensis polysaccharides ameliorate stress-induced premature senescence of hematopoietic cell via protecting bone marrow stromal cells from oxidative injuries caused by 5-fluorouracil. Int J Mol Sci  2017; 18(11)E2265
[http://dx.doi.org/10.3390/ijms18112265] [PMID:  29143796] 
[9] 
Qu C, Lu Y, Liu W. Severe bone marrow suppression accompanying pulmonary infection and hemorrhage of the digestive tract associated with leflunomide and low-dose methotrexate combination therapy. J Pharmacol Pharmacother  2017; 8(1): 35-7.
[http://dx.doi.org/10.4103/jpp.JPP_93_16] [PMID:  28405135] 
[10] 
Cao H, Wang Y, Wang Q, et al. Taxol prevents myocardial ischemia-reperfusion injury by inducing JNK-mediated HO-1 expression. Pharm Biol  2016; 54(3): 555-60.
[PMID:  26270131] 
[11] 
Fruehauf JP, Meyskens FL Jr. Reactive oxygen species: a breath of life or death? Clin Cancer Res  2007; 13(3): 789-94.
[http://dx.doi.org/10.1158/1078-0432.CCR-06-2082] [PMID:  17289868] 
[12] 
Bauer G, Motz M. The antitumor effect of single-domain antibodies directed towards membrane-associated catalase and superoxide dismutase. Anticancer Res  2016; 36(11): 5945-56.
[http://dx.doi.org/10.21873/anticanres.11182] [PMID:  27793920] 
[13] 
Chen YF, Liu H, Luo XJ, et al. The roles of reactive oxygen species (ROS) and autophagy in the survival and death of leukemia cells. Crit Rev Oncol Hematol  2017; 112: 21-30.
[http://dx.doi.org/10.1016/j.critrevonc.2017.02.004] [PMID:  28325262] 
[14] 
Diehn M, Cho RW, Lobo NA, et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature  2009; 458(7239): 780-3.
[http://dx.doi.org/10.1038/nature07733] [PMID:  19194462] 
[15] 
Kobayashi CI, Suda T. Regulation of reactive oxygen species in stem cells and cancer stem cells. J Cell Physiol  2012; 227(2): 421-30.
[http://dx.doi.org/10.1002/jcp.22764] [PMID:  21448925] 
[16] 
Trachootham D, Alexandre J, Huang P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov  2009; 8(7): 579-91.
[http://dx.doi.org/10.1038/nrd2803] [PMID:  19478820] 
[17] 
DeNicola GM, Karreth FA, Humpton TJ, et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature  2011; 475(7354): 106-9.
[http://dx.doi.org/10.1038/nature10189] [PMID:  21734707] 
[18] 
Medici S, Peana M, Nurchi VM, Lachowicz JI, Maria GC, Zoroddu A. Noble metals in medicine: Latest advances. Coord Chem Rev  2015; 284: 329-50.
[http://dx.doi.org/10.1016/j.ccr.2014.08.002] 
[19] 
Circu ML, Aw TY. Reactive oxygen species, cellular redox systems, and apoptosis. Free Radic Biol Med  2010; 48(6): 749-62.
[http://dx.doi.org/10.1016/j.freeradbiomed.2009.12.022] [PMID:  20045723] 
[20] 
Suzuki Y, Ono Y, Hirabayashi Y. Rapid and specific reactive oxygen species generation via NADPH oxidase activation during Fas-mediated apoptosis. FEBS Lett  1998; 425(2): 209-12.
[http://dx.doi.org/10.1016/S0014-5793(98)00228-2] [PMID:  9559649] 
[21] 
Stewart JH IV, Tran TL, Levi N, Tsai WS, Schrump DS, Nguyen DM. The essential role of the mitochondria and reactive oxygen species in Cisplatin-mediated enhancement of fas ligand-induced apoptosis in malignant pleural mesothelioma. J Surg Res  2007; 141(1): 120-31.
[http://dx.doi.org/10.1016/j.jss.2007.03.048] [PMID:  17574045] 
[22] 
Lee MW, Park SC, Kim JH, et al. The involvement of oxidative stress in tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in HeLa cells. Cancer Lett  2002; 182(1): 75-82.
[http://dx.doi.org/10.1016/S0304-3835(02)00074-5] [PMID:  12175526] 
[23] 
González-Flores D, Rodríguez AB, Pariente JA. TNFα-induced apoptosis in human myeloid cell lines HL-60 and K562 is dependent of intracellular ROS generation. Mol Cell Biochem  2014; 390(1-2): 281-7.
[http://dx.doi.org/10.1007/s11010-014-1979-5] [PMID:  24488173] 
[24] 
Zhang W, Kudo H, Kawai K, et al. Tumor necrosis factor-alpha accelerates apoptosis of steatotic hepatocytes from a murine model of non-alcoholic fatty liver disease. Biochem Biophys Res Commun  2010; 391(4): 1731-6.
[http://dx.doi.org/10.1016/j.bbrc.2009.12.144] [PMID:  20043871] 
[25] 
Chao H, Liu Y, Fu X, et al. Lowered iPLA2γ activity causes increased mitochondrial lipid peroxidation and mitochondrial dysfunction in a rotenone-induced model of Parkinson’s disease. Exp Neurol  2018; 300: 74-86.
[http://dx.doi.org/10.1016/j.expneurol.2017.10.031] [PMID:  29104115] 
[26] 
Cao XH, Zhao SS, Liu DY, et al. ROS-Ca(2+) is associated with mitochondria permeability transition pore involved in surfactin-induced MCF-7 cells apoptosis. Chem Biol Interact  2011; 190(1): 16-27.
[http://dx.doi.org/10.1016/j.cbi.2011.01.010] [PMID:  21241685] 
[27] 
Chami M, Prandini A, Campanella M, et al. Bcl-2 and Bax exert opposing effects on Ca2+ signaling, which do not depend on their putative pore-forming region. J Biol Chem  2004; 279(52): 54581-9.
[http://dx.doi.org/10.1074/jbc.M409663200] [PMID:  15485871] 
[28] 
Budanov AV. The role of tumor suppressor p53 in the antioxidant defense and metabolism. Subcell Biochem  2014; 85: 337-58.
[http://dx.doi.org/10.1007/978-94-017-9211-0_18] [PMID:  25201203] 
[29] 
Kim JJ, Lee SB, Park JK, Yoo YD. TNF-alpha-induced ROS production triggering apoptosis is directly linked to Romo1 and Bcl-X(L). Cell Death Differ  2010; 17(9): 1420-34.
[http://dx.doi.org/10.1038/cdd.2010.19] [PMID:  20203691] 
[30] 
Zhang M, Lee SJ, An C, et al. Caveolin-1 mediates Fas-BID signaling in hyperoxia-induced apoptosis. Free Radic Biol Med  2011; 50(10): 1252-62.
[http://dx.doi.org/10.1016/j.freeradbiomed.2011.02.031] [PMID:  21382479] 
[31] 
Zong WX, Thompson CB. Necrotic death as a cell fate. Genes Dev  2006; 20(1): 1-15.
[http://dx.doi.org/10.1101/gad.1376506] [PMID:  16391229] 
[32] 
Fu Z, Deng B, Liao Y, et al. The anti-tumor effect of shikonin on osteosarcoma by inducing RIP1 and RIP3 dependent necroptosis. BMC Cancer  2013; 13: 580.
[http://dx.doi.org/10.1186/1471-2407-13-580] [PMID:  24314238] 
[33] 
Cho YS, Challa S, Moquin D, et al. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell  2009; 137(6): 1112-23.
[http://dx.doi.org/10.1016/j.cell.2009.05.037] [PMID:  19524513] 
[34] 
Rathore R, McCallum JE, Varghese E, Florea AM, Büsselberg D. Overcoming chemotherapy drug resistance by targeting inhibitors of apoptosis proteins (IAPs). Apoptosis  2017; 22(7): 898-919.
[http://dx.doi.org/10.1007/s10495-017-1375-1] [PMID:  28424988] 
[35] 
Bonapace L, Bornhauser BC, Schmitz M, et al. Induction of autophagy-dependent necroptosis is required for childhood acute lymphoblastic leukemia cells to overcome glucocorticoid resistance. J Clin Invest  2010; 120(4): 1310-23.
[http://dx.doi.org/10.1172/JCI39987] [PMID:  20200450] 
[36] 
Han W, Li L, Qiu S, et al. Shikonin circumvents cancer drug resistance by induction of a necroptotic death. Mol Cancer Ther  2007; 6(5): 1641-9.
[http://dx.doi.org/10.1158/1535-7163.MCT-06-0511] [PMID:  17513612] 
[37] 
Safferthal C, Rohde K, Fulda S. Therapeutic targeting of necroptosis by Smac mimetic bypasses apoptosis resistance in acute myeloid leukemia cells. Oncogene  2017; 36(11): 1487-502.
[http://dx.doi.org/10.1038/onc.2016.310] [PMID:  27869161] 
[38] 
Shahsavari Z, Karami-Tehrani F, Salami S, Ghasemzadeh M. RIP1K and RIP3K provoked by shikonin induce cell cycle arrest in the triple negative breast cancer cell line, MDA-MB-468: necroptosis as a desperate programmed suicide pathway. Tumour Biol  2016; 37(4): 4479-91.
[http://dx.doi.org/10.1007/s13277-015-4258-5] [PMID:  26496737] 
[39] 
Steinhart L, Belz K, Fulda S. Smac mimetic and demethylating
agents synergistically trigger cell death in acute myeloid leukemia
cells and overcome apoptosis resistance by inducing necroptosis.
Cell Death Dis 2013; 4e802 
[http://dx.doi.org/10.1038/cddis.2013.320] [PMID:  24030154] 
[40] 
Dikic I, Elazar Z. Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol  2018; 19(6): 349-64.
[http://dx.doi.org/10.1038/s41580-018-0003-4] [PMID:  29618831] 
[41] 
Hamurcu Z, Delibaşı N, Geçene S, et al. Targeting LC3 and Beclin-1 autophagy genes suppresses proliferation, survival, migration and invasion by inhibition of Cyclin-D1 and uPAR/Integrin β1/Src signaling in triple negative breast cancer cells. J Cancer Res Clin Oncol  2018; 144(3): 415-30.
[http://dx.doi.org/10.1007/s00432-017-2557-5] [PMID:  29288363] 
[42] 
Kimmelman AC, White E. Autophagy and tumor metabolism. Cell Metab  2017; 25(5): 1037-43.
[http://dx.doi.org/10.1016/j.cmet.2017.04.004] [PMID:  28467923] 
[43] 
Kumar A, Singh UK, Chaudhary A. Targeting autophagy to overcome drug resistance in cancer therapy. Future Med Chem  2015; 7(12): 1535-42.
[http://dx.doi.org/10.4155/fmc.15.88] [PMID:  26334206] 
[44] 
Nguyen HG, Yang JC, Kung HJ, et al. Targeting autophagy overcomes Enzalutamide resistance in castration-resistant prostate cancer cells and improves therapeutic response in a xenograft model. Oncogene  2014; 33(36): 4521-30.
[http://dx.doi.org/10.1038/onc.2014.25] [PMID:  24662833] 
[45] 
Yu Y, Chen YF, Wu ZM, Bai S. Experimental study of the RIP3 expression and cell death resistance in acute lymphoblastic leukemia Jurkat cells under TNF-α administration. Int J Clin Exp Med  2018; 11: 1845-54.
[46] 
Zou Z, Ni M, Zhang J, et al. miR-30a can inhibit DNA replication by targeting RPA1 thus slowing cancer cell proliferation. Biochem J  2016; 473(14): 2131-9.
[http://dx.doi.org/10.1042/BCJ20160177] [PMID:  27208176] 
[47] 
Chaabane W, Appell ML. Interconnections between apoptotic and autophagic pathways during thiopurine-induced toxicity in cancer cells: the role of reactive oxygen species. Oncotarget  2016; 7(46): 75616-34.
[http://dx.doi.org/10.18632/oncotarget.12313] [PMID:  27689330] 
[48] 
Chen Q, Ye L, Fan J, et al. Autophagy suppression potentiates the anti-glioblastoma effect of asparaginase in vitro and in vivo. Oncotarget  2017; 8(53): 91052-66.
[http://dx.doi.org/10.18632/oncotarget.19409] [PMID:  29207624] 
[49] 
Donadelli M, Dando I, Zaniboni T, et al. Gemcitabine/cannabinoid
combination triggers autophagy in pancreatic cancer cells through a
ROS-mediated mechanism. Cell Death Dis 2011; 2e152 
[http://dx.doi.org/10.1038/cddis.2011.36] [PMID:  21525939] 
[50] 
Liu S, Li X. Autophagy inhibition enhances sensitivity of endometrial carcinoma cells to paclitaxel. Int J Oncol  2015; 46(6): 2399-408.
[http://dx.doi.org/10.3892/ijo.2015.2937] [PMID:  25825088] 
[51] 
Liu Z, Liu J, Li L, et al. Inhibition of autophagy potentiated the antitumor effect of nedaplatin in cisplatin-resistant nasopharyngeal carcinoma cells. PLoS One  2015; 10(8)e0135236
[http://dx.doi.org/10.1371/journal.pone.0135236] [PMID:  26288183] 
[52] 
Shen Y, Yang J, Zhao J, Xiao C, Xu C, Xiang Y. The switch from ER stress-induced apoptosis to autophagy via ROS-mediated JNK/p62 signals: A survival mechanism in methotrexate-resistant choriocarcinoma cells. Exp Cell Res  2015; 334(2): 207-18.
[http://dx.doi.org/10.1016/j.yexcr.2015.04.010] [PMID:  25912909] 
[53] 
Lin CJ, Lee CC, Shih YL, et al. Resveratrol enhances the therapeutic effect of temozolomide against malignant glioma in vitro and in vivo by inhibiting autophagy. Free Radic Biol Med  2012; 52(2): 377-91.
[http://dx.doi.org/10.1016/j.freeradbiomed.2011.10.487] [PMID:  22094224] 
[54] 
Cheng P, Ni Z, Dai X, et al. The novel BH-3 mimetic apogossypolone
induces Beclin-1- and ROS-mediated autophagy in human
hepatocellular carcinoma [corrected] cells. Cell Death Dis 2013;
4e489 
[http://dx.doi.org/10.1038/cddis.2013.17] [PMID:  23392177] 
[55] 
Niu Q, Zhao W, Wang J, et al. LicA induces autophagy through ULK1/Atg13 and ROS pathway in human hepatocellular carcinoma cells. Int J Mol Med  2018; 41(5): 2601-8.
[http://dx.doi.org/10.3892/ijmm.2018.3499] [PMID:  29484365] 
[56] 
Fan TF, Wu TF, Bu LL, et al. Dihydromyricetin promotes autophagy and apoptosis through ROS-STAT3 signaling in head and neck squamous cell carcinoma. Oncotarget  2016; 7(37): 59691-703.
[http://dx.doi.org/10.18632/oncotarget.10836] [PMID:  27474168] 
[57] 
Lu C, Wang W, Jia Y, Liu X, Tong Z, Li B. Inhibition of AMPK/autophagy potentiates parthenolide-induced apoptosis in human breast cancer cells. J Cell Biochem  2014; 115(8): 1458-66.
[http://dx.doi.org/10.1002/jcb.24808] [PMID:  24619908] 
[58] 
Qu X, Sheng J, Shen L, et al. Autophagy inhibitor chloroquine increases sensitivity to cisplatin in QBC939 cholangiocarcinoma cells by mitochondrial ROS. PLoS One  2017; 12(3)e0173712
[http://dx.doi.org/10.1371/journal.pone.0173712] [PMID:  28301876] 
[59] 
Harhaji-Trajkovic L, Vilimanovich U, Kravic-Stevovic T, Bumbasirevic V, Trajkovic V. AMPK-mediated autophagy inhibits apoptosis in cisplatin-treated tumour cells. J Cell Mol Med  2009; 13(9B): 3644-54.
[http://dx.doi.org/10.1111/j.1582-4934.2009.00663.x] [PMID:  20196784] 
[60] 
Yang C, Yang QO, Kong QJ, Yuan W, Ou Yang YP. Parthenolide induces reactive oxygen species-mediated autophagic cell death in human osteosarcoma cells. Cell Physiol Biochem  2016; 40(1-2): 146-54.
[http://dx.doi.org/10.1159/000452532] [PMID:  27855364] 
[61] 
Shinohara H, Taniguchi K, Kumazaki M, et al. Anti-cancer fatty-acid derivative induces autophagic cell death through modulation of PKM isoform expression profile mediated by bcr-abl in chronic myeloid leukemia. Cancer Lett  2015; 360(1): 28-38.
[http://dx.doi.org/10.1016/j.canlet.2015.01.039] [PMID:  25644089] 
[62] 
Itoh T, Ito Y, Ohguchi K, et al. Eupalinin A isolated from Eupatorium chinense L. induces autophagocytosis in human leukemia HL60 cells. Bioorg Med Chem  2008; 16(2): 721-31.
[http://dx.doi.org/10.1016/j.bmc.2007.10.033] [PMID:  17980607] 
[63] 
Chen Y, McMillan-Ward E, Kong J, Israels SJ, Gibson SB. Mitochondrial electron-transport-chain inhibitors of complexes I and II induce autophagic cell death mediated by reactive oxygen species. J Cell Sci  2007; 120(Pt 23): 4155-66.
[http://dx.doi.org/10.1242/jcs.011163] [PMID:  18032788] 
[64] 
Pan X, Liu D, Wang J, et al. Peneciraistin C induces caspase-independent autophagic cell death through mitochondrial-derived reactive oxygen species production in lung cancer cells. Cancer Sci  2013; 104(11): 1476-82.
[http://dx.doi.org/10.1111/cas.12253] [PMID:  23952056] 
[65] 
Yu L, Wan F, Dutta S, et al. Autophagic programmed cell death by selective catalase degradation. Proc Natl Acad Sci USA  2006; 103(13): 4952-7.
[http://dx.doi.org/10.1073/pnas.0511288103] [PMID:  16547133] 
[66] 
Jiang J, Maeda A, Ji J, et al. Are mitochondrial reactive oxygen species required for autophagy? Biochem Biophys Res Commun  2011; 412(1): 55-60.
[http://dx.doi.org/10.1016/j.bbrc.2011.07.036] [PMID:  21806968] 
[67] 
Chen YF, Wu ZM, Luo XJ, Bai S, Zhao LD. Effect of the conditional knockout of bone marrow specific RIPK3 gene on bone marrow hematopoiesis in mice. Int J Clin Exp Pathol  2018; 11: 568-76.
[68] 
Zhang J, Niu C, Ye L, et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature  2003; 425(6960): 836-41.
[http://dx.doi.org/10.1038/nature02041] [PMID:  14574412] 
[69] 
Jang YY, Sharkis SJ. A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche. Blood  2007; 110(8): 3056-63.
[http://dx.doi.org/10.1182/blood-2007-05-087759] [PMID:  17595331] 
[70] 
Ludin A, Gur-Cohen S, Golan K, et al. Reactive oxygen species regulate hematopoietic stem cell self-renewal, migration and development, as well as their bone marrow microenvironment. Antioxid Redox Signal  2014; 21(11): 1605-19.
[http://dx.doi.org/10.1089/ars.2014.5941] [PMID:  24762207] 
[71] 
Ito K, Hirao A, Arai F, et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature  2004; 431(7011): 997-1002.
[http://dx.doi.org/10.1038/nature02989] [PMID:  15496926] 
[72] 
Zhang X, Rielland M, Yalcin S, Ghaffari S. Regulation and function of FoxO transcription factors in normal and cancer stem cells: what have we learned? Curr Drug Targets  2011; 12(9): 1267-83.
[http://dx.doi.org/10.2174/138945011796150325] [PMID:  21443463] 
[73] 
Tothova Z, Kollipara R, Huntly BJ, et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell  2007; 128(2): 325-39.
[http://dx.doi.org/10.1016/j.cell.2007.01.003] [PMID:  17254970] 
[74] 
Chen C, Liu Y, Liu R, et al. TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species. J Exp Med  2008; 205(10): 2397-408.
[http://dx.doi.org/10.1084/jem.20081297] [PMID:  18809716] 
[75] 
Juntilla MM, Patil VD, Calamito M, Joshi RP, Birnbaum MJ, Koretzky GA. AKT1 and AKT2 maintain hematopoietic stem cell function by regulating reactive oxygen species. Blood  2010; 115(20): 4030-8.
[http://dx.doi.org/10.1182/blood-2009-09-241000] [PMID:  20354168] 
[76] 
Liu J, Cao L, Chen J, et al. Bmi1 regulates mitochondrial function and the DNA damage response pathway. Nature  2009; 459(7245): 387-92.
[http://dx.doi.org/10.1038/nature08040] [PMID:  19404261] 
[77] 
Schuringa JJ, Vellenga E. Role of the polycomb group gene BMI1 in normal and leukemic hematopoietic stem and progenitor cells. Curr Opin Hematol  2010; 17(4): 294-9.
[http://dx.doi.org/10.1097/MOH.0b013e328338c439] [PMID:  20308890] 
[78] 
Abbas HA, Maccio DR, Coskun S, et al. Mdm2 is required for survival of hematopoietic stem cells/progenitors via dampening of ROS-induced p53 activity. Cell Stem Cell  2010; 7(5): 606-17.
[http://dx.doi.org/10.1016/j.stem.2010.09.013] [PMID:  21040902] 
[79] 
Taniguchi IE, Gonzalez-Nieto D, Ghiaur G, et al. Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells. Proc Natl Acad Sci USA  2012; 109(23): 9071-6.
[http://dx.doi.org/10.1073/pnas.1120358109] [PMID:  22611193] 
[80] 
Hu M, Zeng H, Chen S, et al. SRC-3 is involved in maintaining hematopoietic stem cell quiescence by regulation of mitochondrial metabolism in mice. Blood  2018; 132(9): 911-23.
[http://dx.doi.org/10.1182/blood-2018-02-831669] [PMID:  29959189] 
[81] 
Kim TG, Kim S, Jung S, et al. CCCTC-binding factor is essential to the maintenance and quiescence of hematopoietic stem cells in mice. Exp Mol Med  2017; 49(8)e371
[http://dx.doi.org/10.1038/emm.2017.124] [PMID:  28857086] 
[82] 
Zhang Y, Dépond M, He L, et al. CXCR4/CXCL12 axis counteracts hematopoietic stem cell exhaustion through selective protection against oxidative stress. Sci Rep  2016; 6: 37827.
[http://dx.doi.org/10.1038/srep37827] [PMID:  27886253] 
[83] 
Fan C, Zheng W, Fu X, Li X, Wong YS, Chen T. Strategy to enhance the therapeutic effect of doxorubicin in human hepatocellular carcinoma by selenocystine, a synergistic agent that regulates the ROS-mediated signaling. Oncotarget  2014; 5(9): 2853-63.
[http://dx.doi.org/10.18632/oncotarget.1854] [PMID:  24797310] 
[84] 
Kim EH, Jang H, Roh JL. A novel polyphenol conjugate sensitizes cisplatin-resistant head and neck cancer cells to cisplatin via nrf2 inhibition. Mol Cancer Ther  2016; 15(11): 2620-9.
[http://dx.doi.org/10.1158/1535-7163.MCT-16-0332] [PMID:  27550943] 
[85] 
Martin-Cordero C, Leon-Gonzalez AJ, Calderon-Montano JM, Burgos-Moron E, Lopez-Lazaro M. Pro-oxidant natural products as anticancer agents. Curr Drug Targets  2012; 13(8): 1006-28.
[http://dx.doi.org/10.2174/138945012802009044] [PMID:  22594470] 
[86] 
El-Sayed el-SM, Abdel-Aziz AA, Helal GK, Saleh S, and Saad AS. Protective effect of N-acetylcysteine against carmustine-induced myelotoxicity in rats. Food Chem Toxicol  2010; 48: 1576-80.
[http://dx.doi.org/10.1016/j.fct.2010.03.027] 
[87] 
Numazawa S, Sugihara K, Miyake S, et al. Possible involvement of oxidative stress in 5-fluorouracil-mediated myelosuppression in mice. Basic Clin Pharmacol Toxicol  2011; 108(1): 40-5.
[http://dx.doi.org/10.1111/j.1742-7843.2010.00621.x] [PMID:  20722640] 
[88] 
Deng J, Zhong YF, Wu YP, et al. Carnosine attenuates cyclophosphamide-induced bone marrow suppression by reducing oxidative DNA damage. Redox Biol  2018; 14: 1-6.
[http://dx.doi.org/10.1016/j.redox.2017.08.003] [PMID:  28826042] 
[89] 
Diaz-Montero CM, Wang Y, Shao L, et al. The glutathione disulfide mimetic NOV-002 inhibits cyclophosphamide-induced hematopoietic and immune suppression by reducing oxidative stress. Free Radic Biol Med  2012; 52(9): 1560-8.
[http://dx.doi.org/10.1016/j.freeradbiomed.2012.02.007] [PMID:  22343421] 
[90] 
Itoh T, Terazawa R, Kojima K, et al. Cisplatin induces production of reactive oxygen species via NADPH oxidase activation in human prostate cancer cells. Free Radic Res  2011; 45(9): 1033-9.
[http://dx.doi.org/10.3109/10715762.2011.591391] [PMID:  21682664] 
[91] 
Naka K, Muraguchi T, Hoshii T, Hirao A. Regulation of reactive oxygen species and genomic stability in hematopoietic stem cells. Antioxid Redox Signal  2008; 10(11): 1883-94.
[http://dx.doi.org/10.1089/ars.2008.2114] [PMID:  18627347] 
[92] 
Richardson C, Yan S, Vestal CG. Oxidative stress, bone marrow failure, and genome instability in hematopoietic stem cells. Int J Mol Sci  2015; 16(2): 2366-85.
[http://dx.doi.org/10.3390/ijms16022366] [PMID:  25622253] 
[93] 
Newman NB, Sidhu MK, Baby R, et al. Long-term bone marrow suppression during postoperative chemotherapy in rectal cancer patients after preoperative chemoradiation therapy. Int J Radiat Oncol Biol Phys  2016; 94(5): 1052-60.
[http://dx.doi.org/10.1016/j.ijrobp.2015.12.374] [PMID:  27026312] 
[94] 
Boohaker RJ, Xu B. The versatile functions of ATM kinase. Biomed J  2014; 37(1): 3-9.
[http://dx.doi.org/10.4103/2319-4170.125655] [PMID:  24667671] 
[95] 
Ruzankina Y, Pinzon-Guzman C, Asare A, et al. Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss. Cell Stem Cell  2007; 1(1): 113-26.
[http://dx.doi.org/10.1016/j.stem.2007.03.002] [PMID:  18371340] 
[96] 
Wang M, Guo L, Wu Q, et al. ATR/Chk1/Smurf1 pathway determines cell fate after DNA damage by controlling RhoB abundance. Nat Commun  2014; 5: 4901.
[http://dx.doi.org/10.1038/ncomms5901] [PMID:  25249323] 
[97] 
Sancar A, Lindsey-Boltz LA, Unsal-Kaçmaz K, Linn S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem  2004; 73: 39-85.
[http://dx.doi.org/10.1146/annurev.biochem.73.011303.073723] [PMID:  15189136] 
[98] 
Shao L, Li H, Pazhanisamy SK, Meng A, Wang Y, Zhou D. Reactive oxygen species and hematopoietic stem cell senescence. Int J Hematol  2011; 94(1): 24-32.
[http://dx.doi.org/10.1007/s12185-011-0872-1] [PMID:  21567162] 
[99] 
von Zglinicki T, Saretzki G, Ladhoff J, d’Adda di Fagagna F, Jackson SP. Human cell senescence as a DNA damage response. Mech Ageing Dev  2005; 126(1): 111-7.
[http://dx.doi.org/10.1016/j.mad.2004.09.034] [PMID:  15610769] 
[100] 
Ito K, Hirao A, Arai F, et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med  2006; 12(4): 446-51.
[http://dx.doi.org/10.1038/nm1388] [PMID:  16565722] 
[101] 
Bartkova J, Lukas J, Guldberg P, et al. The p16-cyclin D/Cdk4-pRb pathway as a functional unit frequently altered in melanoma pathogenesis. Cancer Res  1996; 56(23): 5475-83.
[PMID:  8968104] 
[102] 
Semczuk A, Jakowicki JA. Alterations of pRb1-cyclin D1-cdk4/6-p16(INK4A) pathway in endometrial carcinogenesis. Cancer Lett  2004; 203(1): 1-12.
[http://dx.doi.org/10.1016/j.canlet.2003.09.012] [PMID:  14670612] 
[103] 
Ingold KU, Pratt DA. Advances in radical-trapping antioxidant chemistry in the 21st century: a kinetics and mechanisms perspective. Chem Rev  2014; 114(18): 9022-46.
[http://dx.doi.org/10.1021/cr500226n] [PMID:  25180889] 
[104] 
Saso L, Firuzi O. Pharmacological applications of antioxidants: lights and shadows. Curr Drug Targets  2014; 15(13): 1177-99.
[http://dx.doi.org/10.2174/1389450115666141024113925] [PMID:  25341421] 
[105] 
Li H, Wang Y, Pazhanisamy SK, et al. Mn(III) meso-tetrakis-(N-ethylpyridinium-2-yl) porphyrin mitigates total body irradiation-induced long-term bone marrow suppression. Free Radic Biol Med  2011; 51(1): 30-7.
[http://dx.doi.org/10.1016/j.freeradbiomed.2011.04.016] [PMID:  21565268] 
[106] 
Mehrotra S, Pecaut MJ, Freeman TL, et al. Analysis of a metalloporphyrin antioxidant mimetic (MnTE-2-PyP) as a radiomitigator: prostate tumor and immune status. Technol Cancer Res Treat  2012; 11(5): 447-57.
[http://dx.doi.org/10.7785/tcrt.2012.500260] [PMID:  22475066] 
[107] 
Gumireddy K, Li A, Cao L, et al. NOV-002, A Glutathione Disulfide Mimetic, Suppresses Tumor Cell Invasion and Metastasis. J Carcinog Mutagen  2013; S7-S002.
[108] 
Jenderny S, Lin H, Garrett T, Tew KD, Townsend DM. Protective effects of a glutathione disulfide mimetic (NOV-002) against cisplatin induced kidney toxicity. Biomed Pharmacother  2010; 64(1): 73-6.
[http://dx.doi.org/10.1016/j.biopha.2009.09.009] [PMID:  19896793] 
[109] 
Basu A, Bhattacharjee A, Baral R, Biswas J, Samanta A, Bhattacharya S. Vanadium(III)-l-cysteine enhances the sensitivity of murine breast adenocarcinoma cells to cyclophosphamide by promoting apoptosis and blocking angiogenesis. Tumour Biol  2017; 39(5)1010428317705759
[http://dx.doi.org/10.1177/1010428317705759] [PMID:  28466788] 
[110] 
Basu A, Ghosh P, Bhattacharjee A, Patra AR, Bhattacharya S. Prevention of myelosuppression and genotoxicity induced by cisplatin in murine bone marrow cells: effect of an organovanadium compound vanadium(III)-l-cysteine. Mutagenesis  2015; 30(4): 509-17.
[http://dx.doi.org/10.1093/mutage/gev011] [PMID:  25778689] 
[111] 
Capizzi RL. Amifostine reduces the incidence of cumulative nephrotoxicity from cisplatin: laboratory and clinical aspects. Semin Oncol  1999; 26(2)(Suppl. 7): 72-81.
[PMID:  10348264] 
[112] 
Sinha S, Jothiramajayam M, Ghosh M, Jana A, Chatterji U, Mukherjee A. Vetiver oil (Java) attenuates cisplatin-induced oxidative stress, nephrotoxicity and myelosuppression in Swiss albino mice. Food Chem Toxicol  2015; 81: 120-8.
[http://dx.doi.org/10.1016/j.fct.2015.04.018] [PMID:  25910835] 
[113] 
Alberts DS. Protection by amifostine of cyclophosphamide-induced myelosuppression. Semin Oncol  1999; 26(2)(Suppl. 7): 37-40.
[PMID:  10348259] 
[114] 
Chen T, Shen HM, Deng ZY, et al. A herbal formula, SYKT, reverses doxorubicin-induced myelosuppression and cardiotoxicity by inhibiting ROS-mediated apoptosis. Mol Med Rep  2017; 15(4): 2057-66.
[http://dx.doi.org/10.3892/mmr.2017.6272] [PMID:  28260045] 
[115] 
Guimarães R, Barreira JC, Barros L, Carvalho AM, Ferreira IC. Effects of oral dosage form and storage period on the antioxidant properties of four species used in traditional herbal medicine. Phytother Res  2011; 25(4): 484-92.
[http://dx.doi.org/10.1002/ptr.3284] [PMID:  20740475] 
[116] 
Khan HY, Zubair H, Ullah MF, Ahmad A, Hadi SM. A prooxidant mechanism for the anticancer and chemopreventive properties of plant polyphenols. Curr Drug Targets  2012; 13(14): 1738-49.
[http://dx.doi.org/10.2174/138945012804545560] [PMID:  23140285] 
[117] 
Rezk YA, Balulad SS, Keller RS, Bennett JA. Use of resveratrol to improve the effectiveness of cisplatin and doxorubicin: study in human gynecologic cancer cell lines and in rodent heart. Am J Obstet Gynecol  2006; 194(5): e23-6.
[http://dx.doi.org/10.1016/j.ajog.2005.11.030] [PMID:  16647892] 
[118] 
Zhou QM, Zhang H, Lu YY, Wang XF, Su SB. Curcumin reduced the side effects of mitomycin C by inhibiting GRP58-mediated DNA cross-linking in MCF-7 breast cancer xenografts. Cancer Sci  2009; 100(11): 2040-5.
[http://dx.doi.org/10.1111/j.1349-7006.2009.01297.x] [PMID:  19703194] 
[119] 
Alaikov T, Konstantinov SM, Tzanova T, Dinev K, Topashka-Ancheva M, Berger MR. Antineoplastic and anticlastogenic properties of curcumin. Ann N Y Acad Sci  2007; 1095: 355-70.
[http://dx.doi.org/10.1196/annals.1397.039] [PMID:  17404048] 
[120] 
Chen J, Wanming D, Zhang D, Liu Q, Kang J. Water-soluble antioxidants improve the antioxidant and anticancer activity of low concentrations of curcumin in human leukemia cells. Pharmazie  2005; 60(1): 57-61.
[PMID:  15700780] 
[121] 
Yamamoto T, Hsu S, Lewis J, et al. Green tea polyphenol causes differential oxidative environments in tumor versus normal epithelial cells. J Pharmacol Exp Ther  2003; 307(1): 230-6.
[http://dx.doi.org/10.1124/jpet.103.054676] [PMID:  12954803] 
[122] 
Jain P, Kumar N, Josyula VR, et al. A study on the role of (+)-catechin in suppression of HepG2 proliferation via caspase dependent pathway and enhancement of its in vitro and in vivo cytotoxic potential through liposomal formulation. Eur J Pharm Sci  2013; 50(3-4): 353-65.
[http://dx.doi.org/10.1016/j.ejps.2013.08.005] [PMID:  23954456] 
[123] 
Papiez MA, Baran J, Bukowska-Straková K, Wiczkowski W. Antileukemic action of (-)-epicatechin in the spleen of rats with acute myeloid leukemia. Food Chem Toxicol  2010; 48(12): 3391-7.
[http://dx.doi.org/10.1016/j.fct.2010.09.010] [PMID:  20837083] 
[124] 
Feng R, Ni HM, Wang SY, et al. Cyanidin-3-rutinoside, a natural polyphenol antioxidant, selectively kills leukemic cells by induction of oxidative stress. J Biol Chem  2007; 282(18): 13468-76.
[http://dx.doi.org/10.1074/jbc.M610616200] [PMID:  17360708] 
[125] 
Chen F, Li D, Shen H, et al. Polysaccharides from Trichosanthes Fructus via Ultrasound-Assisted Enzymatic Extraction Using Response Surface Methodology. BioMed Res Int 2017.20176160785
[http://dx.doi.org/10.1155/2017/6160785] [PMID:  29147656] 
[126] 
Hu J, Jia X, Fang X, Li P, He C, Chen M. Ultrasonic extraction, antioxidant and anticancer activities of novel polysaccharides from Chuanxiong rhizome. Int J Biol Macromol  2016; 85: 277-84.
[http://dx.doi.org/10.1016/j.ijbiomac.2015.12.046] [PMID:  26712703] 
[127] 
Jiang YY, Wang L, Zhang L, et al. Characterization, antioxidant and antitumor activities of polysaccharides from Salvia miltiorrhiza Bunge. Int J Biol Macromol  2014; 70: 92-9.
[http://dx.doi.org/10.1016/j.ijbiomac.2014.06.036] [PMID:  24984021] 
[128] 
Liu LQ, Li HS, Nie SP, Shen MY, Hu JL, Xie MY. tea polysaccharide prevents colitis-associated carcinogenesis in mice by inhibiting the proliferation and invasion of tumor cells. Int J Mol Sci  2018; 19(2)E506
[http://dx.doi.org/10.3390/ijms19020506] [PMID:  29419740] 
[129] 
Wei C, He P, He L, et al. Structure characterization and biological activities of a pectic polysaccharide from cupule of Castanea henryi. Int J Biol Macromol  2018; 109: 65-75.
[http://dx.doi.org/10.1016/j.ijbiomac.2017.12.081] [PMID:  29248551] 
[130] 
Xin YF, Wan LL, Peng JL, Guo C. Alleviation of the acute doxorubicin-induced cardiotoxicity by Lycium barbarum polysaccharides through the suppression of oxidative stress. Food Chem Toxicol  2011; 49(1): 259-64.
[http://dx.doi.org/10.1016/j.fct.2010.10.028] [PMID:  21056614] 
[131] 
Zhao QS, Xie BX, Yan J, et al. In vitro antioxidant and antitumor activities of polysaccharides extracted from Asparagus officinalis. Carbohydr Polym  2012; 87: 392-6.
[http://dx.doi.org/10.1016/j.carbpol.2011.07.068] 
[132] 
Cai Z, Li W, Wang H, et al. Antitumor effects of a purified polysaccharide from Rhodiola rosea and its action mechanism. Carbohydr Polym  2012; 90(1): 296-300.
[http://dx.doi.org/10.1016/j.carbpol.2012.05.039] [PMID:  24751044] 
[133] 
Wang H, Yu P, Gou H, et al. Cardioprotective effects of 20(s)-ginsenoside rh2 against doxorubicin-induced cardiotoxicity in vitro and in vivo. Evid Based Complement Alternat Med 2012.2012506214
[http://dx.doi.org/10.1155/2012/506214] [PMID:  23125868] 
[134] 
Zhao J, Xu F, Huang H, et al. Evaluation on Anti-Inflammatory, Analgesic, Antitumor, and Antioxidant Potential of Total Saponins from Nigella glandulifera Seeds. Evid Based Complement Alternat Med 2013.2013827230
[http://dx.doi.org/10.1155/2013/827230] [PMID:  23533525] 
[135] 
Iman V, Mohan S, Abdelwahab SI, et al. Anticancer and anti-inflammatory activities of girinimbine isolated from Murraya koenigii. Drug Des Devel Ther  2016; 11: 103-21.
[http://dx.doi.org/10.2147/DDDT.S115135] [PMID:  28096658] 
[136] 
Sanchez-Gonzalez PD, Lopez-Hernandez FJ, Perez-Barriocanal F, Morales AI, Lopez-Novoa JM. Quercetin reduces cisplatin nephrotoxicity in rats without compromising its anti-tumour activity. Nephrol Dial Transplant  2011; 26(11): 3484-95.
[http://dx.doi.org/10.1093/ndt/gfr195] [PMID:  21602180] 
[137] 
Attia SM, Ahmad SF, Harisa GI, Mansour AM, El Sayed SM, Bakheet SA. Wogonin attenuates etoposide-induced oxidative DNA damage and apoptosis via suppression of oxidative DNA stress and modulation of OGG1 expression. Food Chem Toxicol  2013; 59: 724-30.
[http://dx.doi.org/10.1016/j.fct.2013.07.022] [PMID:  23872129] 
[138] 
Bokemeyer C, Fels LM, Dunn T, et al. Silibinin protects against cisplatin-induced nephrotoxicity without compromising cisplatin or ifosfamide anti-tumour activity. Br J Cancer  1996; 74(12): 2036-41.
[http://dx.doi.org/10.1038/bjc.1996.673] [PMID:  8980410] 
[139] 
Juan ME, Wenzel U, Daniel H, Planas JM. Resveratrol induces apoptosis through ROS-dependent mitochondria pathway in HT-29 human colorectal carcinoma cells. J Agric Food Chem  2008; 56(12): 4813-8.
[http://dx.doi.org/10.1021/jf800175a] [PMID:  18522405] 
[140] 
Bianchi G, Ravera S, Traverso C, et al. Curcumin induces a fatal energetic impairment in tumor cells in vitro and in vivo by inhibiting ATP-synthase activity. Carcinogenesis  2018; 39(9): 1141-50.
[http://dx.doi.org/10.1093/carcin/bgy076] [PMID:  29860383] 
[141] 
Liu SM, Ou SY, Huang HH. Green tea polyphenols induce cell death in breast cancer MCF-7 cells through induction of cell cycle arrest and mitochondrial-mediated apoptosis. J Zhejiang Univ Sci B  2017; 18(2): 89-98.
[http://dx.doi.org/10.1631/jzus.B1600022] [PMID:  28124838] 
[142] 
Yan CM, Chai EQ, Cai HY, Miao GY, Ma W. Oleuropein induces apoptosis via activation of caspases and suppression of phosphatidylinositol 3-kinase/protein kinase B pathway in HepG2 human hepatoma cell line. Mol Med Rep  2015; 11(6): 4617-24.
[http://dx.doi.org/10.3892/mmr.2015.3266] [PMID:  25634350] 
[143] 
Attoub S, Ramadan G, Arafat K, Bajbouj K, Karuvantevida N,
AbuQamar S, Eid A, and Iratni R. Carnosol induces ROS-mediated
beclin1-independent autophagy and apoptosis in triple negative
breast cancer. PLoS One 2014; 9e109630 
[http://dx.doi.org/10.1371/journal.pone.0109630] 
[144] 
Zhang L, Chen QS, Xu PP, et al. Catechins induced acute promyelocytic leukemia cell apoptosis and triggered PML-RARα oncoprotein degradation. J Hematol Oncol  2014; 7: 75.
[http://dx.doi.org/10.1186/s13045-014-0075-3] [PMID:  25270015] 
[145] 
Yang LH, Ho YJ, Lin JF, Yeh CW, Kao SH, Hsu LS. Butein inhibits the proliferation of breast cancer cells through generation of reactive oxygen species and modulation of ERK and p38 activities. Mol Med Rep  2012; 6(5): 1126-32.
[http://dx.doi.org/10.3892/mmr.2012.1023] [PMID:  22895548] 
[146] 
Zhen D, Su L, Miao Y, et al. Purification, partial characterization and inducing tumor cell apoptosis activity of a polysaccharide from Ganoderma applanatum. Int J Biol Macromol  2018; 115: 10-7.
[http://dx.doi.org/10.1016/j.ijbiomac.2018.03.062] [PMID:  29653168] 
[147] 
Zhang S, Nie S, Huang D, Feng Y, Xie M. A novel polysaccharide from Ganoderma atrum exerts antitumor activity by activating mitochondria-mediated apoptotic pathway and boosting the immune system. J Agric Food Chem  2014; 62(7): 1581-9.
[http://dx.doi.org/10.1021/jf4053012] [PMID:  24506418] 
[148] 
Wang J, Li W, Huang X, et al. A polysaccharide from Lentinus edodes inhibits human colon cancer cell proliferation and suppresses tumor growth in athymic nude mice. Oncotarget  2017; 8(1): 610-23.
[http://dx.doi.org/10.18632/oncotarget.13481] [PMID:  27888812] 
[149] 
Liu WB, Xie F, Sun HQ, Meng M, Zhu ZY. Anti-tumor effect of polysaccharide from Hirsutella sinensis on human non-small cell lung cancer and nude mice through intrinsic mitochondrial pathway. Int J Biol Macromol  2017; 99: 258-64.
[http://dx.doi.org/10.1016/j.ijbiomac.2017.02.071] [PMID:  28235606] 
[150] 
Liu G, Kuang S, Wu S, Jin W, Sun C. A novel polysaccharide from Sargassum integerrimum induces apoptosis in A549 cells and prevents angiogensis in vitro and in vivo. Sci Rep  2016; 6: 26722.
[http://dx.doi.org/10.1038/srep26722] [PMID:  27216943] 
[151] 
Ren D, Wang N, Guo J, Yuan L, Yang X. Chemical characterization of Pleurotus eryngii polysaccharide and its tumor-inhibitory effects against human hepatoblastoma HepG-2 cells. Carbohydr Polym  2016; 138: 123-33.
[http://dx.doi.org/10.1016/j.carbpol.2015.11.051] [PMID:  26794745] 
[152] 
Chen J, Yao D, Yuan H, et al. Dipsacus asperoides polysaccharide induces apoptosis in osteosarcoma cells by modulating the PI3K/Akt pathway. Carbohydr Polym  2013; 95(2): 780-4.
[http://dx.doi.org/10.1016/j.carbpol.2013.03.009] [PMID:  23648042] 
[153] 
Ma B, Zhu J, Zhao A, et al. Raddeanin A, a natural triterpenoid saponin compound, exerts anticancer effect on human osteosarcoma via the ROS/JNK and NF-κB signal pathway. Toxicol Appl Pharmacol  2018; 353: 87-101.
[http://dx.doi.org/10.1016/j.taap.2018.05.025] [PMID:  29847772] 
[154] 
Mbaveng AT, Ndontsa BL, Kuete V, et al. A naturally occuring triterpene saponin ardisiacrispin B displayed cytotoxic effects in multi-factorial drug resistant cancer cells via ferroptotic and apoptotic cell death. Phytomedicine  2018; 43: 78-85.
[http://dx.doi.org/10.1016/j.phymed.2018.03.035] [PMID:  29747757] 
[155] 
Lin CL, Lee CH, Chen CM, et al. Protodioscin Induces Apoptosis Through ROS-Mediated Endoplasmic Reticulum Stress via the JNK/p38 Activation Pathways in Human Cervical Cancer Cells. Cell Physiol Biochem  2018; 46(1): 322-34.
[http://dx.doi.org/10.1159/000488433] [PMID:  29590661] 
[156] 
Li S, Cheng B, Hou L, et al. Dioscin inhibits colon cancer cells’ growth by reactive oxygen species-mediated mitochondrial dysfunction and p38 and JNK pathways. Anticancer Drugs  2018; 29(3): 234-42.
[PMID:  29389802] 
[157] 
Zhang S, He Y, Tong Q, Chen Q, Wu X, Huang W. Deltonin induces apoptosis in MDA-MB-231 human breast cancer cells via reactive oxygen species-mediated mitochondrial dysfunction and ERK/AKT signaling pathways. Mol Med Rep  2013; 7(3): 1038-44.
[http://dx.doi.org/10.3892/mmr.2013.1273] [PMID:  23314115] 
[158] 
Kim DS, Jeon BK, Lee YE, Woo WH, Mun YJ. Diosgenin induces apoptosis in hepg2 cells through generation of reactive oxygen species and mitochondrial pathway. Evid Based Complement Alternat Med 2012.2012981675
[http://dx.doi.org/10.1155/2012/981675] [PMID:  22719792] 
[159] 
Wu Q, Deng J, Fan D, et al. Ginsenoside Rh4 induces apoptosis and autophagic cell death through activation of the ROS/JNK/p53 pathway in colorectal cancer cells. Biochem Pharmacol  2018; 148: 64-74.
[http://dx.doi.org/10.1016/j.bcp.2017.12.004] [PMID:  29225132] 
[160] 
Farooqui A, Khan F, Khan I, Ansari IA. Glycyrrhizin induces reactive oxygen species-dependent apoptosis and cell cycle arrest at G0/G1 in HPV18+ human cervical cancer HeLa cell line. Biomed Pharmacother  2018; 97: 752-64.
[http://dx.doi.org/10.1016/j.biopha.2017.10.147] [PMID:  29107932] 
[161] 
Wu JP, Kang NX, Zhang MY, et al. Oleiferoside W from the roots of Camellia oleifera C. Abel, inducing cell cycle arrest and apoptosis in A549 cells. J Asian Nat Prod Res  2017; 6: 1-14.
[PMID:  28679317] 
[162] 
Zhu WB, Tian FJ, Liu LQ. Chikusetsu (CHI) triggers mitochondria-regulated apoptosis in human prostate cancer via reactive oxygen species (ROS) production. Biomed Pharmacother  2017; 90: 446-54.
[http://dx.doi.org/10.1016/j.biopha.2017.03.050] [PMID:  28391166] 
[163] 
Yang JB, Khan M, He YY, et al. Tubeimoside-1 induces oxidative stress-mediated apoptosis and G0/G1 phase arrest in human prostate carcinoma cells in vitro. Acta Pharmacol Sin  2016; 37(7): 950-62.
[http://dx.doi.org/10.1038/aps.2016.34] [PMID:  27292614] 
[164] 
Liu J, Wei X, Wu Y, et al. Giganteaside D induces ROS-mediated apoptosis in human hepatocellular carcinoma cells through the MAPK pathway. Cell Oncol (Dordr)  2016; 39(4): 333-42.
[http://dx.doi.org/10.1007/s13402-016-0273-9] [PMID:  27016209] 
[165] 
Li J, Wu DD, Zhang JX, et al. Mitochondrial pathway mediated by reactive oxygen species involvement in α-hederin-induced apoptosis in hepatocellular carcinoma cells. World J Gastroenterol  2018; 24(17): 1901-10.
[http://dx.doi.org/10.3748/wjg.v24.i17.1901] [PMID:  29740205] 
[166] 
Shan Y, Guan F, Zhao X, et al. Macranthoside B induces apoptosis and autophagy via reactive oxygen species accumulation in human ovarian cancer A2780 cells. Nutr Cancer  2016; 68(2): 280-9.
[http://dx.doi.org/10.1080/01635581.2016.1142587] [PMID:  26943028] 
[167] 
Wang J, Yuan L, Xiao H, Xiao C, Wang Y, Liu X. Momordin Ic induces HepG2 cell apoptosis through MAPK and PI3K/Akt-mediated mitochondrial pathways. Apoptosis  2013; 18(6): 751-65.
[http://dx.doi.org/10.1007/s10495-013-0820-z] [PMID:  23417763] 
[168] 
Ji Y, Ji C, Yue L, Xu H. Saponins isolated from Asparagus induce apoptosis in human hepatoma cell line HepG2 through a mitochondrial-mediated pathway. Curr Oncol  2012; 19(Suppl. 2): eS1-9.
[http://dx.doi.org/10.3747/co.19.1139] [PMID:  22876162] 
[169] 
Mo S, Xiong H, Shu G, et al. Phaseoloideside E, a novel natural triterpenoid saponin identified from Entada phaseoloides, induces apoptosis in Ec-109 esophageal cancer cells through reactive oxygen species generation. J Pharmacol Sci  2013; 122(3): 163-75.
[http://dx.doi.org/10.1254/jphs.12193FP] [PMID:  23782641] 
[170] 
Zhu X, Wang K, Zhang K, Zhu L, Zhou F. Ziyuglycoside II induces cell cycle arrest and apoptosis through activation of ROS/JNK pathway in human breast cancer cells. Toxicol Lett  2014; 227(1): 65-73.
[http://dx.doi.org/10.1016/j.toxlet.2014.03.015] [PMID:  24680927] 
[171] 
Zhang C, Jia X, Bao J, et al. Polyphyllin VII induces apoptosis in HepG2 cells through ROS-mediated mitochondrial dysfunction and MAPK pathways. BMC Complement Altern Med  2016; 16: 58.
[http://dx.doi.org/10.1186/s12906-016-1036-x] [PMID:  26861252] 
[172] 
Wu S, Yang Y, Li F, et al. Chelerythrine induced cell death through ROS-dependent ER stress in human prostate cancer cells. OncoTargets Ther  2018; 11: 2593-601.
[http://dx.doi.org/10.2147/OTT.S157707] [PMID:  29780252] 
[173] 
Jiang JH, Pi J, Jin H, Yang F, Cai JY. Chinese herb medicine matrine induce apoptosis in human esophageal squamous cancer KYSE-150 cells through increasing reactive oxygen species and inhibiting mitochondrial function. Pathol Res Pract  2018; 214(5): 691-9.
[http://dx.doi.org/10.1016/j.prp.2018.03.015] [PMID:  29567333] 
[174] 
Santos LS, Silva VR, Menezes LRA, Soares MBP, Costa EV, Bezerra DP. Xylopine induces oxidative stress and causes g2/m phase arrest, triggering caspase-mediated apoptosis by p53-independent pathway in hct116 cells. Oxid Med Cell Longev 2017.20177126872
[http://dx.doi.org/10.1155/2017/7126872] [PMID:  29362667] 
[175] 
Rattanawong A, Payon V, Limpanasittikul W, Boonkrai C, Mutirangura A, Wonganan P. Cepharanthine exhibits a potent anticancer activity in p53-mutated colorectal cancer cells through upregulation of p21Waf1/Cip1. Oncol Rep  2018; 39(1): 227-38.
[PMID:  29138869] 
[176] 
Eid W, Abdel-Rehim W. Neferine enhances the antitumor effect of mitomycin-c in hela cells through the activation of p38-mapk pathway. J Cell Biochem  2017; 118(10): 3472-9.
[http://dx.doi.org/10.1002/jcb.26006] [PMID:  28328092] 
[177] 
Stefanowicz-Hajduk J, Sparzak-Stefanowska B, Krauze-Baranowska M, Ochocka JR. Securinine from Phyllanthus glaucus Induces Cell Cycle Arrest and Apoptosis in Human Cervical Cancer HeLa Cells. PLoS One  2016; 11(10)e0165372
[http://dx.doi.org/10.1371/journal.pone.0165372] [PMID:  27792748] 
[178] 
Lin YJ, Peng SF, Lin ML, et al. Tetrandrine induces apoptosis of human nasopharyngeal carcinoma npc-tw 076 cells through reactive oxygen species accompanied by an endoplasmic reticulum stress signaling pathway. Molecules  2016; 21(10)E1353
[http://dx.doi.org/10.3390/molecules21101353] [PMID:  27754332] 
[179] 
Wang XD, Li CY, Jiang MM, et al. Induction of apoptosis in human leukemia cells through an intrinsic pathway by cathachunine, a unique alkaloid isolated from Catharanthus roseus. Phytomedicine  2016; 23(6): 641-53.
[http://dx.doi.org/10.1016/j.phymed.2016.03.003] [PMID:  27161405] 
[180] 
Gu S, Yang XC, Xiang XY, et al. Sanguinarine-induced apoptosis in lung adenocarcinoma cells is dependent on reactive oxygen species production and endoplasmic reticulum stress. Oncol Rep  2015; 34(2): 913-9.
[http://dx.doi.org/10.3892/or.2015.4054] [PMID:  26081590] 
[181] 
Li J, Sharkey CC, King MR. Piperlongumine and immune cytokine TRAIL synergize to promote tumor death. Sci Rep  2015; 5: 9987.
[http://dx.doi.org/10.1038/srep09987] [PMID:  25984950] 
[182] 
Park SH, Sung JH, Kim EJ, Chung N. Berberine induces apoptosis via ROS generation in PANC-1 and MIA-PaCa2 pancreatic cell lines. Braz J Med Biol Res  2015; 48(2): 111-9.
[http://dx.doi.org/10.1590/1414-431x20144293] [PMID:  25517919] 
[183] 
Jayasooriya RG, Choi YH, Hyun JW, Kim GY. Camptothecin sensitizes human hepatoma Hep3B cells to TRAIL-mediated apoptosis via ROS-dependent death receptor 5 upregulation with the involvement of MAPKs. Environ Toxicol Pharmacol  2014; 38(3): 959-67.
[http://dx.doi.org/10.1016/j.etap.2014.10.012] [PMID:  25461556] 
[184] 
Das R, Bhattacharya K, Sarkar S, Samanta SK, Pal BC, Mandal C. Mahanine synergistically enhances cytotoxicity of 5-fluorouracil through ROS-mediated activation of PTEN and p53/p73 in colon carcinoma. Apoptosis  2014; 19(1): 149-64.
[http://dx.doi.org/10.1007/s10495-013-0907-6] [PMID:  24052409] 
[185] 
Bi YL, Min M, Shen W, Liu Y. Genistein induced anticancer effects on pancreatic cancer cell lines involves mitochondrial apoptosis, G0/G1cell cycle arrest and regulation of STAT3 signalling pathway. Phytomedicine  2018; 39: 10-6.
[http://dx.doi.org/10.1016/j.phymed.2017.12.001] [PMID:  29433670] 
[186] 
Zhang J, Song J, Wu D, Wang J, Dong W. Hesperetin induces the apoptosis of hepatocellular carcinoma cells via mitochondrial pathway mediated by the increased intracellular reactive oxygen species, ATP and calcium. Med Oncol  2015; 32(4): 101.
[http://dx.doi.org/10.1007/s12032-015-0516-z] [PMID:  25737432] 
[187] 
Sun Q, Lu NN, Feng L. Apigetrin inhibits gastric cancer progression through inducing apoptosis and regulating ROS-modulated STAT3/JAK2 pathway. Biochem Biophys Res Commun  2018; 498(1): 164-70.
[http://dx.doi.org/10.1016/j.bbrc.2018.02.009] [PMID:  29408335] 
[188] 
Zhou M, Shen S, Zhao X, Gong X. Luteoloside induces G0/G1 arrest and pro-death autophagy through the ROS-mediated AKT/mTOR/p70S6K signalling pathway in human non-small cell lung cancer cell lines. Biochem Biophys Res Commun  2017; 494(1-2): 263-9.
[http://dx.doi.org/10.1016/j.bbrc.2017.10.042] [PMID:  29024631] 
[189] 
Zhang L, Wang X, Wang R, et al. Baicalin potentiates TRAIL-induced apoptosis through p38 MAPK activation and intracellular reactive oxygen species production. Mol Med Rep  2017; 16(6): 8549-55.
[http://dx.doi.org/10.3892/mmr.2017.7633] [PMID:  28983599] 
[190] 
Wang Q, Wang H, Jia Y, Pan H, Ding H. Luteolin induces apoptosis by ROS/ER stress and mitochondrial dysfunction in gliomablastoma. Cancer Chemother Pharmacol  2017; 79(5): 1031-41.
[http://dx.doi.org/10.1007/s00280-017-3299-4] [PMID:  28393257] 
[191] 
Hyun HB, Lee WS, Go SI, et al. The flavonoid morin from Moraceae induces apoptosis by modulation of Bcl-2 family members and Fas receptor in HCT 116 cells. Int J Oncol  2015; 46(6): 2670-8.
[http://dx.doi.org/10.3892/ijo.2015.2967] [PMID:  25892545] 
[192] 
Qian C, Wang Y, Zhong Y, et al. Wogonin-enhanced reactive oxygen species-induced apoptosis and potentiated cytotoxic effects of chemotherapeutic agents by suppression Nrf2-mediated signaling in HepG2 cells. Free Radic Res  2014; 48(5): 607-21.
[http://dx.doi.org/10.3109/10715762.2014.897342] [PMID:  24666416] 
[193] 
Yang X, Li X, An L, Bai B, Chen J. Silibinin induced the apoptosis of Hep-2 cells via oxidative stress and down-regulating survivin expression. Eur Arch Otorhinolaryngol  2013; 270(8): 2289-97.
[http://dx.doi.org/10.1007/s00405-013-2444-x] [PMID:  23580032] 
[194] 
Liang W, Cui J, Zhang K, et al. Shikonin induces ROS-based mitochondria-mediated apoptosis in colon cancer. Oncotarget  2017; 8(65): 109094-106.
[http://dx.doi.org/10.18632/oncotarget.22618] [PMID:  29312593] 
[195] 
Wang Y, Luo Q, He X, et al. Emodin induces apoptosis of colon cancer cells via induction of autophagy in a ros-dependent manner. Oncol Res  2018; 26(6): 889-99.
[http://dx.doi.org/10.3727/096504017X15009419625178] [PMID:  28762328] 
Cite As
Current Drug Targets

The Role of Reactive Oxygen Species in Tumor Treatment and its Impact on Bone Marrow Hematopoiesis

Abstract

Graphical Abstract
