Skip to main content

Advertisement

SpringerLink
Log in

Chemotherapy: a double-edged sword in cancer treatment

  • Review
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

A Correction to this article was published on 28 August 2021

This article has been updated

Abstract

Chemotherapy is a well-known and effective treatment for different cancers; unfortunately, it has not been as efficient in the eradication of all cancer cells as been expected. The mechanism of this failure was not fully clarified, yet. Meanwhile, alterations in the physiologic conditions of the tumor microenvironment (TME) were suggested as one of the underlying possibilities. Chemotherapy drugs can activate multiple signaling pathways and augment the secretion of inflammatory mediators. Inflammation may show two opposite roles in the TME. On the one hand, inflammation, as an innate immune response, tries to suppress tumor growth but on the other hand, it might be not powerful enough to eradicate the cancer cells and even it can provide appropriate conditions for cancer promotion and relapse as well. Therefore, the administration of mild anti-inflammatory drugs during chemotherapy might result in more successful clinical results. Here, we will review and discuss this hypothesis.

Graphic abstract

Most chemotherapy agents are triggers of inflammation in the tumor microenvironment through inducing the production of senescence-associated secretory phenotype (SASP) molecules. Some chemotherapy agents can induce systematic inflammation by provoking TLR4 signaling or triggering IL-1B secretion through the inflammasome pathway. NF-kB and MAPK are key signaling pathways of inflammation and could be activated by several chemotherapy drugs. Furthermore, inflammation can play a key role in cancer development, metastasis and exacerbation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Availability of data and material

Not applicable.

Change history

References

  1. You W, Henneberg M (2018) Cancer incidence increasing globally: the role of relaxed natural selection. Evol Appl 11(2):140–152

    Article  PubMed  Google Scholar 

  2. Bray F, Ferlay J, Soerjomataram I (2018) Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 68(6):394–424

    Article  PubMed  Google Scholar 

  3. Maimela NR, Liu S, Zhang Y (2018) Fates of CD8+ T cells in Tumor Microenvironment. Comput Struct Biotechnol J 17:1–13

    PubMed  PubMed Central  Google Scholar 

  4. Hui L, Chen Y (2015) Tumor microenvironment: sanctuary of the devil. Cancer Lett 368(1):7–13

    Article  CAS  PubMed  Google Scholar 

  5. Wels J, Kaplan RN, Rafii S, Lyden D (2008) Migratory neighbors and distant invaders: tumor-associated niche cells. Genes Dev 22(5):559–574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Galdiero MR, Varricchi G, Loffredo S, Mantovani A, Marone G (2018) Roles of neutrophils in cancer growth and progression. J Leukoc Biol 103(3):457–464

    Article  CAS  PubMed  Google Scholar 

  7. Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140(6):883–899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Greten FR, Grivennikov SI (2019) Inflammation and cancer: triggers, mechanisms, and consequences. Immunity 51(1):27–41

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Baskar R, Lee KA, Yeo R, Yeoh K (2012) Cancer and radiation therapy: current advances and future directions. Int J Med Sci 9(3):193–199

    Article  Google Scholar 

  10. Chakraborty C, Sharma AR, Sharma G, Sarkar BK, Lee S-S (2018) The novel strategies for next-generation cancer treatment: miRNA combined with chemotherapeutic agents for the treatment of cancer. Oncotarget 9(11):10164–10174

    Article  PubMed  PubMed Central  Google Scholar 

  11. DeVita VT, Chu E (2008) A history of cancer chemotherapy. Cancer Res 68(21):8643–8653

    Article  CAS  PubMed  Google Scholar 

  12. Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M et al (2001) Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol 19(8):2282–2292

    Article  CAS  PubMed  Google Scholar 

  13. Danhier F, Feron O, Préat V (2010) To exploit the tumor microenvironment: passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. J Control Release 148(2):135–146

    Article  CAS  PubMed  Google Scholar 

  14. Pérez-Herrero E, Fernández-Medarde A (2015) Advanced targeted therapies in cancer: drug nanocarriers, the future of chemotherapy. Eur J Pharm Biopharm 93(March):52–79

    Article  PubMed  Google Scholar 

  15. Sbeity H and Younes R (2015) Review of optimization methods for cancer chemotherapy treatment planning. J Comput Sci Syst Biol 8(2):74–95

    Article  Google Scholar 

  16. Kaufmann SH, Earnshaw WC (2000) Induction of apoptosis by cancer chemotherapy. Exp Cell Res 256(1):42–49

    Article  CAS  PubMed  Google Scholar 

  17. Mesner PW, Budihardjo II, Kaufmann SH (1997) Chemotherapy-induced apoptosis. Adv Pharmacol 41:461–499

    Article  CAS  PubMed  Google Scholar 

  18. Feng Z (2010) p53 regulation of the IGF-1/AKT/mTOR pathways and the endosomal compartment. Cold Spring Harb Perspect Biol 2(2):a001057

    Article  PubMed  PubMed Central  Google Scholar 

  19. Sui X, Chen R, Wang Z, Huang Z, Kong N, Zhang M et al (2013) Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment. Cell Death Dis 4(10):e838–e838

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gewirtz DA, Holt SE, Elmore LW (2008) Accelerated senescence: an emerging role in tumor cell response to chemotherapy and radiation. Biochem Pharmacol 76(8):947–957

    Article  CAS  PubMed  Google Scholar 

  21. Woods D, Turchi JJ (2013) Chemotherapy induced DNA damage response. Cancer Biol Ther 14(5):379–389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bagnyukova T, Serebriiskii IG, Zhou Y, Hopper-Borge EA, Golemis EA, Astsaturov I (2010) Chemotherapy and signaling: how can targeted therapies supercharge cytotoxic agents? Cancer Biol Ther 10:839–853

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Malhotra V, Perry MC (2003) Classical chemotherapy: mechanisms, toxicities and the therapeutic window. Cancer Biol Ther 2(4 Suppl 1):4–6

    Google Scholar 

  24. Pang B, Qiao X, Janssen L, Velds A, Groothuis T, Kerkhoven R et al (2013) Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin. Nat Commun 4:1908

    Article  PubMed  Google Scholar 

  25. Xiao M, Cai J, Cai L, Jia J, Xie L, Zhu Y et al (2017) Let-7e sensitizes epithelial ovarian cancer to cisplatin through repressing DNA double strand break repair. J Ovarian Res 10(1):24

    Article  PubMed  PubMed Central  Google Scholar 

  26. Demaria M, O’Leary MN, Chang J, Shao L, Liu S, Alimirah F et al (2017) Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discov 7(2):165–176

    Article  CAS  PubMed  Google Scholar 

  27. Alexandre J, Hu Y, Lu W, Pelicano H, Huang P (2007) Novel action of paclitaxel against cancer cells: bystander effect mediated by reactive oxygen species. Cancer Res 67(8):3512–3517

    Article  CAS  PubMed  Google Scholar 

  28. Lasry A, Ben-Neriah Y (2015) Senescence-associated inflammatory responses: aging and cancer perspectives. Trends Immunol 36(4):217–228

    Article  CAS  PubMed  Google Scholar 

  29. Wunderlich R, Ruehle PF, Deloch L, Unger K, Hess J, Zitzelsberger H et al (2017) Interconnection between DNA damage, senescence, inflammation, and cancer. Front Biosci Landmark 22(2):348–369

    Article  CAS  Google Scholar 

  30. Muñoz-Espín D, Serrano M (2014) Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol 15(7):482–496

    Article  PubMed  Google Scholar 

  31. Sevko A, Sade-Feldman M, Kanterman J, Michels T, Falk CS, Umansky L et al (2013) Cyclophosphamide promotes chronic inflammation-dependent immunosuppression and prevents antitumor response in melanoma. J Invest Dermatol 133(6):1610–1619

    Article  CAS  PubMed  Google Scholar 

  32. Nafees S, Rashid S, Ali N, Hasan SK, Sultana S (2015) Rutin ameliorates cyclophosphamide induced oxidative stress and inflammation in Wistar rats: role of NFκB/MAPK pathway. Chem Biol Interact 231:98–107

    Article  CAS  PubMed  Google Scholar 

  33. Edwardson DW, Boudreau J, Mapletoft J, Lanner C, Kovala AT, Parissenti AM (2017) Inflammatory cytokine production in tumor cells upon chemotherapy drug exposure or upon selection for drug resistance. PLoS One 12(9):e0183662 1–32

    Article  Google Scholar 

  34. Volk-Draper L, Hall K, Griggs C, Rajput S, Kohio P, DeNardo D et al (2014) Paclitaxel therapy promotes breast cancer metastasis in a TLR4-dependent manner. Cancer Res 74(19):5421–5434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. dos Santos GI, Ladislau-Magescky T, Tessarollo NG, dos Santos DZ, Gimba ERP, Sternberg C et al (2018) Chemosensitizing effects of metformin on cisplatin- and paclitaxel-resistant ovarian cancer cell lines. Pharmacol Rep 70(3):409–417

    Article  PubMed  Google Scholar 

  36. Pusztai L, Mendoza TR, Reuben JM, Martinez MM, Willey JS, Lara J et al (2004) Changes in plasma levels of inflammatory cytokines in response to paclitaxel chemotherapy. Cytokine 25(3):94–102

    Article  CAS  PubMed  Google Scholar 

  37. Soheilifar MH, Taheri RA, Emameh RZ, Moshtaghian A, Kooshki H, Motie MR (2018) Molecular landscape in alveolar soft part sarcoma: implications for molecular targeted therapy. Biomed Pharmacother 103:889–896

    Article  CAS  PubMed  Google Scholar 

  38. Wang L, Chen Q, Qi H, Wang C, Wang C, Zhang J et al (2016) Doxorubicin-induced systemic Inflammation is driven by upregulation of Toll-like receptor TLR4 and endotoxin leakage. Cancer Res 76(22):6631–6642

    Article  CAS  PubMed  Google Scholar 

  39. Nasri F, Sadeghi F, Behranvand N, Samei A, Bolouri MR, Azari T et al (2020) Oridonin could inhibit inflammation and T-cell immunoglobulin and Mucin-3/Galectin-9 (TIM-3/Gal-9) autocrine loop in the acute myeloid leukemia cell line (U937) as compared to doxorubicin. Iran J Allergy, Asthma Immunol 19(6):602–611

    Google Scholar 

  40. Sauter KAD, Wood LJ, Wong J, Iordanov M, Magun BE (2011) Doxorubicin and daunorubicin induce processing and release of interleukin-1β through activation of the NLRP3 inflammasome. Cancer Biol Ther 11(12):1008–1016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wang S, Kotamraju S, Konorev E, Kalivendi S, Joseph J, Kalyanaraman B (2002) Activation of nuclear factor kappaB during doxorubicin-induced apoptosis in endothelial cells and myocytes is pro-apoptotic: the role of hydrogen peroxide. Biochem J 367(pt3):729–740

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Notarbartolo M, Poma P, Perri D, Dusonchet L, Cervello M, D’Alessandro N (2005) Antitumor effects of curcumin, alone or in combination with cisplatin or doxorubicin, on human hepatic cancer cells. Analysis of their possible relationship to changes in NF-kB activation levels and in IAP gene expression. Cancer Lett 224(1):53–65

    Article  CAS  PubMed  Google Scholar 

  43. Arjumand W, Seth A, Sultana S (2011) Rutin attenuates cisplatin induced renal inflammation and apoptosis by reducing NFκB, TNF-α and caspase-3 expression in wistar rats. Food Chem Toxicol 49(9):2013–2021

    Article  CAS  PubMed  Google Scholar 

  44. Elsea CR, Roberts DA, Druker BJ, Wood LJ (2008) Inhibition of p38 MAPK suppresses inflammatory cytokine induction by etoposide, 5-fluorouracil, and doxorubicin without affecting tumoricidal activity. PLoS One 3(6):e2355

    Article  PubMed  PubMed Central  Google Scholar 

  45. Kondylis V, Kumari S, Vlantis K, Pasparakis M (2017) The interplay of IKK, NF-κB and RIPK1 signaling in the regulation of cell death, tissue homeostasis and inflammation. Immunol Rev 277(1):113–127

    Article  CAS  PubMed  Google Scholar 

  46. Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB (2010) Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med 49(11):1603–1616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Medzhitov R (2008) Origin and physiological roles of inflammation. Nature 454(7203):428–435

    Article  CAS  PubMed  Google Scholar 

  48. Medzhitov R (2010) Inflammation 2010: new adventures of an old flame. Cell 140(6):771–776

    Article  CAS  PubMed  Google Scholar 

  49. Crusz SM, Balkwill FR (2015) Inflammation and cancer: advances and new agents. Nat Rev Clin Oncol 12(10):584–596

    Article  CAS  PubMed  Google Scholar 

  50. Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357(9255):539–545

    Article  CAS  PubMed  Google Scholar 

  51. Jahangiri A, Dadmanesh M, Ghorban K (2020) STAT3 inhibition reduced PD‐L1 expression and enhanced antitumor immune responses. J Cell Physiol 235(12):9457–9463

    Article  CAS  PubMed  Google Scholar 

  52. Munkholm P (2003) Review article: the incidence and prevalence of colorectal cancer in inflammatory bowel disease. Aliment Pharmacol Ther 18(s2):1–5

    Article  PubMed  Google Scholar 

  53. Terzić J, Grivennikov S, Karin E, Karin M (2010) Inflammation and colon cancer. Gastroenterology 138(6):2101–2114

    Article  PubMed  Google Scholar 

  54. Itzkowitz SH, Yio X (2004) Inflammation and cancer iv. Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am J Physiol Gastrointest Liver Physiol 287(1):G7–17

    Article  CAS  PubMed  Google Scholar 

  55. Yao H, Rahman I (2009) Current concepts on the role of inflammation in COPD and lung cancer. Curr Opin Pharmacol 9(4):375–383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Chang SH, Mirabolfathinejad SG, Katta H, Cumpian AM, Gong L, Caetano MS et al (2014) T helper 17 cells play a critical pathogenic role in lung cancer. Proc Natl Acad Sci 111(15):5664–5669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Houghton AM (2013) Mechanistic links between COPD and lung cancer. Nat Rev Cancer 13(4):233–245

    Article  CAS  PubMed  Google Scholar 

  58. Zaynagetdinov R, Sherrill TP, Gleaves LA, Hunt P, Han W, McLoed AG et al (2016) Chronic NF-κB activation links COPD and lung cancer through generation of an immunosuppressive microenvironment in the lungs. Oncotarget 7(5):5470–5482

    Article  PubMed  Google Scholar 

  59. Celli BR (2012) Chronic obstructive pulmonary disease and lung cancer: common pathogenesis, shared clinical challenges. Proc Am Thorac Soc 9(2):74–79

    Article  PubMed  Google Scholar 

  60. Durham AL, Adcock IM (2015) The relationship between COPD and lung cancer. Lung Cancer 90(2):121–127

    Article  CAS  PubMed  Google Scholar 

  61. Azad N, Rojanasakul Y, Vallyathan V (2008) Inflammation and lung cancer: roles of reactive oxygen/nitrogen species. J Toxicol Environ Heal Part B Crit Rev 11(1):1–15

    Article  CAS  Google Scholar 

  62. O’Riordan JM, Abdel-Latif MM, Ravi N, McNamara D, Byrne PJ, McDonald GSA et al (2005) Proinflammatory cytokine and nuclear factor kappa-B expression along the inflammation-metaplasia-dysplasia-adenocarcinoma sequence in the esophagus. Am J Gastroenterol 100(6):1257–1264

    Article  PubMed  Google Scholar 

  63. Rieder F, Biancani P, Harnett K, Yerian L, Falk GW (2010) Inflammatory mediators in gastroesophageal reflux disease : impact on esophageal motility, fibrosis, and carcinogenesis. Am J physiol gastrointest Liver Physiol 298:571–581

    Article  Google Scholar 

  64. Farhadi A, Fields J, Banan A, Keshavarzian A (2002) Reactive oxygen species: are they involved in the pathogenesis of GERD, Barrett’s esophagus, and the latter’s progression toward esophageal cancer? Am J Gastroenterol 97(1):22–26

    Article  CAS  PubMed  Google Scholar 

  65. Bishayee A (2014) The Inflammation and Liver Cancer. Adv Exp Med Biol 816:401–435

    Article  CAS  PubMed  Google Scholar 

  66. Berasain C, Castillo J, Perugorria MJ, Latasa MU, Prieto J, Avila MA (2009) Inflammation and liver cancer: new molecular links. Ann N Y Acad Sci 1155:206–221

    Article  CAS  PubMed  Google Scholar 

  67. Dadmanesh M, Ranjbar MM, Ghorban K (2019) Inflammasomes and their roles in the pathogenesis of viral hepatitis and their related complications: an updated systematic review. Immunol Lett 208:11–18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hao F, Cubero FJ, Ramadori P, Liao L, Haas U, Lambertz D et al (2017) Inhibition of Caspase-8 does not protect from alcohol-induced liver apoptosis but alleviates alcoholic hepatic steatosis in mice. Cell Death Dis 8(10):e3152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Nakamoto Y, Kaneko S (2003) Mechanisms of viral hepatitis induced liver injury. Curr Mol Med 3(6):537–544

    Article  CAS  PubMed  Google Scholar 

  70. Pellicoro A, Ramachandran P, Iredale JP, Fallowfield JA (2014) Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat Rev Immunol 14(3):181–194

    Article  CAS  PubMed  Google Scholar 

  71. He G, Karin M (2011) NF-κB and STAT3- key players in liver inflammation and cancer. Cell Res 21(1):159–168

    Article  CAS  PubMed  Google Scholar 

  72. Takeda H, Takai A, Inuzuka T, Marusawa H (2017) Genetic basis of hepatitis virus-associated hepatocellular carcinoma: linkage between infection, inflammation, and tumorigenesis. J Gastroenterol 52(1):26–38

    Article  CAS  PubMed  Google Scholar 

  73. Rajput S, Wilber A (2010) Roles of inflammation in cancer initiation, progression, and metastasis. Front Biosci (Schol Ed) 2:175–183

    Google Scholar 

  74. Gregory AD, Houghton AM (2011) Tumor-associated neutrophils: new targets for cancer therapy. Cancer Res 71(7):2411–2416

    Article  CAS  PubMed  Google Scholar 

  75. Lin W, Karin M (2007) A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest 117(5): 1175–1183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Apte RN, Dotan S, Elkabets M, White MR, Reich E, Carmi Y et al (2006) The involvement of IL-1 in tumorigenesis, tumor invasiveness, metastasis and tumor-host interactions. Cancer Metastasis Rev 25(3):387–408

    Article  CAS  PubMed  Google Scholar 

  77. Momeni M, Ghorban K, Dadmanesh M, Khodadadi H, Bidaki R, Kazemi Arababadi M et al (2016) ASC provides a potential link between depression and inflammatory disorders: a clinical study of depressed Iranian medical students. Nord J Psychiatry 70(4):280–284

    Article  PubMed  Google Scholar 

  78. Saghafi T, Taheri RA, Parkkila S, Zolfaghari ER (2019) Phytochemicals as modulators of long non-coding RNAs and inhibitors of cancer-related carbonic anhydrases. Int J Mol Sci 20(12):2939

    Article  CAS  PubMed Central  Google Scholar 

  79. Wang DJ, Ratnam NM, Byrd JC, Guttridge DC (2014) NF-κB functions in tumor initiation by suppressing the surveillance of both innate and adaptive immune cells. Cell Rep 9(1):90–103

    Article  PubMed  PubMed Central  Google Scholar 

  80. Yu H, Lee H, Herrmann A, Buettner R, Jove R (2014) Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer 14(11):736–746

    Article  CAS  PubMed  Google Scholar 

  81. Zuazo-Gaztelu I, Casanovas O (2018) Unraveling the role of angiogenesis in cancer ecosystems. Frontiers in Oncology. Frontiers Media S.A. 8: 248

  82. Liao D, Johnson RS (2007) Hypoxia: a key regulator of angiogenesis in cancer. Cancer Metastasis Rev 26(2):281–290

    Article  CAS  PubMed  Google Scholar 

  83. Perillo B, Di Donato M, Pezone A, Di Zazzo E, Giovannelli P, Galasso G et al (2020) ROS in cancer therapy: the bright side of the moon. Exp Mol Med 52(2):192–203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Pawlus MR, Wang L, Hu CJ (2014) STAT3 and HIF1α cooperatively activate HIF1 target genes in MDA-MB-231 and RCC4 cells. Oncogene 33(13):1670–1679

    Article  CAS  PubMed  Google Scholar 

  85. Sun HL, Liu YN, Huang YT, Pan SL, Huang DY, Guh JH et al (2007) YC-1 inhibits HIF-1 expression in prostate cancer cells: contribution of Akt/NF-κB signaling to HIF-1α accumulation during hypoxia. Oncogene 26(27):3941–3951

    Article  CAS  PubMed  Google Scholar 

  86. Jung YJ, Isaacs JS, Lee S, Trepel J, Neckers L (2003) IL-1beta-mediated up-regulation of HIF-1alpha via an NFkappaB/COX-2 pathway identifies HIF-1 as a critical link between inflammation and oncogenesis. FASEB J 17(14):2115–2117

    Article  CAS  PubMed  Google Scholar 

  87. Jing Y, Ma N, Fan T, Wang C, Bu X, Jiang G et al (2011) Tumor necrosis factor-alpha promotes tumor growth by inducing vascular endothelial growth factor. Cancer Invest 29(7):485–493

    CAS  PubMed  Google Scholar 

  88. Han J, Xi Q, Meng Q, Liu J, Zhang Y, Han Y et al (2016) Interleukin-6 promotes tumor progression in colitis-associated colorectal cancer through HIF-1α regulation. Oncol Lett 12(6):4665–4670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Calviello G, Di Nicuolo F, Gragnoli S, Piccioni E, Serini S, Maggiano N et al (2004) n-3 PUFAs reduce VEGF expression in human colon cancer cells modulating the COX-2/PGE 2 induced ERK-1 and -2 and HIF-1α induction pathway. Carcinogenesis 25(12):2303–2310

    Article  CAS  PubMed  Google Scholar 

  90. Houghton AMG (2010) The paradox of tumor-associated neutrophils: fueling tumor growth with cytotoxic substances. Cell Cycle 9(9):1732–1737

    Article  CAS  PubMed  Google Scholar 

  91. Yoshida S, Ono M, Shono T, Izumi H, Ishibashi T, Suzuki H et al (1997) Involvement of interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor in tumor necrosis factor alpha-dependent angiogenesis. Mol Cell Biol 17(7):4015–4023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G (2006) Inflammation and cancer: how hot is the link? Biochem Pharmacol 72(11):1605–1621

    Article  CAS  PubMed  Google Scholar 

  93. Voronov E, Carmi Y, Apte RN (2014) The role IL-1 in tumor-mediated angiogenesis. Front Physiol 28(5):114

    Google Scholar 

  94. Lee H, Jeong AJ, Ye SK (2019) Highlighted STAT3 as a potential drug target for cancer therapy. BMB Rep 52(7):415–423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Xia Y, Shen S, Verma IM (2019) NF-κB, an active player in human cancers. Cancer Immunol Res 2(9):823–830

    Article  Google Scholar 

  96. Chaffer CL, Weinberg RA (2011) A perspective on cancer cell metastasis. Science 331(6024):1559–1564

    Article  CAS  PubMed  Google Scholar 

  97. Pastushenko I, Blanpain C (2019) EMT Transition states during tumor progression and metastasis. Trends Cell Biol 29(3): 212–226

    Article  CAS  PubMed  Google Scholar 

  98. Galdiero MR, Garlanda C, Jaillon S, Marone G, Mantovani A (2013) Tumor associated macrophages and neutrophils in tumor progression. J Cell Physiol 228(7):1404–1412

    Article  CAS  PubMed  Google Scholar 

  99. De Larco JE, Wuertz BRK, Furcht LT, De LJE (2004) The potential role of neutrophils in promoting the metastatic phenotype of tumors releasing interleukin-8. Clin Cancer Res 10(612):4895–4900

    Article  PubMed  Google Scholar 

  100. Kargl J, Gregory A, Yang HY, Busch S, Metz H, Houghton AM (2016) Abstract C15: Neutrophil elastase (NE) induces epithelial-mesenchymal transition (EMT) via upregulation of inhibitor of DNA binding 1 (ID1). Cancer Res 76(15 Supplement):C15–C15

    Article  Google Scholar 

  101. Liang W, Ferrara N (2016) The complex role of neutrophils in tumor angiogenesis and metastasis. Cancer Immunol Res 4(2):83–91

    Article  CAS  PubMed  Google Scholar 

  102. Qian B-Z, Zhang H, Li J, He T, Yeo E-J, Soong DYH et al (2015) FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes breast cancer metastasis. J Exp Med 212(9):1433–1448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. McDowell SAC, Quail DF (2019) Immunological regulation of vascular inflammation during cancer metastasis. Front Immunol 10:1984

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Yu L, Mu Y, Sa N, Wang H, Xu W (2014) Tumor necrosis factor α induces epithelial-mesenchymal transition and promotes metastasis via NF-κB signaling pathway-mediated TWIST expression in hypopharyngeal cancer. Oncol Rep 31(1):321–327

    Article  CAS  PubMed  Google Scholar 

  105. Wang S, Yan Y, Cheng Z, Hu Y, Liu T (2018) Sotetsuflavone suppresses invasion and metastasis in non-small-cell lung cancer A549 cells by reversing EMT via the TNF-α/NF-κB and PI3K/AKT signaling pathway. Cell Death Discov 4(1):1–11

    Article  Google Scholar 

  106. Liu S, Shi L, Wang Y, Ye D, Ju H, Ma H et al (2018) Stabilization of slug by NF-κB is essential for TNF-α -induced migration and epithelial-mesenchymal transition in head and neck squamous cell carcinoma cells. Cell Physiol Biochem 47(2):567–578

    Article  CAS  PubMed  Google Scholar 

  107. Buhrmann C, Yazdi M, Popper B, Kunnumakkara AB, Aggarwal BB, Shakibaei M (2019) Induction of the epithelial-to-mesenchymal transition of human colorectal cancer by human TNF-β (Lymphotoxin) and its reversal by resveratrol. Nutrients 11(3):704

    Article  CAS  PubMed Central  Google Scholar 

  108. Zakaria N, Yusoff NM, Zakaria Z, Widera D, Yahaya BH (2018) Inhibition of NF-κB signaling reduces the stemness characteristics of lung cancer stem cells. Front Oncol 8(MAY):166

    Article  PubMed  PubMed Central  Google Scholar 

  109. Ottewell P, Lefley D, Freeman K, Gregory W, Hanby A, Spicer-Hadlington A et al (2019) Breast cancer cellderived IL-1B drives metastasis and colonisation of the bone microenvironment. Cancer Research P1-05-01

  110. Grimes BS, Walser TC, Li R, Jirg Z, Tran L, Dubinett SM (2016) Overexpression of Slug drives malignant phenotypes in models of lung premalignancy and cancer. Am J Respir Crit Care Med 193:A3127

    Google Scholar 

  111. Li T, Zhu J, Zuo S, Chen S, Ma J, Ma Y et al (2019) 1,25(OH)2D3 attenuates IL-1b-induced epithelial-to-mesenchymal transition through inhibiting the expression of LNcTCF7. Oncol Res 27(7):739–750

    Article  PubMed  PubMed Central  Google Scholar 

  112. Su B, Luo T, Zhu J, Fu J, Zhao X, Chen L et al (2015) Interleukin-1β/Iinterleukin-1 receptor-associated kinase 1 inflammatory signaling contributes to persistent Gankyrin activation during hepatocarcinogenesis. Hepatology 61(2):585–597

    Article  CAS  PubMed  Google Scholar 

  113. Goulet CR, Champagne A, Bernard G, Vandal D, Chabaud S, Pouliot F et al (2019) Cancer-associated fibroblasts induce epithelial-mesenchymal transition of bladder cancer cells through paracrine IL-6 signalling. BMC Cancer 19(1):137

    Article  PubMed  PubMed Central  Google Scholar 

  114. Wang L, Cao L, Wang H, Liu B, Zhang Q, Meng Z et al (2017) Cancer-associated fibroblasts enhance metastatic potential of lung cancer cells through IL-6/STAT3 signaling pathway. Oncotarget 8(44):76116–76128

    Article  PubMed  PubMed Central  Google Scholar 

  115. Wu X, Tao P, Zhou Q, Li J, Yu Z, Wang X et al (2017) IL-6 secreted by cancer-associated fibroblasts promotes epithelial-mesenchymal transition and metastasis of gastric cancer via JAK2/STAT3 signaling pathway. Oncotarget 8(13):20741–20750

    Article  PubMed  PubMed Central  Google Scholar 

  116. Zhang X, Hu F, Li G, Li G, Yang X, Liu L et al (2018) Human colorectal cancer-derived mesenchymal stem cells promote colorectal cancer progression through IL-6/JAK2/STAT3 signaling. Cell Death Dis 9(2):1–13

    Article  Google Scholar 

  117. Weng YS, Tseng HY, Chen YA, Shen PC, Al Haq AT, Chen LM et al (2019) MCT-1/miR-34a/IL-6/IL-6R signaling axis promotes EMT progression, cancer stemness and M2 macrophage polarization in triple-negative breast cancer. Mol Cancer 18(1):42

    Article  PubMed  PubMed Central  Google Scholar 

  118. Hamada S, Masamune A, Yoshida N, Takikawa T, Shimosegawa T (2016) IL-6/STAT3 plays a regulatory role in the interaction between pancreatic stellate cells and cancer cells. Dig Dis Sci 61(6):1561–1571

    Article  CAS  PubMed  Google Scholar 

  119. Kamran MZ, Patil P, Gude RP (2013) Role of STAT3 in cancer metastasis and translational advances. Biomed Res Int 2013:421821

    Article  PubMed  PubMed Central  Google Scholar 

  120. Reczek CR, Chandel NS (2017) The two faces of reactive oxygen species in cancer. Annu Rev Cancer Biol 1(1):79–98

    Article  Google Scholar 

  121. Madrigal-Martínez A, Constâncio V, Lucio-Cazaña FJ, Fernández-Martínez AB (2019) PROSTAGLANDIN E 2 stimulates cancer-related phenotypes in prostate cancer PC3 cells through cyclooxygenase-2. J Cell Physiol 234(5):7548–7559

    Article  PubMed  Google Scholar 

  122. Lau YTK, Ramaiyer M, Johnson DE, Grandis JR (2019) Targeting STAT3 in cancer with nucleotide therapeutics. Cancers (Basel) 11(11):1681

    Article  CAS  Google Scholar 

  123. Owen KL, Brockwell NK, Parker BS (2019) Jak-stat signaling: a double-edged sword of immune regulation and cancer progression. Cancers (Basel) 11(12):2002

    Article  CAS  Google Scholar 

  124. Furtek SL, Backos DS, Matheson CJ, Reigan P (2016) Strategies and approaches of targeting STAT3 for cancer treatment. ACS Chem Biol 11 (2):308–318

    Article  CAS  PubMed  Google Scholar 

  125. Zhou C, Ma J, Su M, Shao D, Zhao J, Zhao T et al (2018) Down-regulation of STAT3 induces the apoptosis and G1 cell cycle arrest in esophageal carcinoma ECA109 cells. Cancer Cell Int 18(1):1–12

    Article  CAS  Google Scholar 

  126. Cao YY, Yu J, Liu TT, Yang KX, Yang LY, Chen Q et al (2018) Plumbagin inhibits the proliferation and survival of esophageal cancer cells by blocking STAT3-PLK1-AKT signaling article. Cell Death Dis 9(2):1–13

    Article  Google Scholar 

  127. Zhou W, Chen MK, Yu HT, Zhong ZH, Cai N, Chen GZ et al (2016) The antipsychotic drug pimozide inhibits cell growth in prostate cancer through suppression of STAT3 activation. Int J Oncol 48(1):322–328

    Article  CAS  PubMed  Google Scholar 

  128. Shou J, You L, Yao J, Xie J, Jing J, Jing Z et al (2016) Cyclosporine A sensitizes human non-small cell lung cancer cells to gefitinib through inhibition of STAT3. Cancer Lett 379(1):124–133

    Article  CAS  PubMed  Google Scholar 

  129. Mao Z, Shen X, Dong P, Liu G, Pan S, Sun X et al (2019) Fucosterol exerts antiproliferative effects on human lung cancer cells by inducing apoptosis, cell cycle arrest and targeting of Raf/MEK/ERK signalling pathway. Phytomedicine 61(218):975–981

    Google Scholar 

  130. Tajmohammadi I, Mohammadian J, Sabzichi M, Mahmuodi S, Ramezani M, Aghajani M et al (2019) Identification of Nrf2/STAT3 axis in induction of apoptosis through sub-G 1 cell cycle arrest mechanism in HT-29 colon cancer cells. J Cell Biochem 120(8):14035–14043

    Article  CAS  PubMed  Google Scholar 

  131. Ma Z, Bao X, Gu J (2019) Furowanin A-induced autophagy alleviates apoptosis and promotes cell cycle arrest via inactivation STAT3/Mcl-1 axis in colorectal cancer. Life Sci 218:47–57

    Article  CAS  PubMed  Google Scholar 

  132. Li L, Han L, Sun F, Zhou J, Ohaegbulam KC, Tang X et al (2018) NF-κB RelA renders tumor-associated macrophages resistant to and capable of directly suppressing CD8+ T cells for tumor promotion. Oncoimmunology 7(6):e1435250

    Article  PubMed  PubMed Central  Google Scholar 

  133. Wang D, DuBois RN (2016) The Role of Prostaglandin E2 in Tumor-Associated Immunosuppression. Trends in Molecular Medicine 22(1):1–3

    Article  PubMed  Google Scholar 

  134. Ke J, Yang Y, Che Q, Jiang F, Wang H, Chen Z et al (2016) Prostaglandin E2 (PGE2) promotes proliferation and invasion by enhancing SUMO-1 activity via EP4 receptor in endometrial cancer. Tumor Biol 37(9):12203–12211

    Article  CAS  Google Scholar 

  135. Wherry EJ, Kurachi M (2015) Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol 15(8):486–499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Gassner FJ, Zaborsky N, Neureiter D, Huemer M, Melchardt T, Egle A et al (2014) Chemotherapy induced augmentation of T cells expressing inhibitory receptors is reversed by treatment with lenalidomide in chronic lymphocytic leukemia. Haematol 99(5):67–69

    Article  Google Scholar 

  137. Peitzsch C, Tyutyunnykova A, Pantel K, Dubrovska A (2017) Cancer stem cells: the root of tumor recurrence and metastases. Semin Cancer Biol 44:10–24

    Article  CAS  PubMed  Google Scholar 

  138. Yu Y, Ramena G, Elble RC (2012) The role of cancer stem cells in relapse of solid tumors. Front Biosci (Elite Ed) 4:1528–1541

    Article  Google Scholar 

  139. Mansoori B, Mohammadi A, Davudian S, Shirjang S, Baradaran B (2017) The different mechanisms of cancer drug resistance: a brief review. Adv Pharm Bull 7(3):339–348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Dean M, Fojo T, Bates S (2005) Tumour stem cells and drug resistance. Nat Rev Cancer 5:275–284

    Article  CAS  PubMed  Google Scholar 

  141. Phi LTH, Sari IN, Yang YG, Lee SH, Jun N, Kim KS et al (2018) Cancer stem cells (CSCs) in drug resistance and their therapeutic implications in cancer treatment. Stem Cells Int 2018:5416923

    Article  PubMed  PubMed Central  Google Scholar 

  142. Shigdar S, Li Y, Bhattacharya S, O’Connor M, Pu C, Lin J et al (2014) Inflammation and cancer stem cells. Cancer Lett 345(2):271–278

    Article  CAS  PubMed  Google Scholar 

  143. Capece D, Verzella D, Tessitore A, Alesse E, Capalbo C, Zazzeroni F (2018) Cancer secretome and inflammation: The bright and the dark sides of NF-κB. Semin Cell Dev Biol 78:51–61

    Article  CAS  PubMed  Google Scholar 

  144. Hoesel B, Schmid JA (2013) The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer 12(1):86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Xiong A, Yang Z, Shen Y, Zhou J, Shen Q (2014) Transcription factor STAT3 as a novel molecular target for cancer prevention. Cancers (Bazel) 6(2):926–957

    Article  Google Scholar 

  146. Wang Y, Shen Y, Wang S, Shen Q, Zhou X (2018) The role of STAT3 in leading the crosstalk between human cancers and the immune system. Cancer Lett 415:117–128

    Article  CAS  PubMed  Google Scholar 

  147. Taniguchi K, Karin M (2018) NF-B, inflammation, immunity and cancer: Coming of age. Nat Rev Immunol 18:309–324

    Article  CAS  PubMed  Google Scholar 

  148. Snouwaert JN, Jania L, Nguyen M, Dontu P, Besse J, Akla B et al (2019) Prostaglandin E2 produced by tumor cells or by the host tumor microenvironment is not completely abolished by aspirin or celecoxib and limits the ability of the host immune system to control tumor growth. Cancer Res 79 (13 Supplement):503

    Article  Google Scholar 

  149. Srivastava MK, Sinha P, Clements VK, Rodriguez P, Ostrand-Rosenberg S (2010) Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. Cancer Res 70(1):68–77

    Article  CAS  PubMed  Google Scholar 

  150. Rodriguez PC, Quiceno DG, Zabaleta J, Ortiz B, Zea AH, Piazuelo MB et al (2004) Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res 64(16):5839–5849

    Article  CAS  PubMed  Google Scholar 

  151. Ezernitchi AV, Vaknin I, Cohen-Daniel L, Levy O, Manaster E, Halabi A et al (2006) TCR ζ down-regulation under chronic inflammation is mediated by myeloid suppressor cells differentially distributed between various lymphatic organs. J Immunol 177(7):4763–4772

    Article  CAS  PubMed  Google Scholar 

  152. Nagaraj S, Schrum AG, Cho H-I, Celis E, Gabrilovich DI (2010) Mechanism of T cell tolerance induced by myeloid-derived suppressor cells. J Immunol 184(6):3106–3116

    Article  CAS  PubMed  Google Scholar 

  153. Mazzoni A, Bronte V, Visintin A, Spitzer JH, Apolloni E, Serafini P et al (2002) Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism. J Immunol 168(2):689–695

    Article  CAS  PubMed  Google Scholar 

  154. Hanson EM, Clements VK, Sinha P, Ilkovitch D, Ostrand-Rosenberg S (2009) Myeloid-derived suppressor cells down-regulate L-selectin expression on CD4+ and CD8+ T cells. J Immunol 183(2):937–944

    Article  CAS  PubMed  Google Scholar 

  155. Molon B, Ugel S, Del Pozzo F, Soldani C, Zilio S, Avella D et al (2011) Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. J Exp Med 208(10):1949–1962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Huang B, Pan P-Y, Li Q, Sato AI, Levy DE, Bromberg J et al (2006) Gr-1+ CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Res 66(2):1123–1131

    Article  CAS  PubMed  Google Scholar 

  157. Pan P-Y, Ma G, Weber KJ, Ozao-Choy J, Wang G, Yin B et al (2010) Immune stimulatory receptor CD40 is required for T-cell suppression and T regulatory cell activation mediated by myeloid-derived suppressor cells in cancer. Cancer Res 70(1):99–108

    Article  CAS  PubMed  Google Scholar 

  158. Serafini P, Mgebroff S, Noonan K, Borrello I (2008) Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. Cancer Res 68(13):5439–5449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Ostrand-Rosenberg S, Sinha P, Beury DW, Clements VK (2012) Cross-talk between myeloid-derived suppressor cells (MDSC), macrophages, and dendritic cells enhances tumor-induced immune suppression. Semin cancer boil 22(4):275–281

    Article  CAS  Google Scholar 

  160. Narendra BL, Reddy KE, Shantikumar S, Ramakrishna S (2013) Immune system: a double-edged sword in cancer. Inflamm Res 62(9):823–834

    Article  Google Scholar 

  161. Shalapour S, Font-Burgada J, Di Caro G, Zhong Z, Sanchez-Lopez E, Dhar D et al (2015) Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature 521(7550):94–98

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Liu Z, Fu YX (2020) Chemotherapy induces cancer-fighting B cells. Cell 180(6):1037–1039

    Article  CAS  PubMed  Google Scholar 

  163. Bracci L, Schiavoni G, Sistigu A, Belardelli F (2014) Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ 21(1):15–25

    Article  CAS  PubMed  Google Scholar 

  164. Wijayahadi N, Haron MR, Stanslas J, Yusuf Z (2007) Changes in cellular immunity during chemotherapy for primary breast cancer with anthracycline regimens. J Chemother 19(6):716–723

    Article  CAS  PubMed  Google Scholar 

  165. Nowak AK, Robinson BWS, Lake RA (2002) Gemcitabine exerts a selective effect on the humoral immune response: implications for combination chemo-immunotherapy. Cancer Res 62(8):2353–2358

    CAS  PubMed  Google Scholar 

  166. Emens LA, Middleton G (2015) The interplay of immunotherapy and chemotherapy: harnessing potential synergies. Cancer Immunol Res 3:436–443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Opzoomer JW, Sosnowska D, Anstee JE, Spicer JF, Arnold JN (2019) Cytotoxic chemotherapy as an immune stimulus: A molecular perspective on turning up the immunological heat on cancer. Front Immunol 10:1654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Huang XM, Zhang NR, Lin XT, Zhu CY, Zou YF, Wu XJ et al (2020) Antitumor immunity of low-dose cyclophosphamide: changes in T cells and cytokines TGF-beta and IL-10 in mice with colon-cancer liver metastasis. Gastroenterol Rep 8(1):56–65

    Article  Google Scholar 

  169. Motoyoshi Y, Kaminoda K, Saitoh O, Hamasaki K, Nakao K, Ishii N et al (2006) Different mechanisms for anti-tumor effects of low- and high-dose cyclophosphamide. Oncol Rep 16(1):141–146

    CAS  PubMed  Google Scholar 

  170. Bryniarski K, Szczepanik M, Ptak M, Zemelka M, Ptak W (2009) Influence of cyclophosphamide and its metabolic products on the activity of peritoneal macrophages in mice. Pharmacol Rep 61(3):550–557

    Article  CAS  PubMed  Google Scholar 

  171. Pellicciotta I, Yang C-PH, Goldberg GL, Shahabi S (2011) Epothilone B enhances Class I HLA and HLA-A2 surface molecule expression in ovarian cancer cells. Gynecol Oncol 122(3):625–631

    Article  CAS  PubMed  Google Scholar 

  172. Apetoh L, Ladoire S, Coukos G, Ghiringhelli F (2015) Combining immunotherapy and anticancer agents: the right path to achieve cancer cure? Ann Oncol 26(9):1813–1823

    Article  CAS  PubMed  Google Scholar 

  173. Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G (2008) Immunological aspects of cancer chemotherapy. Nat Rev Immunol 8(1):59–73

    Article  CAS  PubMed  Google Scholar 

  174. Fucikova J, Kepp O, Kasikova L, Petroni G, Yamazaki T, Liu P et al (2020) Detection of immunogenic cell death and its relevance for cancer therapy. Cell Death Dis 11:1–13

    Article  Google Scholar 

  175. Wang YJ, Fletcher R, Yu J, Zhang L (2018) Immunogenic effects of chemotherapy-induced tumor cell death. Genes Dis 5(3):194–203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Ocadlikova D, Lecciso M, Isidori A, Loscocco F, Visani G, Amadori S et al (2019) Chemotherapy-induced tumor cell death at the crossroads between immunogenicity and immunotolerance: focus on acute myeloid leukemia. Front Oncol 9:1004

    Article  PubMed  PubMed Central  Google Scholar 

  177. Galluzzi L, Buqué A, Kepp O, Zitvogel L, Kroemer G (2015) Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell 28(6):690–714

    Article  CAS  PubMed  Google Scholar 

  178. Bailly C, Thuru X, Quensnel B (2020) Combined cytotoxic chemotherapy and immunotherapy of cancer: modern times. NAR Cancer 2(1):zcaa002

    Article  PubMed  PubMed Central  Google Scholar 

  179. Thorn CF, Oshiro C, Marsh S, Hernandez-Boussard T, McLeod H, Klein TE et al (2011) Doxorubicin pathways: Pharmacodynamics and adverse effects. Pharmacogenet Gen 21(7):440–446

    Article  CAS  Google Scholar 

  180. Hu X, Zhang H (2019) Doxorubicin-induced cancer cell senescence shows a time delay effect and is inhibited by epithelial-mesenchymal transition (EMT). Med Sci Monit 25:3617–3623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Wong J, Smith LB, Magun EA, Engstrom T, Kelley-Howard K, Jandhyala DM et al (2013) Small molecule kinase inhibitors block the ZAK-dependent inflammatory effects of Doxorubicin. Cancer Biol Ther 14(1):56–63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Guo R, Wu K, Chen J, Mo L, Hua X, Zheng D et al (2013) Exogenous hydrogen sulfide protects against doxorubicin-induced inflammation and cytotoxicity by inhibiting p38MAPK/NFκB pathway in H9c2 cardiac cells. Cell Physiol Biochem 32(6):1668–1680

    Article  CAS  PubMed  Google Scholar 

  183. Dasari S, Tchounwou PB (2014) Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol 740:364–378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Manohar S, Leung N (2017) Cisplatin nephrotoxicity : a review of the literature. J Nephrol 31(1):15–25

    Article  PubMed  Google Scholar 

  185. Ibrahim A, Al-Hizab FA, Abushouk AI, Abdel-Daim MM (2018) Nephroprotective effects of benzyl isothiocyanate and resveratrol against cisplatin-induced oxidative stress and inflammation. Front Pharmacol 9:1268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Huang YC, Tsai MS, Hsieh PC, Shih JH, Wang TS, Wang YC et al (2017) Galangin ameliorates cisplatin-induced nephrotoxicity by attenuating oxidative stress, inflammation and cell death in mice through inhibition of ERK and NF-kappaB signaling. Toxicol Appl Pharmacol 329:128–139

    Article  CAS  PubMed  Google Scholar 

  187. Humanes B, Camaño S, Lara JM, Sabbisetti V, González-Nicolás MÁ, Bonventre JV et al (2017) Cisplatininduced renal inflammation is ameliorated by cilastatin nephroprotection. Nephrol Dial Transplant 32(10):1645–1655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Weaver BA (2014) How Taxol/paclitaxel kills cancer cells. Mol Biol Cell 25(18):2677–2681

    Article  PubMed  PubMed Central  Google Scholar 

  189. Son S, Shim D-W, Hwang I, Park J-H, Yu J-W (2019) Chemotherapeutic agent paclitaxel mediates priming of NLRP3 inflammasome activation. Front Immunol 10:1108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Vyas D, Laput G, Vyas AK (2014) Chemotherapy-enhanced inflammation may lead to the failure of therapy and metastasis. Onco Targets Ther 7:1015–1023

    Article  PubMed  PubMed Central  Google Scholar 

  191. Moossavi M, Parsamanesh N, Bahrami A, Atkin SL, Sahebkar A (2018) Role of the NLRP3 inflammasome in cancer. Mol Cancer 17(1):1–13

    Article  Google Scholar 

  192. Soares PMG, Mota JMSC, Gomes AS, Oliveira RB, Assreuy AMS, Brito GAC et al (2008) Gastrointestinal dysmotility in 5-fluorouracil-induced intestinal mucositis outlasts inflammatory process resolution. Cancer Chemother Pharmacol 63(1):91–98

    Article  CAS  PubMed  Google Scholar 

  193. Polk A, Vistisen K, Vaage-Nilsen M, Nielsen DL (2014) A systematic review of the pathophysiology of 5-fluorouracil-induced cardiotoxicity. BMC Pharmacol Toxicol 15(1):47

    Article  PubMed  PubMed Central  Google Scholar 

  194. Longley DB, Harkin DP, Johnston PG (2003) 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev cancer 3(5):330–338

    Article  CAS  PubMed  Google Scholar 

  195. Raghu Nadhanan R, Abimosleh SM, Su Y-W, Scherer MA, Howarth GS, Xian CJ (2012) Dietary emu oil supplementation suppresses 5-fluorouracil chemotherapy-induced inflammation, osteoclast formation, and bone loss. Am J Physiol Metab 302(11):E1440–E1449

    Google Scholar 

  196. Fujiwara K, Sakuragi N, Suzuki S, Yoshida N, Maehata K, Nishiya M et al (2003) First-line intraperitoneal carboplatin-based chemotherapy for 165 patients with epithelial ovarian carcinoma: results of long-term follow-up. Gynecol Oncol 90(3):637–643

    Article  CAS  PubMed  Google Scholar 

  197. Sue Y-M, Chou H-C, Chang C-C, Yang N-J, Chou Y, Juan S-H (2014) L-carnitine protects against carboplatin mediated renal injury: AMPK-and PPARα-dependent inactivation of NFAT3. PLoS One 9(8):e104079

    Article  PubMed  PubMed Central  Google Scholar 

  198. Arafa HMM (2008) Carnitine deficiency aggravates carboplatin nephropathy through deterioration of energy status, oxidant/anti-oxidant balance, and inflammatory endocoids. Toxicology 254(1–2):51–60

    Article  CAS  PubMed  Google Scholar 

  199. Konstantinopoulos PA, Fountzilas E, Pillay K, Zerbini LF, Libermann TA, Cannistra SA et al (2008) Carboplatin-induced gene expression changes in vitroare prognostic of survival in epithelial ovarian cancer. BMC Med Gen 1(1):59

    Article  Google Scholar 

  200. Li H, Cimino SK (2020) Clinical impact of the etoposide injection shortage. J Oncol Pharm Pract 26(1):187–192

    Article  PubMed  Google Scholar 

  201. Brooks JP, Azmy V, Thompson A, Luon D, Prozora SD, Price C et al (2020) Etoposide phosphate for pediatric orthopedic malignancies after intravenous etoposide hypersensitivity. J Oncol Pharm Pract 26(1):228–231

    Article  CAS  PubMed  Google Scholar 

  202. Armstrong MB, Bian X, Liu Y, Subramanian C, Ratanaproeksa AB, Shao F et al (2006) Signaling from p53 to NF-κB determines the chemotherapy responsiveness of neuroblastoma. Neoplasia (New York, NY) 8(11):964

    Article  Google Scholar 

  203. Wood LJ, Nail LM, Perrin NA, Elsea CR, Fischer A, Druker BJ (2006) The cancer chemotherapy drug etoposide (VP-16) induces proinflammatory cytokine production and sickness behavior–like symptoms in a mouse model of cancer chemotherapy-related symptoms. Biol Res Nurs 8(2):157–169

    Article  CAS  PubMed  Google Scholar 

  204. Darst M, Al-Hassani M, Li T, Yi Q, Travers JM, Lewis DA et al (2004) Augmentation of chemotherapy-induced cytokine production by expression of the platelet-activating factor receptor in a human epithelial carcinoma cell line. J Immunol 172(10):6330–6335

    Article  CAS  PubMed  Google Scholar 

  205. Alfei S, Marengo B, Domenicotti C (2020) Polyester-based dendrimer nanoparticles combined with etoposide have an improved cytotoxic and pro-oxidant effect on human neuroblastoma cells. Antioxidants 9(1):50

    Article  CAS  PubMed Central  Google Scholar 

  206. Qiu L, Zhou G, Cao S (2020) Targeted inhibition of ULK1 enhances daunorubicin sensitivity in acute myeloid leukemia. Life Sci 243:117234

    Article  CAS  PubMed  Google Scholar 

  207. Gewirtz D (1999) A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol 57(7):727–741

    Article  CAS  PubMed  Google Scholar 

  208. Sauter KAD, Wood LJ, Wong J, Iordanov M, Magun BE (2011) Doxorubicin and daunorubicin induce processing and release of interleukin-1β through activation of the NLRP3 inflammasome: Progress at a snail’s pace. Cancer Biol Ther 11(12):1008–1016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Al-Homsi AS, Roy TS, Cole K, Feng Y, Duffner U (2015) Post-transplant high-dose cyclophosphamide for the prevention of graft-versus-host disease. Biol Blood Marrow Transpl 21(4):604–611

    Article  CAS  Google Scholar 

  210. Lefaki M, Papaevgeniou N, Tur JA, Vorgias CE, Sykiotis GP, Chondrogianni N (2020) The dietary triterpenoid 18α–Glycyrrhetinic acid protects from MMC-induced genotoxicity through the ERK/Nrf2 pathway. Redox Biol 28:101317

    Article  CAS  PubMed  Google Scholar 

  211. Yang Q, Deng Z, Wang D, He J, Zhang D, Tan Y et al (2020) Conjugating aptamer and mitomycin C with reductant-responsive linker leading to synergistically enhanced anti-cancer effect. J Am Chem Soc 142(5):2532–2540

    Article  CAS  PubMed  Google Scholar 

  212. Galadari S, Rahman A, Pallichankandy S, Thayyullathil F (2017) Reactive oxygen species and cancer paradox: to promote or to suppress? Free Radic Biol Med 104:144–164

    Article  CAS  PubMed  Google Scholar 

  213. Liou GY, Storz P (2010) Reactive oxygen species in cancer. Free Radic Res 44(5):479–496

    Article  CAS  PubMed  Google Scholar 

  214. Nagaraja AS, Dorniak PL, Sadaoui NC, Kang Y, Lin T, Armaiz-Pena G et al (2016) Sustained adrenergic signaling leads to increased metastasis in ovarian cancer via increased PGE2 synthesis. Oncogene 35(18):2390–2397

    Article  CAS  PubMed  Google Scholar 

  215. Tong D, Liu Q, Liu G, Xu J, Lan W, Jiang Y et al (2017) Metformin inhibits castration-induced EMT in prostate cancer by repressing COX2/PGE2/STAT3 axis. Cancer Lett 389:23–32

    Article  CAS  PubMed  Google Scholar 

  216. Filipenko I, Schwalm S, Reali L, Pfeilschifter J, Fabbro D, Huwiler A et al (2016) Upregulation of the S1P3 receptor in metastatic breast cancer cells increases migration and invasion by induction of PGE2 and EP2/EP4 activation. Biochim Biophys Acta Mol Cell Biol Lipids 1861(11):1840–1851

    Article  CAS  Google Scholar 

  217. Rajabi M, Mousa SA (2017) The role of angiogenesis in cancer treatment. Biomedicines 5(2):34

    Article  PubMed Central  Google Scholar 

  218. Pai R, Szabo IL, Soreghan BA, Atay S, Kawanaka H, Tarnawski AS (2001) PGE2 stimulates VEGF expression in endothelial cells via ERK2/JNK1 signaling pathways. Biochem Biophys Res Commun 286(5):923–928

    Article  CAS  PubMed  Google Scholar 

  219. Blaser H, Dostert C, Mak TW, Brenner D (2016) TNF and ROS Crosstalk in Inflammation. Trends Cell Biol 26(4):249–261

    Article  CAS  PubMed  Google Scholar 

  220. Sasi SP, Yan X, Enderling H, Park D, Gilbert HY, Curry C et al (2012) Breaking the harmony of TNF-α signaling for cancer treatment. Oncogene 31(37):4117–4127

    Article  CAS  PubMed  Google Scholar 

  221. Ham B, Fernandez MC, D’Costa Z, Brodt P (2016) The diverse roles of the TNF axis in cancer progression and metastasis. Trends Cancer Res 11(1):1–27

    PubMed  PubMed Central  Google Scholar 

  222. Wang X, Lin Y (2008) Tumor necrosis factor and cancer, buddies or foes? Acta Pharmacol Sin 29(11):1275–1288

    Article  PubMed  Google Scholar 

  223. Liu W, Lu X, Shi P, Yang G, Zhou Z, Li W et al (2020) TNF-α increases breast cancer stem-like cells through up-regulating TAZ expression via the non-canonical NF-κB pathway. Sci Rep 10(1):1–11

    Google Scholar 

  224. Landskron G, De La Fuente M, Thuwajit P, Thuwajit C, Hermoso MA (2014) Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res 2014:149185

    Google Scholar 

  225. Shrihari TG (2017) Dual role of inflammatory mediators in cancer. Ecancermedicalscience Cancer Intelligence 11:720

    Google Scholar 

  226. Carmi Y, Dotan S, Rider P, Kaplanov I, White MR, Baron R et al (2013) The role of IL-1β in the early tumor cell-induced angiogenic response. J Immunol 190(7):3500–3509

    Article  CAS  PubMed  Google Scholar 

  227. Bingle L, Brown NJ, Lewis CE (2002) The role of tumour-associated macrophages in tumour progression: Implications for new anticancer therapies. J Pathol 196(3):254–265

    Article  CAS  PubMed  Google Scholar 

  228. Baker KJ, Houston A, Brint E (2019) IL-1 family members in cancer; two sides to every story. Front Immunol 10:1197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Mantovani A, Barajon I, Garlanda C (2018) IL-1 and IL-1 regulatory pathways in cancer progression and therapy. Immunol Rev 281(1):57–61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Wang L (2010) INTERLEUKIN-1 BETA PROMOTES EPITHELIAL-MESENCHYMAL TRANSITION AND A STEM CELL PHENOTYPE OF COLON CANCER CELLS VIA ZEB1/2 by YIJING LI. Kansas State University

  231. Liu S, Liu D, Zeng X, Wang J, Liu J, Cheng J et al (2018) PA28γ acts as a dual regulator of IL-6 and CCL2 and contributes to tumor angiogenesis in oral squamous cell carcinoma. Cancer Lett 428:192–200

    Article  CAS  PubMed  Google Scholar 

  232. Fu Q, Liu P, Sun X, Huang S, Han F, Zhang L et al (2017) Ribonucleic acid interference knockdown of IL-6 enhances the efficacy of cisplatin in laryngeal cancer stem cells by down-regulating the IL-6/STAT3/HIF1 pathway. Cancer Cell Int 17(1):79

    Article  PubMed  PubMed Central  Google Scholar 

  233. Gai X, Zhou P, Xu M, Liu Z, Zheng X, Liu Q (2020) Hyperactivation of IL-6/STAT3 pathway leaded to the poor prognosis of post-TACE HCCs by HIF-1α/SNAI1 axis-induced epithelial to mesenchymal transition. J Cancer 11(3):570–582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Liao Z, Chua D, Tan NS (2019) Reactive oxygen species: a volatile driver of field cancerization and metastasis. Mol Cancer 18(1):65

    Article  PubMed  PubMed Central  Google Scholar 

  235. Tabruyn SP, Griffioen AW (2008) NF-κB: A new player in angiostatic therapy. Angiogenesis 11:101–106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Harrington BS, Annunziata CM (2019) Nf-κb signaling in ovarian cancer. Cancers 11(8):1182

    Article  CAS  PubMed Central  Google Scholar 

  237. Smith SM, Lyu YL, Cai L (2014) NF-κB Affects proliferation and invasiveness of breast cancer cells by regulating cd44 expression. PLoS One 9(9):e106966

    Article  Google Scholar 

  238. Cui X, Shen D, Kong C, Zhang Z, Zeng Y, Lin X et al (2017) NF-κ B suppresses apoptosis and promotes bladder cancer cell proliferation by upregulating survivin expression in vitro and in vivo. Sci Rep 7(1):1–13

    Google Scholar 

  239. Li B, Huang C (2017) Regulation of EMT by STAT3 in gastrointestinal cancer (Review). Int J Oncol 50(3):753–767

    Article  CAS  PubMed  Google Scholar 

  240. Xu Q, Briggs J, Park S, Niu G, Kortylewski M, Zhang S et al (2005) Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways. Oncogene 24(36):5552–5560

    Article  CAS  PubMed  Google Scholar 

  241. Qin JJ, Yan L, Zhang J, Zhang WD (2019) STAT3 as a potential therapeutic target in triple negative breast cancer: a systematic review. J Exp Clin Cancer Res 38(1):195

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This study was partly supported by grant number 16572 from Iran University of Medical Sciences, Tehran, Iran.

Author information

Authors and Affiliations

  1. Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran

    Nafiseh Behranvand, Farzad Nasri & Reza Falak

  2. Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

    Nafiseh Behranvand, Farzad Nasri & Reza Falak

  3. Department of Energy and Environmental Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran

    Reza Zolfaghari Emameh

  4. Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran

    Pouria Khani

  5. Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran

    Asieh Hosseini

  6. Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands

    Johan Garssen

  7. Department Immunology, Danone Nutricia research, Uppsalalaan 12, 3584 CT, Utrecht, The Netherlands

    Johan Garssen

Authors
  1. Nafiseh Behranvand
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Farzad Nasri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Reza Zolfaghari Emameh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pouria Khani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Asieh Hosseini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Johan Garssen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Reza Falak
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors had substantial contributor in data mining and writing the text and have read and approved the final manuscript. The study is guaranteed by corresponding author.

Corresponding author

Correspondence to Reza Falak.

Ethics declarations

Competing interests

The authors declare that they have no competing interests.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The original online version of this article was revised: Third author's name was incorrect.

Supplementary Information

Below is the link to the electronic supplementary material.

262_2021_3013_MOESM1_ESM.pdf

Supplementary Figure: Some chemotherapy drugs can increase inflammation in the TME. Most of the chemotherapy drugs cause tumor cells to become senescent, which can increase inflammation by producing senescence-associated secretory phenotype (SASP) including inflammatory cytokines, inflammatory chemokines, adhesion molecules, growth factors, and MMPs, e.g., IL-1, IL-6, IL-8, GM-CSF, and MCP-2. Doxorubicin and paclitaxel induce systematic inflammation by provoking TLR4 signaling. Doxorubicin, paclitaxel, and daunorubicin trigger IL-1B secretion through the inflammasome pathway. NF-kB and MAPK as crucial signaling pathways of inflammation are induced by most of the chemotherapy drugs and enhance generation of inflammatory elements. Supplementary file1 (PDF 368 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Behranvand, N., Nasri, F., Zolfaghari Emameh, R. et al. Chemotherapy: a double-edged sword in cancer treatment. Cancer Immunol Immunother 71, 507–526 (2022). https://doi.org/10.1007/s00262-021-03013-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-021-03013-3

Keywords

Search

Navigation