A Novel Nanodrug Suppresses Lung Cancer Growth and Metastasis in C57BL/6 Mouse Model by Altering CD8+ Cell Infiltration and Oxidative Stress
-
Sajjad Shekarchian
,
Marzieh Eghtedardoost
,
Hannaneh Golshahi
,
Helia Behrouzfar
,
Zahra Fakhroueian
,
Roya Yaraee
Abstract
Lung cancer is a leading cause of cancer deaths worldwide and new therapeutic approaches are needed. This study investigates the efficacy of a new zinc oxide-based nanomedicine in a mouse model of heterotopic lung cancer.
C57BL/6 mouse model with Lewis lung carcinoma (LL2) cells was used. The mice were treated with different doses of nanodrug, cisplatin, or phosphate-buffered saline. Tumor growth, metastasis, markers for oxidative stress, and immune responses, in particular the infiltration of CD8+ T cells, were examined.
The nanodrug significantly reduced tumor size, inhibited metastasis, and improved survival compared to the control group. Moreover, no significant toxic effect was observed in hematological, biochemical and histopathological analyses. Furthermore, the nanodrug altered the tumor microenvironment in favor of immune system activation by modulating the level of oxidative stress and increasing CD8+ cell infiltration.
The results show that this new nanomedicine may be a candidate for an effective treatment for lung cancer.
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4. Wiesmann N, Tremel W, Brieger J. Zinc oxide nanoparticles for therapeutic purposes in cancer medicine. J Mater Chem B. 2020;8(23):4973-89.
5. Abdolmohammadi MH, Fallahian F, Fakhroueian Z, Kamalian M, Keyhanvar P, M. Harsini F, Shafiekhani A. Application of new ZnO nanoformulation and Ag/Fe/ZnO nanocomposites as water-based nanofluids to consider in vitro cytotoxic effects against MCF-7 breast cancer
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6. Fakhroueian Z, Vahabpour R, Assmar M, Massiha A, Zahedi A, Esmaeilzadeh P, et al. ZnO Q-Dots as a Potent Therapeutic Nanomedicine for in Vitro Cytotoxicity Evaluation of Mouth KB44, Breast MCF7, Colon HT29 and HeLa Cancer Cell Lines, Mouse Ear Swelling Tests in Vivo and Its Side Effects Using the Animal Model. Artif Cells Nanomed Biotechnol. 2018;46(sup2):96-111.
7. Ghaffari S-B, Sarrafzadeh M-H, Fakhroueian Z, Shahriari S, Khorramizadeh MR. Functionalization of ZnO nanoparticles by 3-mercaptopropionic acid for aqueous curcumin delivery: Synthesis, characterization, and anticancer assessment. Mater Sci Eng C Mater Biol Appl. 2017;79:465-72.
8. Lung cancer 26 June 2023 [Available from: https://www.who.int/news-room/fact-sheets/detail/lung-cancer.
9. Rivera MP, Detterbeck F, Mehta AC. Diagnosis of lung cancer: the guidelines. Chest. 2003;123(1):129S-36S.
10. Collins LG, Haines C, Perkel R, Enck RE. Lung cancer: diagnosis and management. Am Family Fhysician. 2007;75(1):56-63.
11. Fennell D, Summers Y, Cadranel J, Benepal T, Christoph D, Lal R, et al. Cisplatin in the modern era: The backbone of first-line chemotherapy for non-small cell lung cancer. Cancer Treat Rev. 2016;44:42-50.
12. Svaton M, Zemanova M, Zemanova P, Kultan J, Fischer O, Skrickova J, et al. Impact of concomitant medication administered at the time of initiation of nivolumab therapy on outcome in non-small cell lung cancer. Anticancer Res. 2020;40(4):2209-17.
13. Hoy H, Lynch T, Beck M. Surgical treatment of lung cancer. Critical Care Nurs Clin. 2019;31(3):303-13.
14. Inoue M, Sawabata N, Okumura M. Surgical intervention for small-cell lung cancer: what is the surgical role? General thoracic and cardiovascular surgery. 2012;60:401-5.
15. Lackey A, Donington JS, editors. Surgical management of lung cancer. Semin Intervent Radiol. 2013;30(2):133-40.
16. Carbone DP, Gandara DR, Antonia SJ, Zielinski C, Paz-Ares L. Non–small-cell lung cancer: role of the immune system and potential for immunotherapy. J Thoracic Oncol. 2015;10(7):974-84.
17. Caliri AW, Tommasi S, Besaratinia A. Relationships among smoking, oxidative stress, inflammation, macromolecular damage, and cancer. Mut Res Rev Mut Res. 2021;787:108365.
18. Hayes JD, Dinkova-Kostova AT, Tew KD. Oxidative stress in cancer. Cancer cell. 2020;38(2):167-97.
19. Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med. 2010;49(11):1603-16.
20. Prado-Garcia H, Romero-Garcia S, Aguilar-Cazares D, Meneses-Flores M, Lopez-Gonzalez JS. Tumor-induced CD8+ T-cell dysfunction in lung cancer patients. Clin Develop Immunol. 2012;2012.
21. Bisht G, Rayamajhi S. ZnO nanoparticles: a promising anticancer agent. Nanobiomedicine. 2016;3:9.
22. Horie M, Tabei Y. Role of oxidative stress in nanoparticles toxicity. Free Radic Res. 2021;55(4):331-42.
23. Pandurangan M, Veerappan M, Kim DH. Cytotoxicity of zinc oxide nanoparticles on antioxidant enzyme activities and mRNA expression in the cocultured C2C12 and 3T3-L1 cells. Appl Biochem Biotechnol. 2015;175:1270-80.
24. Hira I, Kumar A, Kumari R, Saini AK, Saini RV. Pectin-guar gum-zinc oxide nanocomposite enhances human lymphocytes cytotoxicity towards lung and breast carcinomas. Mater Sci Eng C Mater Biol Appl. 2018;90:494-503.
25. Fakhroueian Z. Synthesis and in vitro Evaluation of A Green Nanomedicine for the Treatment of Pa-tients with COVID-19 Virus and Lung and Breast Cancers. J Nanotech Smart Mater. 2022;8:1-21.
26. Aston WJ, Hope DE, Nowak AK, Robinson BW, Lake RA, Lesterhuis WJ. A systematic investigation of the maximum tolerated dose of cytotoxic chemotherapy with and without supportive care in mice. BMC cancer. 2017;17(1):1-10.
27. Perše M. Cisplatin mouse models: Treatment, toxicity and translatability. Biomedicines. 2021;9(10):1406.
28. Boland J, Atkinson K, Britton K, Darveniza P, Johnson S, Biggs J. Tissue distribution and toxicity of cyclosporin A in the mouse. Pathology. 1984;16(2):117-23.
29. Hashemi S, Asrar Z, Pourseyedi S, Nadernejad N. Green synthesis of ZnO nanoparticles by Olive (Olea europaea). IET nanobiotechnology. 2016;10(6):400-4.
30. Nalwa K, Thakur A, Sharma N. Synthesis of ZnO nanoparticles and its application in adsorption. Advanced Materials Proceedings. 2017;2(11):697-703.
31. Fakhroueian Z, Vahabpour R, Assmar M, Massiha A, Zahedi A, Esmaeilzadeh P, et al. ZnO Q-dots as a potent therapeutic nanomedicine for in vitro cytotoxicity evaluation of mouth KB44, breast MCF7, colon HT29 and HeLa cancer cell lines, mouse ear swelling tests in vivo and its side effects using the animal model. Artif Cells Nanomed Biotechnol. 2018;46(sup2):96-111.
32. Suganthi K, Rajan K. Temperature induced changes in ZnO–water nanofluid: zeta potential, size distribution and viscosity profiles. Int J Heat Mass Transfer. 2012;55(25-26):7969-80.
33. Fakhroueian Z, Massiha A, Esmaeilzadeh P, Assmar M, Zahedi A, Esmaeilzadeh P, et al. In vivo animal model evaluation of a powerful oral nanomedicine for treating breast cancer in BALB/c mice using 4T1 cell lines without chemotherapy. Adv Nanoparticles. 2022;11(03):73-109.
34. Aftab S, Shah A, Nadhman A, Kurbanoglu S, Ozkan SA, Dionysiou DD, et al. Nanomedicine: An effective tool in cancer therapy. Int J Pharmaceutics. 2018;540(1-2):132-49.
35. Liang C, Xu L, Song G, Liu Z. Emerging nanomedicine approaches fighting tumor metastasis: animal models, metastasis-targeted drug delivery, phototherapy, and immunotherapy. Chem Society Rev. 2016;45(22):6250-69.
36. Gupta R, Polaka S, Rajpoot K, Tekade M, Sharma MC, Tekade RK. Importance of toxicity testing in drug discovery and research. Pharmacokinetics and toxicokinetic considerations: Elsevier; 2022. p. 117-44.
37. Preham O, Pinho FA, Pinto AI, Rani GF, Brown N, Hitchcock IS, et al. CD4+ T cells alter the stromal microenvironment and repress medullary erythropoiesis in murine visceral leishmaniasis. Front Immunol. 2018;9:2958.
38. Lyman JL. Blood urea nitrogen and creatinine. Emerg Med Clin North Am. 1986;4(2):223-33.
39. Lala V, Zubair M, Minter DA. Liver function tests. StatPearls [internet]: StatPearls Publishing; 2022.
40. Aboelella NS, Brandle C, Kim T, Ding Z-C, Zhou G. Oxidative stress in the tumor microenvironment and its relevance to cancer immunotherapy. Cancers. 2021;13(5):986.
41. Peres LAB, Cunha Júnior ADd. Acute nephrotoxicity of cisplatin: molecular mechanisms. Brazilian J Nephrol. 2013;35:332-40.
42. Biswas A, Kar U, Jana NR. Cytotoxicity of ZnO nanoparticles under dark conditions via oxygen vacancy dependent reactive oxygen species generation. Phys Chem Chem Phys. 2022;24(22):13965-75.
43. Rasmussen JW, Martinez E, Louka P, Wingett DG. Zinc oxide nanoparticles for selective destruction of tumor cells and potential for drug delivery applications. Expert Opin Drug Deliv. 2010;7(9):1063-77.
44. Xia T, Kovochich M, Liong M, Madler L, Gilbert B, Shi H, et al. Comparison of the mechanism of toxicity of zinc oxide and cerium oxide nanoparticles based on dissolution and oxidative stress properties. ACS nano. 2008;2(10):2121-34.
45. Penning TM. Genotoxicity of ortho-quinones: reactive oxygen species versus covalent modification. Toxico Res. 2017;6(6):740-54.
46. Di Conza G, Ho P-C, Cubillos-Ruiz JR, Huang SC-C. Control of immune cell function by the unfolded protein response. Nat Rev Immunol. 2023:1-17.
47. Zhang L, Chu W, Zheng L, Li J, Ren Y, Xue L, et al. Zinc oxide nanoparticles from Cyperus rotundus attenuates diabetic retinopathy by inhibiting NLRP3 inflammasome activation in STZ‐induced diabetic rats. J Biochem Mol Toxicol. 2020;34(12):e22583.
48. Liang X, Zhang D, Liu W, Yan Y, Zhou F, Wu W, Yan Z. Reactive oxygen species trigger NF-κB-mediated NLRP3 inflammasome activation induced by zinc oxide nanoparticles in A549 cells. Toxicol Indust Health. 2017;33(10):737-45.
49. Abd El-Khalik SR, Nasif E, Arakeep HM, Rabah H. The prospective ameliorative role of zinc oxide nanoparticles in STZ-induced diabetic nephropathy in rats: Mechanistic targeting of autophagy and regulating Nrf2/TXNIP/NLRP3 inflammasome signaling. Bioll Trace Element Res. 2022:1-11.
50. Morelli AP, Tortelli Jr TC, Pavan ICB, Silva FR, Granato DC, Peruca GF, et al. Metformin impairs cisplatin resistance effects in A549 lung cancer cells through mTOR signaling and other metabolic pathways. Intl J Oncol. 2021;58(6):1-15.
51. Singh Z, Karthigesu IP, Singh P, Rupinder K. Use of malondialdehyde as a biomarker for assessing oxidative stress in different disease pathologies: a review. Iran J Public Health. 2014;43(Supple 3):7-16.
52. Mahmoud SM, Paish EC, Powe DG, Macmillan RD, Grainge MJ, Lee AH, et al. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol. 2011;29(15):1949-55.
53. Li F, Li C, Cai X, Xie Z, Zhou L, Cheng B, et al. The association between CD8+ tumor-infiltrating lymphocytes and the clinical outcome of cancer immunotherapy: A systematic review and meta-analysis. EClinical Medicine. 2021;41.
54. Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen P, Lardon F, Vermorken JB. Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer patients. BMC Immunol. 2010;11(1):1-12.
55. Sakatani T, Kita Y, Fujimoto M, Sano T, Hamada A, Nakamura K, et al. IFN-gamma expression in the tumor microenvironment and CD8-positive tumor-infiltrating lymphocytes as prognostic markers in urothelial cancer patients receiving pembrolizumab. Cancers. 2022;14(2):263.
56. Perez BA, Kim S, Wang M, Karimi AM, Powell C, Li J, et al. Prospective single-arm phase 1 and 2 study: ipilimumab and nivolumab with thoracic radiation therapy after platinum chemotherapy in extensive-stage small cell lung cancer. Int J Radiat Oncol Biol Phys. 2021;109(2):425-35.
57. Madonna G, Ballesteros-Merino C, Feng Z, Bifulco C, Capone M, Giannarelli D, et al. PD-L1 expression with immune-infiltrate evaluation and outcome prediction in melanoma patients treated with ipilimumab. Oncoimmunology. 2018;7(12):e1405206.
58. Arriola E, Wheater M, Lopez MA, Thomas G, Ottensmeier C. Evaluation of immune infiltration in the colonic mucosa of patients with ipilimumab-related colitis. Oncoimmunology. 2016;5(9):e1209615.
59. Di Carlo E, Forni G, Lollini P, Colombo MP, Modesti A, Musiani P. The intriguing role of polymorphonuclear neutrophils in antitumor reactions. Blood. 2001;97(2):339-45.
60. Alessi JV, Ricciuti B, Alden SL, Bertram AA, Lin JJ, Sakhi M, et al. Low peripheral blood derived neutrophil-to-lymphocyte ratio (dNLR) is associated with increased tumor T-cell infiltration and favorable outcomes to first-line pembrolizumab in non-small cell lung cancer. J Immunotherapy Cancer. 2021;9(11).
61. Belikov AV, Schraven B, Simeoni L. T cells and reactive oxygen species. J Biomed Sci. 2015;22:1-11.
62. Kasuga I, Makino S, Kiyokawa H, Katoh H, Ebihara Y, Ohyashiki K. Tumor‐related leukocytosis is linked with poor prognosis in patients with lung carcinoma. Cancer. 2001;92(9):2399-405.
2. Anjum S, Hashim M, Malik SA, Khan M, Lorenzo JM, Abbasi BH, Hano C. Recent advances in zinc oxide nanoparticles (ZnO NPs) for cancer diagnosis, target drug delivery, and treatment. Cancers. 2021;13(18):4570.
3. Jiang J, Pi J, Cai J. The advancing of zinc oxide nanoparticles for biomedical applications. Bioinorg Chem Appl. 2018;2018.
4. Wiesmann N, Tremel W, Brieger J. Zinc oxide nanoparticles for therapeutic purposes in cancer medicine. J Mater Chem B. 2020;8(23):4973-89.
5. Abdolmohammadi MH, Fallahian F, Fakhroueian Z, Kamalian M, Keyhanvar P, M. Harsini F, Shafiekhani A. Application of new ZnO nanoformulation and Ag/Fe/ZnO nanocomposites as water-based nanofluids to consider in vitro cytotoxic effects against MCF-7 breast cancer
cells. Artif Cells Nanomed Biotechnol. 2017;45(8):1769-77.
6. Fakhroueian Z, Vahabpour R, Assmar M, Massiha A, Zahedi A, Esmaeilzadeh P, et al. ZnO Q-Dots as a Potent Therapeutic Nanomedicine for in Vitro Cytotoxicity Evaluation of Mouth KB44, Breast MCF7, Colon HT29 and HeLa Cancer Cell Lines, Mouse Ear Swelling Tests in Vivo and Its Side Effects Using the Animal Model. Artif Cells Nanomed Biotechnol. 2018;46(sup2):96-111.
7. Ghaffari S-B, Sarrafzadeh M-H, Fakhroueian Z, Shahriari S, Khorramizadeh MR. Functionalization of ZnO nanoparticles by 3-mercaptopropionic acid for aqueous curcumin delivery: Synthesis, characterization, and anticancer assessment. Mater Sci Eng C Mater Biol Appl. 2017;79:465-72.
8. Lung cancer 26 June 2023 [Available from: https://www.who.int/news-room/fact-sheets/detail/lung-cancer.
9. Rivera MP, Detterbeck F, Mehta AC. Diagnosis of lung cancer: the guidelines. Chest. 2003;123(1):129S-36S.
10. Collins LG, Haines C, Perkel R, Enck RE. Lung cancer: diagnosis and management. Am Family Fhysician. 2007;75(1):56-63.
11. Fennell D, Summers Y, Cadranel J, Benepal T, Christoph D, Lal R, et al. Cisplatin in the modern era: The backbone of first-line chemotherapy for non-small cell lung cancer. Cancer Treat Rev. 2016;44:42-50.
12. Svaton M, Zemanova M, Zemanova P, Kultan J, Fischer O, Skrickova J, et al. Impact of concomitant medication administered at the time of initiation of nivolumab therapy on outcome in non-small cell lung cancer. Anticancer Res. 2020;40(4):2209-17.
13. Hoy H, Lynch T, Beck M. Surgical treatment of lung cancer. Critical Care Nurs Clin. 2019;31(3):303-13.
14. Inoue M, Sawabata N, Okumura M. Surgical intervention for small-cell lung cancer: what is the surgical role? General thoracic and cardiovascular surgery. 2012;60:401-5.
15. Lackey A, Donington JS, editors. Surgical management of lung cancer. Semin Intervent Radiol. 2013;30(2):133-40.
16. Carbone DP, Gandara DR, Antonia SJ, Zielinski C, Paz-Ares L. Non–small-cell lung cancer: role of the immune system and potential for immunotherapy. J Thoracic Oncol. 2015;10(7):974-84.
17. Caliri AW, Tommasi S, Besaratinia A. Relationships among smoking, oxidative stress, inflammation, macromolecular damage, and cancer. Mut Res Rev Mut Res. 2021;787:108365.
18. Hayes JD, Dinkova-Kostova AT, Tew KD. Oxidative stress in cancer. Cancer cell. 2020;38(2):167-97.
19. Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med. 2010;49(11):1603-16.
20. Prado-Garcia H, Romero-Garcia S, Aguilar-Cazares D, Meneses-Flores M, Lopez-Gonzalez JS. Tumor-induced CD8+ T-cell dysfunction in lung cancer patients. Clin Develop Immunol. 2012;2012.
21. Bisht G, Rayamajhi S. ZnO nanoparticles: a promising anticancer agent. Nanobiomedicine. 2016;3:9.
22. Horie M, Tabei Y. Role of oxidative stress in nanoparticles toxicity. Free Radic Res. 2021;55(4):331-42.
23. Pandurangan M, Veerappan M, Kim DH. Cytotoxicity of zinc oxide nanoparticles on antioxidant enzyme activities and mRNA expression in the cocultured C2C12 and 3T3-L1 cells. Appl Biochem Biotechnol. 2015;175:1270-80.
24. Hira I, Kumar A, Kumari R, Saini AK, Saini RV. Pectin-guar gum-zinc oxide nanocomposite enhances human lymphocytes cytotoxicity towards lung and breast carcinomas. Mater Sci Eng C Mater Biol Appl. 2018;90:494-503.
25. Fakhroueian Z. Synthesis and in vitro Evaluation of A Green Nanomedicine for the Treatment of Pa-tients with COVID-19 Virus and Lung and Breast Cancers. J Nanotech Smart Mater. 2022;8:1-21.
26. Aston WJ, Hope DE, Nowak AK, Robinson BW, Lake RA, Lesterhuis WJ. A systematic investigation of the maximum tolerated dose of cytotoxic chemotherapy with and without supportive care in mice. BMC cancer. 2017;17(1):1-10.
27. Perše M. Cisplatin mouse models: Treatment, toxicity and translatability. Biomedicines. 2021;9(10):1406.
28. Boland J, Atkinson K, Britton K, Darveniza P, Johnson S, Biggs J. Tissue distribution and toxicity of cyclosporin A in the mouse. Pathology. 1984;16(2):117-23.
29. Hashemi S, Asrar Z, Pourseyedi S, Nadernejad N. Green synthesis of ZnO nanoparticles by Olive (Olea europaea). IET nanobiotechnology. 2016;10(6):400-4.
30. Nalwa K, Thakur A, Sharma N. Synthesis of ZnO nanoparticles and its application in adsorption. Advanced Materials Proceedings. 2017;2(11):697-703.
31. Fakhroueian Z, Vahabpour R, Assmar M, Massiha A, Zahedi A, Esmaeilzadeh P, et al. ZnO Q-dots as a potent therapeutic nanomedicine for in vitro cytotoxicity evaluation of mouth KB44, breast MCF7, colon HT29 and HeLa cancer cell lines, mouse ear swelling tests in vivo and its side effects using the animal model. Artif Cells Nanomed Biotechnol. 2018;46(sup2):96-111.
32. Suganthi K, Rajan K. Temperature induced changes in ZnO–water nanofluid: zeta potential, size distribution and viscosity profiles. Int J Heat Mass Transfer. 2012;55(25-26):7969-80.
33. Fakhroueian Z, Massiha A, Esmaeilzadeh P, Assmar M, Zahedi A, Esmaeilzadeh P, et al. In vivo animal model evaluation of a powerful oral nanomedicine for treating breast cancer in BALB/c mice using 4T1 cell lines without chemotherapy. Adv Nanoparticles. 2022;11(03):73-109.
34. Aftab S, Shah A, Nadhman A, Kurbanoglu S, Ozkan SA, Dionysiou DD, et al. Nanomedicine: An effective tool in cancer therapy. Int J Pharmaceutics. 2018;540(1-2):132-49.
35. Liang C, Xu L, Song G, Liu Z. Emerging nanomedicine approaches fighting tumor metastasis: animal models, metastasis-targeted drug delivery, phototherapy, and immunotherapy. Chem Society Rev. 2016;45(22):6250-69.
36. Gupta R, Polaka S, Rajpoot K, Tekade M, Sharma MC, Tekade RK. Importance of toxicity testing in drug discovery and research. Pharmacokinetics and toxicokinetic considerations: Elsevier; 2022. p. 117-44.
37. Preham O, Pinho FA, Pinto AI, Rani GF, Brown N, Hitchcock IS, et al. CD4+ T cells alter the stromal microenvironment and repress medullary erythropoiesis in murine visceral leishmaniasis. Front Immunol. 2018;9:2958.
38. Lyman JL. Blood urea nitrogen and creatinine. Emerg Med Clin North Am. 1986;4(2):223-33.
39. Lala V, Zubair M, Minter DA. Liver function tests. StatPearls [internet]: StatPearls Publishing; 2022.
40. Aboelella NS, Brandle C, Kim T, Ding Z-C, Zhou G. Oxidative stress in the tumor microenvironment and its relevance to cancer immunotherapy. Cancers. 2021;13(5):986.
41. Peres LAB, Cunha Júnior ADd. Acute nephrotoxicity of cisplatin: molecular mechanisms. Brazilian J Nephrol. 2013;35:332-40.
42. Biswas A, Kar U, Jana NR. Cytotoxicity of ZnO nanoparticles under dark conditions via oxygen vacancy dependent reactive oxygen species generation. Phys Chem Chem Phys. 2022;24(22):13965-75.
43. Rasmussen JW, Martinez E, Louka P, Wingett DG. Zinc oxide nanoparticles for selective destruction of tumor cells and potential for drug delivery applications. Expert Opin Drug Deliv. 2010;7(9):1063-77.
44. Xia T, Kovochich M, Liong M, Madler L, Gilbert B, Shi H, et al. Comparison of the mechanism of toxicity of zinc oxide and cerium oxide nanoparticles based on dissolution and oxidative stress properties. ACS nano. 2008;2(10):2121-34.
45. Penning TM. Genotoxicity of ortho-quinones: reactive oxygen species versus covalent modification. Toxico Res. 2017;6(6):740-54.
46. Di Conza G, Ho P-C, Cubillos-Ruiz JR, Huang SC-C. Control of immune cell function by the unfolded protein response. Nat Rev Immunol. 2023:1-17.
47. Zhang L, Chu W, Zheng L, Li J, Ren Y, Xue L, et al. Zinc oxide nanoparticles from Cyperus rotundus attenuates diabetic retinopathy by inhibiting NLRP3 inflammasome activation in STZ‐induced diabetic rats. J Biochem Mol Toxicol. 2020;34(12):e22583.
48. Liang X, Zhang D, Liu W, Yan Y, Zhou F, Wu W, Yan Z. Reactive oxygen species trigger NF-κB-mediated NLRP3 inflammasome activation induced by zinc oxide nanoparticles in A549 cells. Toxicol Indust Health. 2017;33(10):737-45.
49. Abd El-Khalik SR, Nasif E, Arakeep HM, Rabah H. The prospective ameliorative role of zinc oxide nanoparticles in STZ-induced diabetic nephropathy in rats: Mechanistic targeting of autophagy and regulating Nrf2/TXNIP/NLRP3 inflammasome signaling. Bioll Trace Element Res. 2022:1-11.
50. Morelli AP, Tortelli Jr TC, Pavan ICB, Silva FR, Granato DC, Peruca GF, et al. Metformin impairs cisplatin resistance effects in A549 lung cancer cells through mTOR signaling and other metabolic pathways. Intl J Oncol. 2021;58(6):1-15.
51. Singh Z, Karthigesu IP, Singh P, Rupinder K. Use of malondialdehyde as a biomarker for assessing oxidative stress in different disease pathologies: a review. Iran J Public Health. 2014;43(Supple 3):7-16.
52. Mahmoud SM, Paish EC, Powe DG, Macmillan RD, Grainge MJ, Lee AH, et al. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol. 2011;29(15):1949-55.
53. Li F, Li C, Cai X, Xie Z, Zhou L, Cheng B, et al. The association between CD8+ tumor-infiltrating lymphocytes and the clinical outcome of cancer immunotherapy: A systematic review and meta-analysis. EClinical Medicine. 2021;41.
54. Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen P, Lardon F, Vermorken JB. Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer patients. BMC Immunol. 2010;11(1):1-12.
55. Sakatani T, Kita Y, Fujimoto M, Sano T, Hamada A, Nakamura K, et al. IFN-gamma expression in the tumor microenvironment and CD8-positive tumor-infiltrating lymphocytes as prognostic markers in urothelial cancer patients receiving pembrolizumab. Cancers. 2022;14(2):263.
56. Perez BA, Kim S, Wang M, Karimi AM, Powell C, Li J, et al. Prospective single-arm phase 1 and 2 study: ipilimumab and nivolumab with thoracic radiation therapy after platinum chemotherapy in extensive-stage small cell lung cancer. Int J Radiat Oncol Biol Phys. 2021;109(2):425-35.
57. Madonna G, Ballesteros-Merino C, Feng Z, Bifulco C, Capone M, Giannarelli D, et al. PD-L1 expression with immune-infiltrate evaluation and outcome prediction in melanoma patients treated with ipilimumab. Oncoimmunology. 2018;7(12):e1405206.
58. Arriola E, Wheater M, Lopez MA, Thomas G, Ottensmeier C. Evaluation of immune infiltration in the colonic mucosa of patients with ipilimumab-related colitis. Oncoimmunology. 2016;5(9):e1209615.
59. Di Carlo E, Forni G, Lollini P, Colombo MP, Modesti A, Musiani P. The intriguing role of polymorphonuclear neutrophils in antitumor reactions. Blood. 2001;97(2):339-45.
60. Alessi JV, Ricciuti B, Alden SL, Bertram AA, Lin JJ, Sakhi M, et al. Low peripheral blood derived neutrophil-to-lymphocyte ratio (dNLR) is associated with increased tumor T-cell infiltration and favorable outcomes to first-line pembrolizumab in non-small cell lung cancer. J Immunotherapy Cancer. 2021;9(11).
61. Belikov AV, Schraven B, Simeoni L. T cells and reactive oxygen species. J Biomed Sci. 2015;22:1-11.
62. Kasuga I, Makino S, Kiyokawa H, Katoh H, Ebihara Y, Ohyashiki K. Tumor‐related leukocytosis is linked with poor prognosis in patients with lung carcinoma. Cancer. 2001;92(9):2399-405.
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How to Cite
1.
Shekarchian S, Eghtedardoost M, Golshahi H, Behrouzfar H, Fakhroueian Z, Yaraee R. A Novel Nanodrug Suppresses Lung Cancer Growth and Metastasis in C57BL/6 Mouse Model by Altering CD8+ Cell Infiltration and Oxidative Stress. Iran J Allergy Asthma Immunol. 2025;:1-21.
