Modulatory Effects of Metformin Alone and in Combination with Cimetidine and Ibuprofen on T Cell-related Parameters in a Breast Cancer Model
-
Fereshteh Taghipour
,
Omolbanin Oladpour
,
Mohammad Taghi Rezayati
,
Hossain Khorramdelazad
,
Maryam Nemati
,
Zahra Taghipour
,
Javad Masoumi
,
Zuhair Mohammad Hassan
,
Abdollah Jafarzadeh
Abstract
Metformin, cimetidine, and ibuprofen separately exhibit immunomodulatory and anti-tumorigenic effects. Herein, the impacts of metformin alone and in combination with cimetidine/ibuprofen on some Th1- and regulatory T (Treg) cell-related parameters were evaluated using a breast cancer (BC) model.
For establishing the BC model, four groups of Balb/c mice were challenged with the carcinoma cell line. After 11-30 days post-induction, they were treated intraperitoneally (with metformin (200 mg/kg), "metformin plus cimetidine (20 mg/kg)"; "metformin plus ibuprofen (20 mg/kg)", or with all three drugs in mentioned doses. Untreated BC and without tumor mice were enrolled as control groups. On day 31, splenic Th1 and Treg cell frequencies, serum interferon-gamma (IFN-γ), and transforming growth factor-beta (TGF-β) concentration, and intra-tumoral T-bet, TGF-β, and forkhead box protein P3 (FOXP3) expression were measured; using flow cytometry, enzyme-linked immunosorbent assay (ELISA), and real-time-PCR, respectively.
Treatment of the BC mice with metformin alone and in combination with cimetidine and/or ibuprofen enhanced the frequency of Th1 cells, and IFN-γ concentration, while it resulted in a decrease in the frequency of Treg cells, serum TGF-β concentration, and the expression of FOXP3 and TGF-β compared with un-treated BC mice. FOXP3 expression in the metformin-treated group was lower in mice who received combination therapy. Survival rate and body weight were increased, while tumor size and spleen index were reduced in mice treated with metformin alone and its combination with cimetidine and/or ibuprofen. No remarkable differences were found between metformin-treated mice and those who received combination therapies regarding Th1 and Treg cell percentages, TGF-β expression, body weight, tumor size, and spleen index.
The benefits of combinational therapy may be largely attributed to metformin. Immunotherapeutic potentials of metformin in cancers need further considerations.
1. Momenimovahed Z, Salehiniya H. Epidemiological characteristics of and risk factors for breast cancer in the world. Breast cancer. 2019;11(4):151-64.
2. Lukong KE. Understanding breast cancer - The long and winding road. BBA Clin. 2017;7(4):64-77.
3. Sheikhi A, Jafarzadeh A, Kokhaei P, Hojjat-Farsangi M. Whole Tumor Cell Vaccine Adjuvants: Comparing IL-12 to IL-2 and IL-15. Iran J Immunol. 2016;13(3):148-66.
4. Jafarzadeh A, Minaee K, Farsinejad AR, Nemati M, Khosravimashizi A, Daneshvar H, et al. Evaluation of the circulating levels of IL-12 and IL-33 in patients with breast cancer: influences of the tumor stages and cytokine gene polymorphisms. Iran J Basic Med Sci. 2015;18(12):1189-98.
5. Bogen B, Fauskanger M, Haabeth OA, Tveita A. CD4(+) T cells indirectly kill tumor cells via induction of cytotoxic macrophages in mouse models. Cancer Immunol Immunother. 2019;68(11):1865-73.
6. Khalife E, Khodadadi A, Talaeizadeh A, Rahimian L, Nemati M, Jafarzadeh A. Overexpression of Regulatory T Cell-Related Markers (FOXP3, CTLA-4 and GITR) by Peripheral Blood Mononuclear Cells from Patients with Breast Cancer. Asian Pac J Cancer Prev. 2018;19(11):3019-25.
7. Kim JH, Kim BS, Lee SK. Regulatory T Cells in Tumor Microenvironment and Approach for Anticancer Immunotherapy. Immune Netw. 2020;20(1):e4.
8. Marcucci F, Romeo E, Caserta CA, Rumio C, Lefoulon F. Context-Dependent Pharmacological Effects of Metformin on the Immune System. Trends Pharmacol Sci. 2020;41(3):162-71.
9. Saraei P, Asadi I, Kakar MA, Moradi-Kor N. The beneficial effects of metformin on cancer prevention and therapy: a comprehensive review of recent advances. Cancer Manag Res. 2019;11(4):3295-313.
10. Kim K, Yang WH, Jung YS, Cha JH. A new aspect of an old friend: the beneficial effect of metformin on anti-tumor immunity. BMB Rep. 2020;53(10):512-20.
11. Eikawa S, Nishida M, Mizukami S, Yamazaki C, Nakayama E, Udono H. Immune-mediated antitumor effect by type 2 diabetes drug, metformin. Proc Natl Acad Sci U S A. 2015;112(6):1809-14.
12. Oliveras-Ferraros C, Cufí S, Vazquez-Martin A, Menendez OJ, Bosch-Barrera J, Martin-Castillo B, et al. Metformin rescues cell surface major histocompatibility complex class I (MHC-I) deficiency caused by oncogenic transformation. Cell Cycle. 2012;11(5):865-70.
13. Kubecova M, Kolostova K, Pinterova D, Kacprzak G, Bobek V. Cimetidine: an anticancer drug? Eur J Pharm Sci. 2011;42(5):439-44.
14. Kawase J, Ozawa S, Kobayashi K, Imaeda Y, Umemoto S, Matsumoto S, et al. Increase in E-selectin expression in umbilical vein endothelial cells by anticancer drugs and inhibition by cimetidine. Oncol Rep. 2009;22(6):1293-7.
15. Jafarzadeh A, Nemati M, Khorramdelazad H, Hassan ZM. Immunomodulatory properties of cimetidine: Its therapeutic potentials for treatment of immune-related diseases. Int Immunopharmacol. 2019;70:156-66.
16. Pang LY, Hurst EA, Argyle DJ. Cyclooxygenase-2: A Role in Cancer Stem Cell Survival and Repopulation of Cancer Cells during Therapy. Stem Cells Int. 2016;2016:2048731.
17. Misra S, Sharma K. COX-2 signaling and cancer: new players in old arena. Curr Drug Targets. 2014;15(3):347-59.
18. Aranda JV, Salomone F, Valencia GB, Beharry KD. Non-steroidal Anti-inflammatory Drugs in Newborns and Infants. Pediatr Clin North Am. 2017;64(6):1327-40.
19. Pennock ND, Martinson HA, Guo Q, Betts CB, Jindal S, Tsujikawa T, et al. Ibuprofen supports macrophage differentiation, T cell recruitment, and tumor suppression in a model of postpartum breast cancer. J Immunother Cancer. 2018;6(1):98-102.
20. Shen W, Zhang X, Du R, Gao W, Wang J, Bao Y, et al. Ibuprofen mediates histone modification to diminish cancer cell stemness properties via a COX2-dependent manner. Br J Cancer. 2020;23(5):730-41.
21. Malekian S, Rahmati M, Sari S, Kazemimanesh M, Kheirbakhsh R, Muhammadnejad A, et al. Expression of Diverse Angiogenesis Factor in Different Stages of the 4T1 Tumor as a Mouse Model of Triple-Negative Breast Cancer. Adv Pharm Bulletin. 2020;10(2):323-8.
22. Kazemi M, Jafarzadeh A, Nemati M, Taghipour F, Oladpour O, Rezayati MT, et al. Zingerone improves the immune responses in an animal model of breast cancer. J Complement Integr Med. 2021.
23. Li D, Qin Q, Wang XY, Shi HS, Luo M, Guo FC, et al. Intratumoral expression of mature human neutrophil peptide-1 potentiates the therapeutic effect of doxorubicin in a mouse 4T1 breast cancer model. Oncology Rep. 2014;31(3):1287-95.
24. Zaafar DK, Zaitone SA, Moustafa YM. Role of metformin in suppressing 1,2-dimethylhydrazine-induced colon cancer in diabetic and non-diabetic mice: effect on tumor angiogenesis and cell proliferation. PloS One. 2014;9(6):e100562.
25. Jafarzadeh A, Nemati M, Rezayati MT, Ebrahimi M, Hassan ZM. Cimetidine enhances delayed-type hypersensitivity responses and serum interleukin (IL)-2, -10, -12, and IL-17 levels after burn injury in an animal model. J Immunotoxicol. 2013;10(2):201-9.
26. Li W, Xu RJ, Lin ZY, Zhuo GC, Zhang HH. Effects of a cyclooxygenase-1-selective inhibitor in a mouse model of ovarian cancer, administered alone or in combination with ibuprofen, a nonselective cyclooxygenase inhibitor. Med Oncol. 2009;26(2):170-7.
27. Aghili T, Arshami J, Tahmasbi AM, Haghparast AR. Effects of Hypericum perforatum extract on IgG titer, leukocytes subset and spleen index in rats. Avicenna J Phytomed. 2014;4(6):413-9.
28. Yazdi MH, Mahdavi M, Faghfuri E, Faramarzi MA, Sepehrizadeh Z, Hassan ZM, et al. Th1 Immune Response Induction by Biogenic Selenium Nanoparticles in Mice with Breast Cancer: Preliminary Vaccine Model. Iran J Biotechnol. 2015;13(2):1-9.
29. Scharping NE, Menk AV, Whetstone RD, Zeng X, Delgoffe GM. Efficacy of PD-1 Blockade Is Potentiated by Metformin-Induced Reduction of Tumor Hypoxia. Cancer Immunol Res. 2017;5(1):9-16.
30. Xu P, Yin K, Tang X, Tian J, Zhang Y, Ma J, et al. Metformin inhibits the function of granulocytic myeloid-derived suppressor cells in tumor-bearing mice. Biomed Pharmacother. 2019;120(8):109458.
31. Amin D, Richa T, Mollaee M, Zhan T, Tassone P, Johnson J, et al. Metformin Effects on FOXP3(+) and CD8(+) T Cell Infiltrates of Head and Neck Squamous Cell Carcinoma. Laryngoscope. 2020;130(9):E490-e8.
32. Chen GG, Woo PYM, Ng SCP, Wong GKC, Chan DTM, van Hasselt CA, et al. Impact of metformin on immunological markers: Implication in its anti-tumor mechanism. Pharmacol Ther. 2020:107585.
33. Hasmim M, Noman MZ, Messai Y, Bordereaux D, Gros G, Baud V, et al. Cutting edge: Hypoxia-induced Nanog favors the intratumoral infiltration of regulatory T cells and macrophages via direct regulation of TGF-beta1. J Immunol. 2013;191(12):5802-6.
34. Xue J, Li L, Li N, Li F, Qin X, Li T, et al. Metformin suppresses cancer cell growth in endometrial carcinoma by inhibiting PD-L1. Eur J Pharmacol. 2019;859(24):172541.
35. Cha JH, Yang WH, Xia W, Wei Y, Chan LC, Lim SO, et al. Metformin Promotes Antitumor Immunity via Endoplasmic-Reticulum-Associated Degradation of PD-L1. Mol Cell. 2018;71(4):606-20.
36. Saito A, Kitayama J, Horie H, Koinuma K, Ohzawa H, Yamaguchi H, et al. Metformin changes the immune microenvironment of colorectal cancer in patients with type 2 diabetes mellitus. Cancer Sci. 2020;111(11):4012-20.
37. Wang S, Lin Y, Xiong X, Wang L, Guo Y, Chen Y, et al. Low-Dose Metformin Reprograms the Tumor Immune Microenvironment in Human Esophageal Cancer: Results of a Phase II Clinical Trial. Clin Cancer Res. 2020;26(18):4921-32.
38. Tsukioki T, Shien T, Tanaka T, Suzuki Y, Kajihara Y, Hatono M, et al. Influences of preoperative metformin on immunological factors in early breast cancer. Cancer Chemother Pharmacol. 2020;86(1):55-63.
39. Zheng Y, Xu M, Li X, Jia J, Fan K, Lai G. Cimetidine suppresses lung tumor growth in mice through proapoptosis of myeloid-derived suppressor cells. Mol Immunol. 2013;54(1):74-83.
40. Ali AH, Hale L, Yalamanchili B, Ahmed M, Ahmed M, Zhou R, et al. The Effect of Perioperative Cimetidine Administration on Time to Colorectal Cancer Recurrence. Am J Ther. 2018;25(4):e405-e11.
41. Li Y, Yang GL, Yuan HY, Bai DJ, Wang K, Lin CR, et al. Effects of perioperative cimetidine administration on peripheral blood lymphocytes and tumor infiltrating lymphocytes in patients with gastrointestinal cancer: results of a randomized controlled clinical trial. Hepatogastroenterology. 2005;52(62):504-8.
42. Upadhyay A, Amanullah A, Chhangani D, Joshi V, Mishra R, Mishra A. Ibuprofen Induces Mitochondrial-Mediated Apoptosis Through Proteasomal Dysfunction. Mol Neurobiol. 2016;53(10):6968-81.
43. Akrami H, Aminzadeh S, Fallahi H. Inhibitory effect of ibuprofen on tumor survival and angiogenesis in gastric cancer cell. Tumour Biol. 2015;36(5):3237-43.
44. Yao M, Zhou W, Sangha S, Albert A, Chang AJ, Liu TC, et al. Effects of nonselective cyclooxygenase inhibition with low-dose ibuprofen on tumor growth, angiogenesis, metastasis, and survival in a mouse model of colorectal cancer. Clin Cancer Res. 2005;11(4):1618-28.
45. Bittoni MA, Carbone DP, Harris RE. Ibuprofen and fatal lung cancer: A brief report of the prospective results from the Third National Health and Nutrition Examination Survey (NHANES III). Mol Clin Oncol. 2017;6(6):917-20.
2. Lukong KE. Understanding breast cancer - The long and winding road. BBA Clin. 2017;7(4):64-77.
3. Sheikhi A, Jafarzadeh A, Kokhaei P, Hojjat-Farsangi M. Whole Tumor Cell Vaccine Adjuvants: Comparing IL-12 to IL-2 and IL-15. Iran J Immunol. 2016;13(3):148-66.
4. Jafarzadeh A, Minaee K, Farsinejad AR, Nemati M, Khosravimashizi A, Daneshvar H, et al. Evaluation of the circulating levels of IL-12 and IL-33 in patients with breast cancer: influences of the tumor stages and cytokine gene polymorphisms. Iran J Basic Med Sci. 2015;18(12):1189-98.
5. Bogen B, Fauskanger M, Haabeth OA, Tveita A. CD4(+) T cells indirectly kill tumor cells via induction of cytotoxic macrophages in mouse models. Cancer Immunol Immunother. 2019;68(11):1865-73.
6. Khalife E, Khodadadi A, Talaeizadeh A, Rahimian L, Nemati M, Jafarzadeh A. Overexpression of Regulatory T Cell-Related Markers (FOXP3, CTLA-4 and GITR) by Peripheral Blood Mononuclear Cells from Patients with Breast Cancer. Asian Pac J Cancer Prev. 2018;19(11):3019-25.
7. Kim JH, Kim BS, Lee SK. Regulatory T Cells in Tumor Microenvironment and Approach for Anticancer Immunotherapy. Immune Netw. 2020;20(1):e4.
8. Marcucci F, Romeo E, Caserta CA, Rumio C, Lefoulon F. Context-Dependent Pharmacological Effects of Metformin on the Immune System. Trends Pharmacol Sci. 2020;41(3):162-71.
9. Saraei P, Asadi I, Kakar MA, Moradi-Kor N. The beneficial effects of metformin on cancer prevention and therapy: a comprehensive review of recent advances. Cancer Manag Res. 2019;11(4):3295-313.
10. Kim K, Yang WH, Jung YS, Cha JH. A new aspect of an old friend: the beneficial effect of metformin on anti-tumor immunity. BMB Rep. 2020;53(10):512-20.
11. Eikawa S, Nishida M, Mizukami S, Yamazaki C, Nakayama E, Udono H. Immune-mediated antitumor effect by type 2 diabetes drug, metformin. Proc Natl Acad Sci U S A. 2015;112(6):1809-14.
12. Oliveras-Ferraros C, Cufí S, Vazquez-Martin A, Menendez OJ, Bosch-Barrera J, Martin-Castillo B, et al. Metformin rescues cell surface major histocompatibility complex class I (MHC-I) deficiency caused by oncogenic transformation. Cell Cycle. 2012;11(5):865-70.
13. Kubecova M, Kolostova K, Pinterova D, Kacprzak G, Bobek V. Cimetidine: an anticancer drug? Eur J Pharm Sci. 2011;42(5):439-44.
14. Kawase J, Ozawa S, Kobayashi K, Imaeda Y, Umemoto S, Matsumoto S, et al. Increase in E-selectin expression in umbilical vein endothelial cells by anticancer drugs and inhibition by cimetidine. Oncol Rep. 2009;22(6):1293-7.
15. Jafarzadeh A, Nemati M, Khorramdelazad H, Hassan ZM. Immunomodulatory properties of cimetidine: Its therapeutic potentials for treatment of immune-related diseases. Int Immunopharmacol. 2019;70:156-66.
16. Pang LY, Hurst EA, Argyle DJ. Cyclooxygenase-2: A Role in Cancer Stem Cell Survival and Repopulation of Cancer Cells during Therapy. Stem Cells Int. 2016;2016:2048731.
17. Misra S, Sharma K. COX-2 signaling and cancer: new players in old arena. Curr Drug Targets. 2014;15(3):347-59.
18. Aranda JV, Salomone F, Valencia GB, Beharry KD. Non-steroidal Anti-inflammatory Drugs in Newborns and Infants. Pediatr Clin North Am. 2017;64(6):1327-40.
19. Pennock ND, Martinson HA, Guo Q, Betts CB, Jindal S, Tsujikawa T, et al. Ibuprofen supports macrophage differentiation, T cell recruitment, and tumor suppression in a model of postpartum breast cancer. J Immunother Cancer. 2018;6(1):98-102.
20. Shen W, Zhang X, Du R, Gao W, Wang J, Bao Y, et al. Ibuprofen mediates histone modification to diminish cancer cell stemness properties via a COX2-dependent manner. Br J Cancer. 2020;23(5):730-41.
21. Malekian S, Rahmati M, Sari S, Kazemimanesh M, Kheirbakhsh R, Muhammadnejad A, et al. Expression of Diverse Angiogenesis Factor in Different Stages of the 4T1 Tumor as a Mouse Model of Triple-Negative Breast Cancer. Adv Pharm Bulletin. 2020;10(2):323-8.
22. Kazemi M, Jafarzadeh A, Nemati M, Taghipour F, Oladpour O, Rezayati MT, et al. Zingerone improves the immune responses in an animal model of breast cancer. J Complement Integr Med. 2021.
23. Li D, Qin Q, Wang XY, Shi HS, Luo M, Guo FC, et al. Intratumoral expression of mature human neutrophil peptide-1 potentiates the therapeutic effect of doxorubicin in a mouse 4T1 breast cancer model. Oncology Rep. 2014;31(3):1287-95.
24. Zaafar DK, Zaitone SA, Moustafa YM. Role of metformin in suppressing 1,2-dimethylhydrazine-induced colon cancer in diabetic and non-diabetic mice: effect on tumor angiogenesis and cell proliferation. PloS One. 2014;9(6):e100562.
25. Jafarzadeh A, Nemati M, Rezayati MT, Ebrahimi M, Hassan ZM. Cimetidine enhances delayed-type hypersensitivity responses and serum interleukin (IL)-2, -10, -12, and IL-17 levels after burn injury in an animal model. J Immunotoxicol. 2013;10(2):201-9.
26. Li W, Xu RJ, Lin ZY, Zhuo GC, Zhang HH. Effects of a cyclooxygenase-1-selective inhibitor in a mouse model of ovarian cancer, administered alone or in combination with ibuprofen, a nonselective cyclooxygenase inhibitor. Med Oncol. 2009;26(2):170-7.
27. Aghili T, Arshami J, Tahmasbi AM, Haghparast AR. Effects of Hypericum perforatum extract on IgG titer, leukocytes subset and spleen index in rats. Avicenna J Phytomed. 2014;4(6):413-9.
28. Yazdi MH, Mahdavi M, Faghfuri E, Faramarzi MA, Sepehrizadeh Z, Hassan ZM, et al. Th1 Immune Response Induction by Biogenic Selenium Nanoparticles in Mice with Breast Cancer: Preliminary Vaccine Model. Iran J Biotechnol. 2015;13(2):1-9.
29. Scharping NE, Menk AV, Whetstone RD, Zeng X, Delgoffe GM. Efficacy of PD-1 Blockade Is Potentiated by Metformin-Induced Reduction of Tumor Hypoxia. Cancer Immunol Res. 2017;5(1):9-16.
30. Xu P, Yin K, Tang X, Tian J, Zhang Y, Ma J, et al. Metformin inhibits the function of granulocytic myeloid-derived suppressor cells in tumor-bearing mice. Biomed Pharmacother. 2019;120(8):109458.
31. Amin D, Richa T, Mollaee M, Zhan T, Tassone P, Johnson J, et al. Metformin Effects on FOXP3(+) and CD8(+) T Cell Infiltrates of Head and Neck Squamous Cell Carcinoma. Laryngoscope. 2020;130(9):E490-e8.
32. Chen GG, Woo PYM, Ng SCP, Wong GKC, Chan DTM, van Hasselt CA, et al. Impact of metformin on immunological markers: Implication in its anti-tumor mechanism. Pharmacol Ther. 2020:107585.
33. Hasmim M, Noman MZ, Messai Y, Bordereaux D, Gros G, Baud V, et al. Cutting edge: Hypoxia-induced Nanog favors the intratumoral infiltration of regulatory T cells and macrophages via direct regulation of TGF-beta1. J Immunol. 2013;191(12):5802-6.
34. Xue J, Li L, Li N, Li F, Qin X, Li T, et al. Metformin suppresses cancer cell growth in endometrial carcinoma by inhibiting PD-L1. Eur J Pharmacol. 2019;859(24):172541.
35. Cha JH, Yang WH, Xia W, Wei Y, Chan LC, Lim SO, et al. Metformin Promotes Antitumor Immunity via Endoplasmic-Reticulum-Associated Degradation of PD-L1. Mol Cell. 2018;71(4):606-20.
36. Saito A, Kitayama J, Horie H, Koinuma K, Ohzawa H, Yamaguchi H, et al. Metformin changes the immune microenvironment of colorectal cancer in patients with type 2 diabetes mellitus. Cancer Sci. 2020;111(11):4012-20.
37. Wang S, Lin Y, Xiong X, Wang L, Guo Y, Chen Y, et al. Low-Dose Metformin Reprograms the Tumor Immune Microenvironment in Human Esophageal Cancer: Results of a Phase II Clinical Trial. Clin Cancer Res. 2020;26(18):4921-32.
38. Tsukioki T, Shien T, Tanaka T, Suzuki Y, Kajihara Y, Hatono M, et al. Influences of preoperative metformin on immunological factors in early breast cancer. Cancer Chemother Pharmacol. 2020;86(1):55-63.
39. Zheng Y, Xu M, Li X, Jia J, Fan K, Lai G. Cimetidine suppresses lung tumor growth in mice through proapoptosis of myeloid-derived suppressor cells. Mol Immunol. 2013;54(1):74-83.
40. Ali AH, Hale L, Yalamanchili B, Ahmed M, Ahmed M, Zhou R, et al. The Effect of Perioperative Cimetidine Administration on Time to Colorectal Cancer Recurrence. Am J Ther. 2018;25(4):e405-e11.
41. Li Y, Yang GL, Yuan HY, Bai DJ, Wang K, Lin CR, et al. Effects of perioperative cimetidine administration on peripheral blood lymphocytes and tumor infiltrating lymphocytes in patients with gastrointestinal cancer: results of a randomized controlled clinical trial. Hepatogastroenterology. 2005;52(62):504-8.
42. Upadhyay A, Amanullah A, Chhangani D, Joshi V, Mishra R, Mishra A. Ibuprofen Induces Mitochondrial-Mediated Apoptosis Through Proteasomal Dysfunction. Mol Neurobiol. 2016;53(10):6968-81.
43. Akrami H, Aminzadeh S, Fallahi H. Inhibitory effect of ibuprofen on tumor survival and angiogenesis in gastric cancer cell. Tumour Biol. 2015;36(5):3237-43.
44. Yao M, Zhou W, Sangha S, Albert A, Chang AJ, Liu TC, et al. Effects of nonselective cyclooxygenase inhibition with low-dose ibuprofen on tumor growth, angiogenesis, metastasis, and survival in a mouse model of colorectal cancer. Clin Cancer Res. 2005;11(4):1618-28.
45. Bittoni MA, Carbone DP, Harris RE. Ibuprofen and fatal lung cancer: A brief report of the prospective results from the Third National Health and Nutrition Examination Survey (NHANES III). Mol Clin Oncol. 2017;6(6):917-20.
| Files | ||
| Issue | Vol 20 No 5 (2021) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v20i5.7410 | |
| Keywords | ||
| Breast neoplasms Cimetidine Ibuprofen Metformin Mice T-lymphocytes | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Taghipour F, Oladpour O, Rezayati MT, Khorramdelazad H, Nemati M, Taghipour Z, Masoumi J, Hassan ZM, Jafarzadeh A. Modulatory Effects of Metformin Alone and in Combination with Cimetidine and Ibuprofen on T Cell-related Parameters in a Breast Cancer Model. Iran J Allergy Asthma Immunol. 2021;20(5):600-613.
