Does Valsartan Affect the Cytotoxicity of Doxorubicin When Used as a Cardioprotective Drug Against Doxorubicin-Induced Cardiotoxicity ?
Main Article Content
Keywords
Doxorubicin, Valsartan, cardiotoxicity, synergism, angiotensin receptor blockers
Abstract
Background: Doxorubicin is widely used as a chemotherapeutic drug. It has several serious side effects, including cardiotoxicity. Valsartan is an angiotensin II receptor blocker that plays a cardioprotective role against doxorubicin-induced cardiotoxicity. Aim: The aim of our study is to evaluate whether the combination of valsartan and doxorubicin affects the therapeutic efficacy of doxorubicin in treating cancer using an in vitro breast cancer cell line (MCF-7). Methods: Different concentrations of doxorubicin, valsartan, and their combination were tested to detect their cytotoxic effects on the cell line using MTT colorimetric assay method. Three duplicates of each concentration and control were made. Results: Valsartan had a mild cytotoxic effect only at higher concentrations, with an estimated IC50 value of 125.8 μg/ml, while doxorubicin, had more potent cytotoxicity, with an estimated IC50 value of 87.43 μg/ml. The IC50 of the doxorubicin-valsartan combination was lower than the IC50 of both drugs when used alone, with a DRI more than 1 (3.56) and an IAI less than 1 (0.94). Conclusions: There is synergism between doxorubicin and valsartan on MCF-7 breast cancer cells, suggesting a potential role for the combination in cancer treatment. The combination induces cytotoxicity in lower doses than when doxorubicin used alone.
References
1. Mattioli R, Ilari A, Colotti B, Mosca L, Fazi F, Colotti G. Doxorubicin and other anthracyclines in cancers: Activity, chemoresistance, and its overcoming. Mol Aspects Med. 2023 Oct;93:101205. doi: 10.1016/j.mam.2023.101205.
2. Sritharan S, Sivalingam N. A comprehensive review on the time-tested anticancer drug doxorubicin. Life Sci. 2021 Aug 1;278:119527. doi: 10.1016/j.lfs.2021.119527.
3. Tacar O, Sriamornsak P, Dass CR. Doxorubicin: An update on anticancer molecular action, toxicity, and novel drug delivery systems. J Pharm Pharmacol. 2013 Feb;65(2):157-70. doi: 10.1111/j.2042-7158.2012.01567.x.
4. Renu K, V G A, P B TP, Arunachalam S. Molecular mechanism of doxorubicin-induced cardiomyopathy - An update. Eur J Pharmacol. 2018 Jan 5;818:241-53. doi: 10.1016/j.ejphar.2017.10.043.
5. Sheibani M, Azizi Y, Shayan M, Nezamoleslami S, Eslami F, Farjoo MH, et al. Doxorubicin-Induced Cardiotoxicity: An Overview of Pre-clinical Therapeutic Approaches. Cardiovasc Toxicol. 2022 Apr;22(4):292-310. doi: 10.1007/s12012-022-09721-1.
6. Hoeger CW, Turissini C, Asnani AH. Doxorubicin cardiotoxicity: Pathophysiology Updates. Curr Treat Options Cardiovasc Med. 2020;22:1-17. doi: 10.1007/s11936-020-00842-w.
7. Linders AN, Dias IB, López Fernández T, Tocchetti CG, Bomer N, Van der Meer P, et al. A review of the pathophysiological mechanisms of doxorubicin-induced cardiotoxicity and aging. NPJ Aging. 2024 Jan 23;10(1):9. doi: 10.1038/s41514-024-00135-7.
8. Vitale R, Marzocco S, Popolo A. Role of oxidative stress and inflammation in Doxorubicin-Induced Cardiotoxicity: A brief account. Int J Mol Sci. 2024 Jul 8;25(13):7477. doi: 10.3390/ijms25137477.
9. Potamitis C, Chatzigeorgiou P, Siapi E, Viras K, Mavromoustakos T, Hodzic A, et al. Interactions of the AT1 antagonist valsartan with dipalmitoyl-phosphatidylcholine bilayers. Biochim Biophys Acta. 2011 Jun;1808(6):1753-63. doi: 10.1016/j.bbamem.2011.02.002.
10. Accetto R, Chazova IY, Sirenko Y, Vincelj J, Widimsky J Jr, Barbič-Žagar B. The efficacy and safety of valsartan and the combination of valsartan and hydrochlorothiazide in the treatment of patients with mild to moderate arterial hypertension - the VICTORY trial. Kardiol Pol. 2017;75(1):55-64. doi: 10.5603/KP.a2016.0135.
11. Morrow DA, Velazquez EJ, Desai AS, DeVore AD, Lepage S, Park JG, et al. Sacubitril/valsartan in Patients Hospitalized With Decompensated Heart Failure. J Am Coll Cardiol. 2024 Mar 26;83(12):1123-32. doi: 10.1016/j.jacc.2024.01.027.
12. Chatur S, Beldhuis IE, Claggett BL, McCausland FR, Neuen BL, Desai AS, et al. Sacubitril/valsartan in patients with heart failure and deterioration in eGFR to <30 mL/min/1.73 m². JACC Heart Fail. 2024 Oct;12(10):1692-703. doi: 10.1016/j.jchf.2024.03.014.
13. Alhazzani K, Alotaibi MR, Alotaibi FN, Aljerian K, As Sobeai HM, Alhoshani AR, et al. Protective effect of valsartan against doxorubicin-induced cardiotoxicity: Histopathology and metabolomics in vivo study. J Biochem Mol Toxicol. 2021 Sep;35(9):e22842. doi: 10.1002/jbt.22842.
14. Cheng D, Chen L, Tu W, Wang H, Wang Q, Meng L, et al. Protective effects of valsartan administration on doxorubicin induced myocardial injury in rats and the role of oxidative stress and NOX2/NOX4 signaling. Mol Med Rep. 2020 Nov;22(5):4151-62. doi: 10.3892/mmr.2020.11521.
15. He Y, Zhu Q, Chen M, Huang Q, Wang W, Li Q, et al. The changing 50% inhibitory concentration (IC50) of cisplatin: A pilot study on the artifacts of the MTT assay and the precise measurement of density-dependent chemoresistance in ovarian cancer. Oncotarget. 2016 Oct 25;7(43):70803-21. doi: 10.18632/oncotarget.12223.
16. Freshney RI. Subculture and cell lines. Culture of Animal Cells: A Manual of Basic Technique. 2005 Oct 14.
17. Chang TT, Chou TC. Rational approach to the clinical protocol design for drug combinations: A review. Acta Paediatr Taiwan. 2000 Nov-Dec;41(6):294-302. PMID: 11198934.
18. Zhang N, Fu JN, Chou TC. Synergistic combination of microtubule-targeting anticancer fludelone with cytoprotective panaxytriol derived from Panax ginseng against MX-1 cells in vitro: Experimental design and data analysis using the combination index method. Am J Cancer Res. 2015 Dec 15;6(1):97-104.
19. Martyniak A, Tomasik PJ. A new perspective on the renin-angiotensin system. Diagnostics (Basel). 2022 Dec 21;13(1):16. doi: 10.3390/diagnostics13010016.
20. Vargas Vargas RA, Varela Millán JM, Fajardo Bonilla E. Renin-angiotensin system: Basic and clinical aspects - A general perspective. Endocrinol Diabetes Nutr (Engl Ed). 2022 Jan;69(1):52-62. doi: 10.1016/j.endien.2022.01.005.
21. Kambayashi Y, Bardhan S, Takahashi K, Tsuzuki S, Inui H, Hamakubo T, et al. Molecular cloning of a novel angiotensin II receptor isoform involved in phosphotyrosine phosphatase inhibition. J Biol Chem. 1993 Nov 25;268(33):24543-6.
22. Mukoyama M, Nakajima M, Horiuchi M, Sasamura H, Pratt RE, Dzau VJ. Expression cloning of type 2 angiotensin II receptor reveals a unique class of seven-transmembrane receptors. J Biol Chem. 1993 Nov 25;268(33):24539-42. PMID: 8227010.
23. Acconcia F. The network of Angiotensin Receptors in breast cancer. Cells. 2020 May 27;9(6):1336. doi: 10.3390/cells9061336.
24. Delforce SJ, Lumbers ER, Corbisier de Meaultsart C, Wang Y, Proietto A, Otton G, et al. Expression of renin-angiotensin system (RAS) components in endometrial cancer. Endocr Connect. 2017 Jan;6(1):9-19. doi: 10.1530/EC-16-0082.
25. Matavelli LC, Siragy HM. AT2 receptor activities and pathophysiological implications. J Cardiovasc Pharmacol. 2015 Mar;65(3):226-32. doi: 10.1097/FJC.0000000000000208.
26. Namsolleck P, Recarti C, Foulquier S, Steckelings UM, Unger T. AT(2) receptor and tissue injury: Therapeutic implications. Curr Hypertens Rep. 2014 Feb;16(2):416. doi: 10.1007/s11906-013-0416-6.
27. Laghlam D, Jozwiak M, Nguyen LS. Renin-angiotensin-aldosterone system and immunomodulation: A State-of-the-Art Review. Cells. 2021 Jul 13;10(7):1767. doi: 10.3390/cells10071767.
28. Zhao Y, Wang H, Li X, Cao M, Lu H, Meng Q, et al. Ang II-AT1R increases cell migration through PI3K/AKT and NF-κB pathways in breast cancer. J Cell Physiol. 2014 Nov;229(11):1855-62. doi: 10.1002/jcp.24639.
29. Zhao Y, Chen X, Cai L, Yang Y, Sui G, Fu S. Angiotensin II/angiotensin II type I receptor (AT1R) signaling promotes MCF-7 breast cancer cell survival via the PI3-kinase/Akt pathway. J Cell Physiol. 2010 Oct;225(1):168-73. doi: 10.1002/jcp.22209.
30. Nouet S, Nahmias C. Signal transduction from the angiotensin II AT2 receptor. Trends Endocrinol Metab. 2000 Jan-Feb;11(1):1-6. doi: 10.1016/s1043-2760(99)00205-2.
31. Puddefoot JR, Udeozo UK, Barker S, Vinson GP. The role of angiotensin II in the regulation of breast cancer cell adhesion and invasion. Endocr Relat Cancer. 2006 Sep;13(3):895-903. doi: 10.1677/erc.1.01136.
32. Xie G, Cheng T, Lin J, Zhang L, Zheng J, Liu Y, et al. Local angiotensin II contributes to tumor resistance to checkpoint immunotherapy. J Immunother Cancer. 2018 Sep 12;6(1):88. doi: 10.1186/s40425-018-0401-3.
33. Haznedaroglu IC, Malkan UY. Local bone marrow renin-angiotensin system in the genesis of leukemia and other malignancies. Eur Rev Med Pharmacol Sci. 2016 Oct;20(19):4089-4111. PMID: 27775788.
34. Hanif K, Bid HK, Konwar R. Reinventing the ACE inhibitors: Some old and new implications of ACE inhibition. Hypertens Res. 2010 Jan;33(1):11-21. doi: 10.1038/hr.2009.184.
35. Deshayes F, Nahmias C. Angiotensin receptors: A new role in cancer? Trends Endocrinol Metab. 2005 Sep;16(7):293-9. doi: 10.1016/j.tem.2005.07.009.
36. Ohashi H, Takagi H, Oh H, Suzuma K, Suzuma I, Miyamoto N, et al. Phosphatidylinositol 3-kinase/Akt regulates angiotensin II-induced inhibition of apoptosis in microvascular endothelial cells by governing survivin expression and suppression of caspase-3 activity. Circ Res. 2004 Apr 2;94(6):785-93. doi: 10.1161/01.RES.0000121103.03275.EC.
37. Uemura H, Nakaigawa N, Ishiguro H, Kubota Y. Antiproliferative efficacy of angiotensin II receptor blockers in prostate cancer. Curr Cancer Drug Targets. 2005 Aug;5(5):307-23. doi: 10.2174/1568009054629663.
38. Anandanadesan R, Gong Q, Chipitsyna G, Witkiewicz A, Yeo CJ, Arafat HA, et al. Angiotensin II induces vascular endothelial growth factor in pancreatic cancer cells through an angiotensin II type 1 receptor and ERK1/2 signaling. J Gastrointest Surg. 2008 Jan;12(1):57-66. doi: 10.1007/s11605-007-0403-9.
39. Kosugi M, Miyajima A, Kikuchi E, Kosaka T, Horiguchi Y, Murai M. Effect of angiotensin II type 1 receptor antagonist on tumor growth and angiogenesis in a xenograft model of human bladder cancer. Hum Cell. 2007 Feb;20(1):1-9. doi: 10.1111/j.1749-0774.2007.00025.x.
40. Yang X, Zhu MJ, Sreejayan N, Ren J, Du M. Angiotensin II promotes smooth muscle cell proliferation and migration through the release of heparin-binding epidermal growth factor and activation of the EGF-receptor pathway. Mol Cells. 2005 Oct 31;20(2):263-70.
41. Kortylewski M, Kujawski M, Wang T, Wei S, Zhang S, et al. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med. 2005 Dec;11(12):1314-21. doi: 10.1038/nm1325.
42. Rasha F, Ramalingam L, Gollahon L, Rahman RL, Rahman SM, Menikdiwela K, et al. Mechanisms linking the renin-angiotensin system, obesity, and breast cancer. Endocr Relat Cancer. 2019 Dec 1;26(12):R653-72. doi: 10.1530/ERC-19-0314.
43. Takiguchi T, Takahashi-Yanaga F, Ishikane S, Tetsuo F, Hosoda H, Arioka M, et al. Angiotensin II promotes primary tumor growth and metastasis formation of murine TNBC 4T1 cells through the fibroblasts surrounding cancer cells. Eur J Pharmacol. 2021 Oct 15;909:174415. doi: 10.1016/j.ejphar.2021.174415.
44. Chauhan VP, Martin JD, Liu H, Lacorre DA, Jain SR, Kozin SV, et al. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumor blood vessels. Nat Commun. 2013;4:2516. doi: 10.1038/ncomms3516.
45. Rhodes DR, Ateeq B, Cao Q, Tomlins SA, Mehra R, Laxman B, et al. AGTR1 overexpression defines a subset of breast cancer and confers sensitivity to losartan, an AGTR1 antagonist. Proc Natl Acad Sci U S A. 2009 Jun 23;106(25):10284-9. doi: 10.1073/pnas.0900351106.
46. Woo Y, Jung YJ. Angiotensin II receptor blockers induce autophagy in prostate cancer cells. Oncol Lett. 2017 May;13(5):3579-85. doi: 10.3892/ol.2017.5872.
47. Sun H, Li T, Zhuang R, Cai W, Zheng Y. Do renin-angiotensin system inhibitors influence the recurrence, metastasis, and survival in cancer patients? Evidence from a meta-analysis including 55 studies. Medicine (Baltimore). 2017 Mar;96(13):e6394. doi: 10.1097/MD.0000000000006394.
48. Li XY, Sun JF, Hu SQ. The renin-angiotensin system blockers as adjunctive therapy for cancer: A meta-analysis of survival outcomes. Eur Rev Med Pharmacol Sci. 2017 Mar;21(6):1375-83. PMID: 28387887.
2. Sritharan S, Sivalingam N. A comprehensive review on the time-tested anticancer drug doxorubicin. Life Sci. 2021 Aug 1;278:119527. doi: 10.1016/j.lfs.2021.119527.
3. Tacar O, Sriamornsak P, Dass CR. Doxorubicin: An update on anticancer molecular action, toxicity, and novel drug delivery systems. J Pharm Pharmacol. 2013 Feb;65(2):157-70. doi: 10.1111/j.2042-7158.2012.01567.x.
4. Renu K, V G A, P B TP, Arunachalam S. Molecular mechanism of doxorubicin-induced cardiomyopathy - An update. Eur J Pharmacol. 2018 Jan 5;818:241-53. doi: 10.1016/j.ejphar.2017.10.043.
5. Sheibani M, Azizi Y, Shayan M, Nezamoleslami S, Eslami F, Farjoo MH, et al. Doxorubicin-Induced Cardiotoxicity: An Overview of Pre-clinical Therapeutic Approaches. Cardiovasc Toxicol. 2022 Apr;22(4):292-310. doi: 10.1007/s12012-022-09721-1.
6. Hoeger CW, Turissini C, Asnani AH. Doxorubicin cardiotoxicity: Pathophysiology Updates. Curr Treat Options Cardiovasc Med. 2020;22:1-17. doi: 10.1007/s11936-020-00842-w.
7. Linders AN, Dias IB, López Fernández T, Tocchetti CG, Bomer N, Van der Meer P, et al. A review of the pathophysiological mechanisms of doxorubicin-induced cardiotoxicity and aging. NPJ Aging. 2024 Jan 23;10(1):9. doi: 10.1038/s41514-024-00135-7.
8. Vitale R, Marzocco S, Popolo A. Role of oxidative stress and inflammation in Doxorubicin-Induced Cardiotoxicity: A brief account. Int J Mol Sci. 2024 Jul 8;25(13):7477. doi: 10.3390/ijms25137477.
9. Potamitis C, Chatzigeorgiou P, Siapi E, Viras K, Mavromoustakos T, Hodzic A, et al. Interactions of the AT1 antagonist valsartan with dipalmitoyl-phosphatidylcholine bilayers. Biochim Biophys Acta. 2011 Jun;1808(6):1753-63. doi: 10.1016/j.bbamem.2011.02.002.
10. Accetto R, Chazova IY, Sirenko Y, Vincelj J, Widimsky J Jr, Barbič-Žagar B. The efficacy and safety of valsartan and the combination of valsartan and hydrochlorothiazide in the treatment of patients with mild to moderate arterial hypertension - the VICTORY trial. Kardiol Pol. 2017;75(1):55-64. doi: 10.5603/KP.a2016.0135.
11. Morrow DA, Velazquez EJ, Desai AS, DeVore AD, Lepage S, Park JG, et al. Sacubitril/valsartan in Patients Hospitalized With Decompensated Heart Failure. J Am Coll Cardiol. 2024 Mar 26;83(12):1123-32. doi: 10.1016/j.jacc.2024.01.027.
12. Chatur S, Beldhuis IE, Claggett BL, McCausland FR, Neuen BL, Desai AS, et al. Sacubitril/valsartan in patients with heart failure and deterioration in eGFR to <30 mL/min/1.73 m². JACC Heart Fail. 2024 Oct;12(10):1692-703. doi: 10.1016/j.jchf.2024.03.014.
13. Alhazzani K, Alotaibi MR, Alotaibi FN, Aljerian K, As Sobeai HM, Alhoshani AR, et al. Protective effect of valsartan against doxorubicin-induced cardiotoxicity: Histopathology and metabolomics in vivo study. J Biochem Mol Toxicol. 2021 Sep;35(9):e22842. doi: 10.1002/jbt.22842.
14. Cheng D, Chen L, Tu W, Wang H, Wang Q, Meng L, et al. Protective effects of valsartan administration on doxorubicin induced myocardial injury in rats and the role of oxidative stress and NOX2/NOX4 signaling. Mol Med Rep. 2020 Nov;22(5):4151-62. doi: 10.3892/mmr.2020.11521.
15. He Y, Zhu Q, Chen M, Huang Q, Wang W, Li Q, et al. The changing 50% inhibitory concentration (IC50) of cisplatin: A pilot study on the artifacts of the MTT assay and the precise measurement of density-dependent chemoresistance in ovarian cancer. Oncotarget. 2016 Oct 25;7(43):70803-21. doi: 10.18632/oncotarget.12223.
16. Freshney RI. Subculture and cell lines. Culture of Animal Cells: A Manual of Basic Technique. 2005 Oct 14.
17. Chang TT, Chou TC. Rational approach to the clinical protocol design for drug combinations: A review. Acta Paediatr Taiwan. 2000 Nov-Dec;41(6):294-302. PMID: 11198934.
18. Zhang N, Fu JN, Chou TC. Synergistic combination of microtubule-targeting anticancer fludelone with cytoprotective panaxytriol derived from Panax ginseng against MX-1 cells in vitro: Experimental design and data analysis using the combination index method. Am J Cancer Res. 2015 Dec 15;6(1):97-104.
19. Martyniak A, Tomasik PJ. A new perspective on the renin-angiotensin system. Diagnostics (Basel). 2022 Dec 21;13(1):16. doi: 10.3390/diagnostics13010016.
20. Vargas Vargas RA, Varela Millán JM, Fajardo Bonilla E. Renin-angiotensin system: Basic and clinical aspects - A general perspective. Endocrinol Diabetes Nutr (Engl Ed). 2022 Jan;69(1):52-62. doi: 10.1016/j.endien.2022.01.005.
21. Kambayashi Y, Bardhan S, Takahashi K, Tsuzuki S, Inui H, Hamakubo T, et al. Molecular cloning of a novel angiotensin II receptor isoform involved in phosphotyrosine phosphatase inhibition. J Biol Chem. 1993 Nov 25;268(33):24543-6.
22. Mukoyama M, Nakajima M, Horiuchi M, Sasamura H, Pratt RE, Dzau VJ. Expression cloning of type 2 angiotensin II receptor reveals a unique class of seven-transmembrane receptors. J Biol Chem. 1993 Nov 25;268(33):24539-42. PMID: 8227010.
23. Acconcia F. The network of Angiotensin Receptors in breast cancer. Cells. 2020 May 27;9(6):1336. doi: 10.3390/cells9061336.
24. Delforce SJ, Lumbers ER, Corbisier de Meaultsart C, Wang Y, Proietto A, Otton G, et al. Expression of renin-angiotensin system (RAS) components in endometrial cancer. Endocr Connect. 2017 Jan;6(1):9-19. doi: 10.1530/EC-16-0082.
25. Matavelli LC, Siragy HM. AT2 receptor activities and pathophysiological implications. J Cardiovasc Pharmacol. 2015 Mar;65(3):226-32. doi: 10.1097/FJC.0000000000000208.
26. Namsolleck P, Recarti C, Foulquier S, Steckelings UM, Unger T. AT(2) receptor and tissue injury: Therapeutic implications. Curr Hypertens Rep. 2014 Feb;16(2):416. doi: 10.1007/s11906-013-0416-6.
27. Laghlam D, Jozwiak M, Nguyen LS. Renin-angiotensin-aldosterone system and immunomodulation: A State-of-the-Art Review. Cells. 2021 Jul 13;10(7):1767. doi: 10.3390/cells10071767.
28. Zhao Y, Wang H, Li X, Cao M, Lu H, Meng Q, et al. Ang II-AT1R increases cell migration through PI3K/AKT and NF-κB pathways in breast cancer. J Cell Physiol. 2014 Nov;229(11):1855-62. doi: 10.1002/jcp.24639.
29. Zhao Y, Chen X, Cai L, Yang Y, Sui G, Fu S. Angiotensin II/angiotensin II type I receptor (AT1R) signaling promotes MCF-7 breast cancer cell survival via the PI3-kinase/Akt pathway. J Cell Physiol. 2010 Oct;225(1):168-73. doi: 10.1002/jcp.22209.
30. Nouet S, Nahmias C. Signal transduction from the angiotensin II AT2 receptor. Trends Endocrinol Metab. 2000 Jan-Feb;11(1):1-6. doi: 10.1016/s1043-2760(99)00205-2.
31. Puddefoot JR, Udeozo UK, Barker S, Vinson GP. The role of angiotensin II in the regulation of breast cancer cell adhesion and invasion. Endocr Relat Cancer. 2006 Sep;13(3):895-903. doi: 10.1677/erc.1.01136.
32. Xie G, Cheng T, Lin J, Zhang L, Zheng J, Liu Y, et al. Local angiotensin II contributes to tumor resistance to checkpoint immunotherapy. J Immunother Cancer. 2018 Sep 12;6(1):88. doi: 10.1186/s40425-018-0401-3.
33. Haznedaroglu IC, Malkan UY. Local bone marrow renin-angiotensin system in the genesis of leukemia and other malignancies. Eur Rev Med Pharmacol Sci. 2016 Oct;20(19):4089-4111. PMID: 27775788.
34. Hanif K, Bid HK, Konwar R. Reinventing the ACE inhibitors: Some old and new implications of ACE inhibition. Hypertens Res. 2010 Jan;33(1):11-21. doi: 10.1038/hr.2009.184.
35. Deshayes F, Nahmias C. Angiotensin receptors: A new role in cancer? Trends Endocrinol Metab. 2005 Sep;16(7):293-9. doi: 10.1016/j.tem.2005.07.009.
36. Ohashi H, Takagi H, Oh H, Suzuma K, Suzuma I, Miyamoto N, et al. Phosphatidylinositol 3-kinase/Akt regulates angiotensin II-induced inhibition of apoptosis in microvascular endothelial cells by governing survivin expression and suppression of caspase-3 activity. Circ Res. 2004 Apr 2;94(6):785-93. doi: 10.1161/01.RES.0000121103.03275.EC.
37. Uemura H, Nakaigawa N, Ishiguro H, Kubota Y. Antiproliferative efficacy of angiotensin II receptor blockers in prostate cancer. Curr Cancer Drug Targets. 2005 Aug;5(5):307-23. doi: 10.2174/1568009054629663.
38. Anandanadesan R, Gong Q, Chipitsyna G, Witkiewicz A, Yeo CJ, Arafat HA, et al. Angiotensin II induces vascular endothelial growth factor in pancreatic cancer cells through an angiotensin II type 1 receptor and ERK1/2 signaling. J Gastrointest Surg. 2008 Jan;12(1):57-66. doi: 10.1007/s11605-007-0403-9.
39. Kosugi M, Miyajima A, Kikuchi E, Kosaka T, Horiguchi Y, Murai M. Effect of angiotensin II type 1 receptor antagonist on tumor growth and angiogenesis in a xenograft model of human bladder cancer. Hum Cell. 2007 Feb;20(1):1-9. doi: 10.1111/j.1749-0774.2007.00025.x.
40. Yang X, Zhu MJ, Sreejayan N, Ren J, Du M. Angiotensin II promotes smooth muscle cell proliferation and migration through the release of heparin-binding epidermal growth factor and activation of the EGF-receptor pathway. Mol Cells. 2005 Oct 31;20(2):263-70.
41. Kortylewski M, Kujawski M, Wang T, Wei S, Zhang S, et al. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med. 2005 Dec;11(12):1314-21. doi: 10.1038/nm1325.
42. Rasha F, Ramalingam L, Gollahon L, Rahman RL, Rahman SM, Menikdiwela K, et al. Mechanisms linking the renin-angiotensin system, obesity, and breast cancer. Endocr Relat Cancer. 2019 Dec 1;26(12):R653-72. doi: 10.1530/ERC-19-0314.
43. Takiguchi T, Takahashi-Yanaga F, Ishikane S, Tetsuo F, Hosoda H, Arioka M, et al. Angiotensin II promotes primary tumor growth and metastasis formation of murine TNBC 4T1 cells through the fibroblasts surrounding cancer cells. Eur J Pharmacol. 2021 Oct 15;909:174415. doi: 10.1016/j.ejphar.2021.174415.
44. Chauhan VP, Martin JD, Liu H, Lacorre DA, Jain SR, Kozin SV, et al. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumor blood vessels. Nat Commun. 2013;4:2516. doi: 10.1038/ncomms3516.
45. Rhodes DR, Ateeq B, Cao Q, Tomlins SA, Mehra R, Laxman B, et al. AGTR1 overexpression defines a subset of breast cancer and confers sensitivity to losartan, an AGTR1 antagonist. Proc Natl Acad Sci U S A. 2009 Jun 23;106(25):10284-9. doi: 10.1073/pnas.0900351106.
46. Woo Y, Jung YJ. Angiotensin II receptor blockers induce autophagy in prostate cancer cells. Oncol Lett. 2017 May;13(5):3579-85. doi: 10.3892/ol.2017.5872.
47. Sun H, Li T, Zhuang R, Cai W, Zheng Y. Do renin-angiotensin system inhibitors influence the recurrence, metastasis, and survival in cancer patients? Evidence from a meta-analysis including 55 studies. Medicine (Baltimore). 2017 Mar;96(13):e6394. doi: 10.1097/MD.0000000000006394.
48. Li XY, Sun JF, Hu SQ. The renin-angiotensin system blockers as adjunctive therapy for cancer: A meta-analysis of survival outcomes. Eur Rev Med Pharmacol Sci. 2017 Mar;21(6):1375-83. PMID: 28387887.
Article Sidebar
Published
Jan 15, 2026
Article Details
How to Cite
1.
Does Valsartan Affect the Cytotoxicity of Doxorubicin When Used as a Cardioprotective Drug Against Doxorubicin-Induced Cardiotoxicity ?. Iraqi Natl J Med [Internet]. 2026 Jan. 15 [cited 2026 Jan. 17];8(1):44-9. Available from: https://www.iqnjm.com/index.php/homepage/article/view/263
Issue
Section
Original Articles
This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License.