Metformin alleviates bevacizumab-induced vascular endothelial injury in mice through growth differentiation factor 15 upregulation

Document Type : Original Article

Authors

1 Department of Cardiovascular, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China

2 Department of Cardiovascular, The First Hospital of Hebei Medical University, Shijiazhuang, China

3 Department of Obstetrics,The Fourth Hospital of Shijiazhuang,Shijiazhuang, China

4 Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China

5 Department of Cardiology, Peking University Third Hospital, 49 Huayuanbei Road, Haidian District, Beijing 100191, China

6 Department of Cardiology, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin 300052, China

Abstract

Objective(s): Bevacizumab is a commonly used anticancer drug in clinical practice, but it often leads to adverse reactions such as vascular endothelial damage, hypertension, arterial and venous thrombosis, and bleeding. This study investigated the protective effects of metformin against bevacizumab-induced vascular injury in a mouse model and examined the possible involvement of GDF15/PI3K/AKT/FOXO/PPARγ signaling in the effects.
Materials and Methods: C57 male mice were purchased. To investigate metformin, the mice were assigned to the saline, bevacizumab (15 mg every 3 days), metformin (1200 mg/day), and bevacizumab+metformin groups. To investigate GDF15, the mice were assigned to the siNC+bevacizumab, siNC+bevacizumab+metformin, siGDF15+bevacizumab, and siGDF15+bevacizumab+metformin groups. Histological staining was used to evaluate vascular injury. Flow cytometry was used to evaluate apoptosis. ELISA was used to measure plasma endothelial injury markers and proinflammatory cytokines. qRT-PCR and western blot were used to determine the expression of GDF15 and PI3K/AKT/FOXO/PPARγ in aortic tissues.
Results: Metformin alleviated bevacizumab-induced abdominal aortic injury, endothelial cell apoptosis, and systemic inflammation in mice (all P<0.05). Metformin up-regulated GDF15 expression and PI3K/AKT/FOXO/PPARγ signaling in the abdominal aorta of mice treated with bevacizumab (all P<0.05). siGDF15 abolished the vascular protective and anti-inflammatory effects of metformin (all P<0.05). siGDF15 suppressed PI3K/AKT/FOXO/PPARγ signaling in the abdominal aorta of mice treated with bevacizumab (all P<0.05).
Conclusion: Metformin attenuates bevacizumab-induced vascular endothelial injury, apoptosis, and systemic inflammation by activating GDF15/PI3K/AKT/FOXO/PPARγ signaling.

Keywords

References

1. Wang B, He F, Hu Y, Wang Q, Wang D, Sha Y, et al. Cancer incidence and mortality and risk factors in member countries of the “Belt and Road” initiative. BMC Cancer 2022;22:582-596.
2. Nojiri T, Inoue M, Takeuchi Y, Maeda H, Shintani Y, Sawabata N, et al. Impact of cardiopulmonary complications of lung cancer surgery on long-term outcomes. Surg Today 2015;45:740-745.
3. Kozower BD, Sheng S, O’Brien SM, Liptay MJ, Lau CL, Jones DR, et al. STS database risk models: Predictors of mortality and major morbidity for lung cancer resection. Ann Thorac Surg 2010;90:875-881.
4. Abdelsalam M, Abu-Hegazy M, El-Hadaad HA, Wahba H, Egila H, Esmael A. Pathophysiology, mechanism, and outcome of ischemic stroke in cancer patients. J Stroke Cerebrovasc Dis 2020;29:105299.
5. Ansari MJ, Bokov D, Markov A, Jalil AT, Shalaby MN, Suksatan W, et al. Cancer combination therapies by angiogenesis inhibitors; A comprehensive review. Cell Commun Signal 2022;20:49-71.
6. Teleanu RI, Chircov C, Grumezescu AM, Teleanu DM. Tumor angiogenesis and antiangiogenic strategies for cancer treatment. J Clin Med 2019;9:84-104.
7. Liu ZL, Chen HH, Zheng LL, Sun LP, Shi L. Angiogenic signaling pathways and antiangiogenic therapy for cancer. Signal Transduct Target Ther 2023;8:198-236.
8. Cao Y, Langer R, Ferrara N. Targeting angiogenesis in oncology, ophthalmology and beyond. Nat Rev Drug Discov 2023;22:476-495.
9. Small HY, Montezano AC, Rios FJ, Savoia C, Touyz RM. Hypertension due to antiangiogenic cancer therapy with vascular endothelial growth factor inhibitors: Understanding and managing a new syndrome. Can J Cardiol 2014;30:534-543.
10. Jang S, Zheng C, Tsai HT, Fu AZ, Barac A, Atkins MB, et al. Cardiovascular toxicity after antiangiogenic therapy in persons older than 65 years with advanced renal cell carcinoma. Cancer 2016;122:124-130.
11. Gimbrone MA, Jr., Garcia-Cardena G. Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circ Res 2016;118:620-636.
12. Sun HJ, Wu ZY, Nie XW, Bian JS. Role of endothelial dysfunction in cardiovascular diseases: the link between inflammation and hydrogen sulfide. Front Pharmacol 2019;10:1568-1582.
13. Nakaya A, Kurata T, Yokoi T, Iwamoto S, Torii Y, Katashiba Y, et al. Retrospective analysis of bevacizumab-induced hypertension and clinical outcome in patients with colorectal cancer and lung cancer. Cancer Med 2016;5:1381-1387.
14. Nalluri SR, Chu D, Keresztes R, Zhu X, Wu S. Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: A meta-analysis. JAMA 2008;300:2277-2285.
15. Randall LM, Monk BJ. Bevacizumab toxicities and their management in ovarian cancer. Gynecol Oncol 2010;117:497-504.
16. Cunningham D, Lang I, Marcuello E, Lorusso V, Ocvirk J, Shin DB, et al. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancet Oncol 2013;14:1077-1085.
17. Totzeck M, Mincu RI, Rassaf T. Cardiovascular adverse events in patients with cancer treated with bevacizumab: A meta-analysis of more than 20000 patients. J Am Heart Assoc 2017;6:e006278-6298.
18. Bennouna J, Sastre J, Arnold D, Osterlund P, Greil R, Van Cutsem E, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): A randomised phase 3 trial. Lancet Oncol 2013;14:29-37.
19. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-2342.
20. Roumie CL, Chipman J, Min JY, Hackstadt AJ, Hung AM, Greevy RA, Jr., et al. Association of treatment with metformin vs sulfonylurea with major adverse cardiovascular events among patients with diabetes and reduced kidney function. JAMA 2019;322:1167-1177.
21. Luo F, Das A, Chen J, Wu P, Li X, Fang Z. Metformin in patients with and without diabetes: a paradigm shift in cardiovascular disease management. Cardiovasc Diabetol 2019;18:54-62.
22. 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;11:3295-313.
23. Lord SR, Harris AL. Is it still worth pursuing the repurposing of metformin as a cancer therapeutic? Br J Cancer 2023;128:958-66.
24. Salvatore T, Pafundi PC, Galiero R, Rinaldi L, Caturano A, Vetrano E, et al. Can Metformin exert as an active drug on endothelial dysfunction in diabetic subjects? Biomedicines 2020;9:3-28.
25. Fan Y, Cheng H, Liu Y, Liu S, Lowe S, Li Y, et al. Metformin anticancer: Reverses tumor hypoxia induced by bevacizumab and reduces the expression of cancer stem cell markers CD44/CD117 in human ovarian cancer SKOV3 cells. Front Pharmacol  2022;13:955984-955995.
26. Marrone KA, Zhou X, Forde PM, Purtell M, Brahmer JR, Hann CL, et al. A Randomized phase II study of metformin plus paclitaxel/carboplatin/bevacizumab in patients with chemotherapy-naive advanced or metastatic nonsquamous non-small cell lung cancer. Oncologist 2018;23:859-865.
27. Vanhoutte PM, Shimokawa H, Feletou M, Tang EH. Endothelial dysfunction and vascular disease - a 30th anniversary update. Acta Physiol 2017;219:22-96.
28. Johnen H, Kuffner T, Brown DA, Wu BJ, Stocker R, Breit SN. Increased expression of the TGF-b superfamily cytokine MIC-1/GDF15 protects ApoE(-/-) mice from the development of atherosclerosis. Cardiovasc Pathol 2012;21:499-505.
29. Ha G, De Torres F, Arouche N, Benzoubir N, Ferratge S, Hatem E, et al. GDF15 secreted by senescent endothelial cells improves vascular progenitor cell functions. PLoS One 2019;14:e0216602-0216618.
30. Gerstein HC, Pare G, Hess S, Ford RJ, Sjaarda J, Raman K, et al. Growth differentiation factor 15 as a novel biomarker for metformin. Diabetes Care 2017;40:280-283.
31. Day EA, Ford RJ, Smith BK, Mohammadi-Shemirani P, Morrow MR, Gutgesell RM, et al. Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss. Nat Metab 2019;1:1202-1208.
32. Chen L, Yin Y, Liu G. Metformin alleviates bevacizumab-induced vascular endothelial injury by upregulating GDF15 and activating the PI3K/AKT/FOXO/PPARgamma signaling pathway. Ann Transl Med 2021;9:1547-1561.
33. Soraya H, Khorrami A, Garjani A, Maleki-Dizaji N, Garjani A. Acute treatment with metformin improves cardiac function following isoproterenol induced myocardial infarction in rats. Pharmacol Rep 2012;64:1476-1484.
34. Quaile MP, Melich DH, Jordan HL, Nold JB, Chism JP, Polli JW, et al. Toxicity and toxicokinetics of metformin in rats. Toxicol Appl Pharmacol 2010;243:340-347.
35. Wu HR. Effect of recombinant human VEGF_(165)b protein and bevacizumab on expression of CD34 and cell apoptosis in human gastric carcinoma xenografts in nude mice. W Chin J Digest 2014;22:1058.
36. Zhang J. Time window of bevacizumab-induced tumour vascular normalisation and experimental study in combination with paclitaxel for lung cancer in homozygous mice. Chin J Clin Oncol 2017;22:6.
37. Yamazaki K, Nagase M, Tamagawa H, Ueda S, Tamura T, Murata K, et al. Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G). Ann Oncol 2016;27:1539-1546.
38. Costa R, Carneiro A, Rocha A, Pirraco A, Falcao M, Vasques L, et al. Bevacizumab and ranibizumab on microvascular endothelial cells: A comparative study. J Cell Biochem 2009;108:1410-1417.
39. Bota M, Fischer-Fodor E, Bochis OV, Cenariu M, Popa G, Blag CL, et al. Combined effect of propranolol, vincristine and bevacizumab on HUVECs and BJ cells. Exp Ther Med 2019;17:307-315.
40. El-Hajjar L, Jalaleddine N, Shaito A, Zibara K, Kazan JM, El-Saghir J, et al. Bevacizumab induces inflammation in MDA-MB-231 breast cancer cell line and in a mouse model. Cell Signal  2019;53:400-412.
41. Hattori Y, Suzuki K, Hattori S, Kasai K. Metformin inhibits cytokine-induced nuclear factor kappaB activation via AMP-activated protein kinase activation in vascular endothelial cells. Hypertension 2006;47:1183-1188.
42. Hung CH, Chan SH, Chu PM, Lin HC, Tsai KL. Metformin regulates oxLDL-facilitated endothelial dysfunction by modulation of SIRT1 through repressing LOX-1-modulated oxidative signaling. Oncotarget 2016;7:10773-10787.
43. Li X, Kover KL, Heruth DP, Watkins DJ, Moore WV, Jackson K, et al. New insight into metformin action: Regulation of ChREBP and FOXO1 activities in endothelial cells. Mol Endocrinol 2015;29:1184-1194.
44. Yang Y, Dong R, Hu D, Chen Z, Fu M, Wang DW, et al. Liver kinase B1/AMP-activated protein kinase pathway activation attenuated the progression of endotoxemia in the diabetic mice. Cell Physiol Biochem 2017;42:761-779.
45. Niu C, Chen Z, Kim KT, Sun J, Xue M, Chen G, et al. Metformin alleviates hyperglycemia-induced endothelial impairment by downregulating autophagy via the Hedgehog pathway. Autophagy  2019;15:843-870.
46. Li Y, Gappy S, Liu X, Sassalos T, Zhou T, Hsu A, et al. Metformin suppresses proinflammatory cytokines in vitreous of diabetes patients and human retinal vascular endothelium. PLoS One 2022;17:e0268451-0268467.
47. Indraccolo S, Randon G, Zulato E, Nardin M, Aliberti C, Pomerri F, et al. Metformin: A modulator of bevacizumab activity in cancer? A case report. Cancer Biol Ther 2015;16:210-214.
48. Silvestre-Roig C, Braster Q, Ortega-Gomez A, Soehnlein O. Neutrophils as regulators of cardiovascular inflammation. Nat Rev Cardiol 2020;17:327-340.
49. Li J, Yang L, Qin W, Zhang G, Yuan J, Wang F. Adaptive induction of growth differentiation factor 15 attenuates endothelial cell apoptosis in response to high glucose stimulus. PLoS One 2013;8:e65549-65556.
50. Coll AP, Chen M, Taskar P, Rimmington D, Patel S, Tadross JA, et al. GDF15 mediates the effects of metformin on body weight and energy balance. Nature 2020;578:444-448.
51. Klein AB, Nicolaisen TS, Johann K, Fritzen AM, Mathiesen CV, Gil C, et al. The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance. Cell Rep 2022;40:111258-111270.
52. Li A, Zhao F, Zhao Y, Liu H, Wang Z. ATF4-mediated GDF15 suppresses LPS-induced inflammation and MUC5AC in human nasal epithelial cells through the PI3K/Akt pathway. Life Sci  2021;275:119356.
53. Li S, Ma YM, Zheng PS, Zhang P. GDF15 promotes the proliferation of cervical cancer cells by phosphorylating AKT1 and Erk1/2 through the receptor ErbB2. J Exp Clin Cancer Res 2018;37:80-93.
54. Keating GM. Bevacizumab: A review of its use in advanced cancer. Drugs 2014;74:1891-1925.
55. Soraya H, Esfahanian N, Shakiba Y, Ghazi-Khansari M, Nikbin B, Hafezzadeh H, et al. Antiangiogenic effects of metformin, an AMPK activator, on human umbilical vein endothelial cells and on granulation tissue in rat. Iran J Basic Med Sci 2012;15:1202-1209.
Iranian Journal of Basic Medical Sciences
Volume 27, Issue 3
March 2024
Pages 343-351

Files

Share

How to cite

Statistics