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Evaluation of selected antidiabetics in cardiovascular complications associated with cancer cachexia

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Abstract

So far, the cardio-protective potential of antidiabetics is proved, but their effect on cardiovascular complications associated with cancer cachexia is not explored until now. Insulin resistance and glucose intolerance along with systemic inflammation are prominent in cachexia but the potential effect of antidiabetic agents especially those belonging to biguanide, DPP4 inhibitors and SGLT2 on the heart are not studied till now. In present study, the effect of metformin, vildagliptin, teneligliptin, dapagliflozin and empagliflozin on cardiovascular complications associated with cancer cachexia by using B16F1 induced metastatic cancer cachexia and urethane-induced cancer cachexia was studied. These antidiabetic agents proved to be beneficial against cachexia-induced atrophy of the heart, preserved ventricular weights, maintained cardiac hypertrophic index, preserved the wasting of cardiac muscles assessed by HE staining, Masson trichrome staining, periodic acid Schiff staining and picro-Sirius red staining. Altered cardiac gene expression was attenuated after treatment with selected antidiabetics, thus preventing cardiac atrophy. Also, antidiabetic agents treatment improved the serum creatinine kinase MB, Sodium potassium ATPase and collagen in the heart. Reduction in blood pressure and heart rate was observed after treatment with antidiabetic agents. Results of our study show that the selected antidiabetics prove to be beneficial in attenuating the cardiac atrophy and helps in regulation of hemodynamic stauts in cancer cachexia-induced cardiovascular complications. Our study provides some direction towards use of selected antidiabetic agents in the management of cardiovascular complications associated with cancer cachexia and the study outcomes can be useful in desiging clinical trials.

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Data availability

The data used in the current study are available from the corresponding author on reasonable request.

References

  1. Springer, Tschirner, Haghikia, Von Haehling, Lal, Grzesiak et al (2014) Prevention of liver cancer cachexia-induced cardiac wasting and heart failure. Eur Heart J 35:932–941. https://doi.org/10.1093/eurheartj/eht302

    Article  CAS  PubMed  Google Scholar 

  2. Xu et al (2011) Myocardial dysfunction in an animal model of cancer cachexia. Life Sci 88:406–410. https://doi.org/10.1016/j.lfs.2010.12.010

    Article  CAS  PubMed  Google Scholar 

  3. Fearon et al (2011) Definition and classification of cancer cachexia: an international consensus. Lancet Oncol 12:489–495. https://doi.org/10.1016/S1470-2045(10)70218-7

    Article  PubMed  Google Scholar 

  4. Lim et al (2020) Development and progression of cancer cachexia: perspectives from bench to bedside. Sports Med Health Sci 2:177–185. https://doi.org/10.1016/j.smhs.2020.10.003

    Article  PubMed  PubMed Central  Google Scholar 

  5. Stevens et al (2015) Losartan treatment attenuates tumor-induced myocardial dysfunction. J Mol Cell Cardiol 85:37–47. https://doi.org/10.1016/j.yjmcc.2015.05.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Marceca et al (2020) Management of cancer cachexia: attempting to develop new pharmacological agents for new effective therapeutic options. Front Oncol 10:298. https://doi.org/10.3389/fonc.2020.00298

    Article  PubMed  PubMed Central  Google Scholar 

  7. Li X et al (2017) Cardiac complications in cancer treatment—a review. Hell J Cardiol 58:190–193. https://doi.org/10.1016/j.hjc.2016.12.003

    Article  Google Scholar 

  8. Stone K et al (2021) Monitoring for chemotherapy-related cardiotoxicity in the form of left ventricular systolic dysfunction : a review of current recommendations. JCO Oncol Pract. https://doi.org/10.1200/OP.20.00924

    Article  PubMed  Google Scholar 

  9. Murphy (2016) The pathogenesis and treatment of cardiac atrophy in cancer cachexia. Am J Physiol—Heart Circ Physiol 310:H466–H477. https://doi.org/10.1152/ajpheart.00720.2015

    Article  PubMed  Google Scholar 

  10. Kumar et al (2016) Cardiovascular safety of anti-diabetic drugs. Eur Heart J—Cardiovasc Pharmacother 2:32–43. https://doi.org/10.1093/ehjcvp/pvv035

    Article  CAS  PubMed  Google Scholar 

  11. Nobes et al (2012) A prospective, randomized pilot study evaluating the effects of metformin and lifestyle intervention on patients with prostate cancer receiving androgen deprivation therapy. BJU Int 109:1495–1502. https://doi.org/10.1111/j.1464-410X.2011.10555.x

    Article  CAS  PubMed  Google Scholar 

  12. Hashikata, Yamaoka-Tojo, Kakizaki, Nemoto, Fujiyoshi, Namba et al (2016) Teneligliptin improves left ventricular diastolic function and endothelial function in patients with diabetes. Heart and Vessels 31:1303–1310. https://doi.org/10.1007/s00380-015-0724-7

    Article  PubMed  Google Scholar 

  13. McMurray, Ponikowski, Bolli, Lukashevich, Kozlovski, Kothny et al (2018) Effects of vildagliptin on ventricular function in patients with type 2 diabetes mellitus and heart failure: a randomized placebo-controlled trial. JACC Heart Fail 6:8–17. https://doi.org/10.1016/j.jchf.2017.08.004

    Article  PubMed  Google Scholar 

  14. Eliaa A-K et al (2020) Empagliflozin and doxorubicin synergistically inhibit the survival of triple-negative breast cancer cells via interfering with the mTOR pathway and inhibition of calmodulin. In vitro and molecular docking studies. ACS Pharmacol Transl Sci 3:1330–1338. https://doi.org/10.1021/acsptsci.0c00144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chang et al (2020) Dapagliflozin suppresses ER stress and protects doxorubicin-induced cardiotoxicity in breast cancer patients. Arch Toxicol 95:659–671. https://doi.org/10.1007/s00204-020-02951-8

    Article  CAS  PubMed  Google Scholar 

  16. Bora, Patel (2021) Investigation into the role of anti-diabetic agents in cachexia associated with metastatic cancer. Life Sci 274:119329. https://doi.org/10.1016/J.LFS.2021.119329

    Article  CAS  PubMed  Google Scholar 

  17. Li J et al (2011) Hydrodynamic cell delivery for simultaneous establishment of tumor growth in mouse lung, liver and kidney. Cancer Biol Ther 12:737–741. https://doi.org/10.4161/cbt.12.8.16442

    Article  PubMed  PubMed Central  Google Scholar 

  18. Wang S, Yang Ma, Li C et al (2016) Activation of liver X receptor inhibits the development of pulmonary carcinomas induced by 3-methylcholanthrene and butylated hydroxytoluene in BALB/c mice. Sci Rep 6:1–11. https://doi.org/10.1038/srep27295

    Article  CAS  Google Scholar 

  19. Parasuraman et al (2010) Blood sample collection in small laboratory animals. J Pharmacol Pharmacother 1:87–93. https://doi.org/10.4103/0976-500X.72350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Goyal et al (2008) Effect of telmisartan on cardiovascular complications associated with streptozotocin diabetic rats. Mol Cell Biochem 314:123–131. https://doi.org/10.1007/s11010-008-9772-y

    Article  CAS  PubMed  Google Scholar 

  21. Goyal et al (2011) Beneficial role of telmisartan on cardiovascular complications associated with STZ-induced type 2 diabetes in rats. Pharmacol Rep 63:956–966. https://doi.org/10.1016/S1734-1140(11)70611-9

    Article  CAS  PubMed  Google Scholar 

  22. Goyal et al (2009) Investigation into the cardiac effects of spironolactone in the experimental model of type 1 diabetes. J Cardiovasc Pharmacol 54:502–509. https://doi.org/10.1097/FJC.0b013e3181be75cc

    Article  CAS  PubMed  Google Scholar 

  23. Patel BM et al (2013) Effect of spironolactone on cardiovascular complications associated with type-2 diabetes in rats. Exp Clin Endocrinol Diabetes 121:441–447. https://doi.org/10.1055/s-0033-1345168

    Article  CAS  PubMed  Google Scholar 

  24. Patel BM et al (2014) Cardioprotective effects of magnesium valproate in type 2 diabetes mellitus. Eur J Pharmacol 728:128–134. https://doi.org/10.1016/j.ejphar.2014.01.063

    Article  CAS  PubMed  Google Scholar 

  25. Patel BM, Bhadada (2014) Type 2 diabetes-induced cardiovascular complications: comparative evaluation of spironolactone, atenolol, metoprolol, ramipril and perindopril. Clin Exp Hypertens 36:340–347. https://doi.org/10.3109/10641963.2013.827699

    Article  CAS  PubMed  Google Scholar 

  26. Rayabarapu, Patel (2014) Beneficial role of tamoxifen in isoproterenol-induced myocardial infarction. Can J Physiol Pharmacol 92:849–857. https://doi.org/10.1139/cjpp-2013-0348

    Article  CAS  PubMed  Google Scholar 

  27. Rabadiya et al (2018) Magnesium valproate ameliorates type 1 diabetes and cardiomyopathy in diabetic rats through estrogen receptors. Biomed Pharmacother 97:919–927. https://doi.org/10.1016/j.biopha.2017.10.137

    Article  CAS  PubMed  Google Scholar 

  28. Patel BM et al (2012) Perindopril protects against streptozotocin-induced hyperglycemic myocardial damage/alterations. Hum Exp Toxicol 31:1132–1143. https://doi.org/10.1177/0960327112446817

    Article  CAS  PubMed  Google Scholar 

  29. Patel et al (2014) Beneficial role of tamoxifen in experimentally induced cardiac hypertrophy. Pharmacol Rep 66:264–272. https://doi.org/10.1016/j.pharep.2014.02.004

    Article  CAS  PubMed  Google Scholar 

  30. Sharma et al (2019) Beneficial effect of silymarin in pressure overload induced experimental cardiac hypertrophy. Cardiovasc Toxicol 19:23–35. https://doi.org/10.1007/s12012-018-9470-2

    Article  CAS  PubMed  Google Scholar 

  31. Raghunathan et al (2014) Evaluation of buspirone on streptozotocin induced type 1 diabetes and its associated complications. Biomed Res Int. https://doi.org/10.1155/2014/948427

    Article  PubMed  PubMed Central  Google Scholar 

  32. Tsai C, Sun Y, Leu C et al (2012) Obesity suppresses circulating level and function of endothelial progenitor cells and heart function. J Transl Med. https://doi.org/10.1186/1479-5876-10-137

    Article  PubMed  PubMed Central  Google Scholar 

  33. Nojiri, Shimizu, Funakoshi, Yamaguchi, Zhou, Kawakami et al (2006) Oxidative stress causes heart failure with impaired mitochondrial respiration. J Biol Chem 281:33789–33801. https://doi.org/10.1074/jbc.M602118200

    Article  CAS  PubMed  Google Scholar 

  34. Tsubouchi Y et al (2014) Ghrelin relieves cancer cachexia associated with the development of lung adenocarcinoma in mice. Eur J Pharmacol 743:1–10. https://doi.org/10.1016/j.ejphar.2014.09.025

    Article  CAS  PubMed  Google Scholar 

  35. Patel HJ, Patel (2017) TNF-α and cancer cachexia: Molecular insights and clinical implications. Life Sci 170:56–63. https://doi.org/10.1016/j.lfs.2016.11.033

    Article  CAS  PubMed  Google Scholar 

  36. Tian A et al (2011) Evidence for cardiac atrophic remodeling in cancer-induced cachexia in mice. Int J Oncol 39:1321–1326. https://doi.org/10.3892/ijo.2011.1150

    Article  CAS  PubMed  Google Scholar 

  37. Rausch et al (2021) Understanding the common mechanisms of heart and skeletal muscle wasting in cancer cachexia. Oncogenesis. https://doi.org/10.1038/s41389-020-00288-6

    Article  PubMed  PubMed Central  Google Scholar 

  38. Xie et al (2013) Pathological ventricular remodeling: therapies: part 2 of 2. Circulation 128:1021–1030. https://doi.org/10.1161/CIRCULATIONAHA.113.001879

    Article  PubMed  Google Scholar 

  39. Nissen et al (2019) Collagens and cancer associated fibroblasts in the reactive stroma and its relation to cancer biology. J Exp Clin Cancer Res. https://doi.org/10.1186/s13046-019-1110-6

    Article  PubMed  PubMed Central  Google Scholar 

  40. Belloum et al (2017) Cancer-induced cardiac cachexia: pathogenesis and impact of physical activity (Review). Oncol Rep 37:2543–2552. https://doi.org/10.3892/or.2017.5542

    Article  CAS  PubMed  Google Scholar 

  41. Ay et al (2002) Creatine kinase-MB elevation after stroke is not cardiac in origin comparison with troponin T levels. Stroke 33:286–289. https://doi.org/10.1161/hs0102.101544

    Article  CAS  PubMed  Google Scholar 

  42. Abul-fadle et al (2020) Effect of spexin treatment on cardiometabolic changes in obese type 2 by. Al-Azhar Med J 49:735–758. https://doi.org/10.12816/amj.2020.82588

    Article  Google Scholar 

  43. Aydin et al (2019) Biomarkers in acute myocardial infarction: current perspectives. Vascular health and risk management. Dove Medical Press Ltd, Macclesfield. https://doi.org/10.2147/VHRM.S166157

    Book  Google Scholar 

  44. Fedorova et al (2003) Myocardial PKC β2 and the sensitivity of Na/K-ATPase to marinobufagenin are reduced by cicletanine in Dahl hypertension. Hypertension 41:505–511. https://doi.org/10.1161/01.HYP.0000053446.43894.9F

    Article  CAS  PubMed  Google Scholar 

  45. Horton et al (2007) Burn injury decreases myocardial Na-K-ATPase activity: role of PKC inhibition. Am J Physiol—Regul Integr Comp Physiol. https://doi.org/10.1152/ajpregu.00219.2007

    Article  PubMed  Google Scholar 

  46. Sun et al (2020) DR-region of Na+/K+-ATPase is a target to ameliorate hepatic insulin resistance in obese diabetic mice. Theranostics 10:6149–6166. https://doi.org/10.7150/thno.46053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Iannello et al (2007) Animal and human tissue Na, K-ATPase in normal and insulin-resistant states: regulation, behaviour and interpretative hypothesis on NEFA effects. Obes Rev 8:231–251. https://doi.org/10.1111/j.1467-789X.2006.00276.x

    Article  CAS  PubMed  Google Scholar 

  48. Seo-Mayer et al (2011) Preactivation of AMPK by metformin may ameliorate the epithelial cell damage caused by renal ischemia. Am J Physiol—Renal Physiol 301:1346. https://doi.org/10.1152/ajprenal.00420.2010

    Article  CAS  Google Scholar 

  49. Maejima (2020) SGLT2 inhibitors play a salutary role in heart failure via modulation of the mitochondrial function. Front Cardiovasc Med. https://doi.org/10.3389/fcvm.2019.00186

    Article  PubMed  PubMed Central  Google Scholar 

  50. Hesen et al (2017) A systematic review and meta-analysis of the protective effects of metformin in experimental myocardial infarction. PLoS ONE 12:1–18. https://doi.org/10.1371/journal.pone.0183664

    Article  CAS  Google Scholar 

  51. Lexis et al (2014) Chronic metformin treatment is associated with reduced myocardial infarct size in diabetic patients with ST-segment elevation myocardial infarction. Cardiovasc Drugs Ther 28:163–171. https://doi.org/10.1007/s10557-013-6504-7

    Article  CAS  PubMed  Google Scholar 

  52. Cavender et al (2017) Serial measurement of high-sensitivity troponin i and cardiovascular outcomes in patients with type 2 diabetes mellitus in the examine trial (examination of cardiovascular outcomes with alogliptin versus standard of care). Circulation 135:1911–1921. https://doi.org/10.1161/CIRCULATIONAHA.116.024632

    Article  CAS  PubMed  Google Scholar 

  53. Januzzi et al (2017) Effects of canagliflozin on cardiovascular biomarkers in older adults with type 2 diabetes. J Am Coll Cardiol 70:704–712. https://doi.org/10.1016/j.jacc.2017.06.016

    Article  CAS  PubMed  Google Scholar 

  54. Wysong et al (2011) NF-κB inhibition protects against tumor-induced cardiac atrophy in vivo. Am J Pathol 178:1059–1068. https://doi.org/10.1016/j.ajpath.2010.12.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Muntzel et al (1999) Metformin attenuates salt-induced hypertension in spontaneously hypertensive rats. Hypertension 33:1135–1140. https://doi.org/10.1161/01.HYP.33.5.1135

    Article  CAS  PubMed  Google Scholar 

  56. Takamiya et al (2020) Multicenter prospective observational study of teneligliptin, a selective dipeptidyl peptidase-4 inhibitor, in patients with poorly controlled type 2 diabetes: focus on glycemic control, hypotensive effect, and safety Chikushi anti-diabetes mellitus trial. Clin Exp Hypertens 42:197–204. https://doi.org/10.1080/10641963.2019.1601207

    Article  CAS  PubMed  Google Scholar 

  57. Ferdinand et al (2019) Antihyperglycemic and blood pressure effects of empagliflozin in black patients with type 2 diabetes mellitus and hypertension. Circulation 139:2098–2109. https://doi.org/10.1161/CIRCULATIONAHA.118.036568

    Article  CAS  PubMed  Google Scholar 

  58. Liakos et al (2015) Update on long-term efficacy and safety of dapagliflozin in patients with type 2 diabetes mellitus. Ther Adv Endocrinol Metab. https://doi.org/10.1177/2042018814560735

    Article  PubMed  PubMed Central  Google Scholar 

  59. Goyal, Mehta (2012) Beneficial role of spironolactone, telmisartan and their combination on isoproterenol-induced cardiac hypertrophy. Acta Cardiol 67:203–211. https://doi.org/10.1080/ac.67.2.2154211

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors express their sincere gratitude towards the Institute of Pharmacy, Nirma University, Ahmedabad, India for providing all the essential amenities in the making of this research paper. This research work is a component of doctoral thesis (PhD thesis) work of Vivek R. Bora to be submitted to Nirma University, Ahmedabad, India.

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Authors and Affiliations

  1. Department of Pharmacology, Institute of Pharmacy, Nirma University, Sarkhej- Gandhinagar Highway, Ahmedabad, Gujarat, 382481, India

    Vivek R. Bora & Bhoomika M. Patel

  2. Department of Biochemistry, M. S. University of Baroda, Vadodara, Gujarat, 390002, India

    Dhruv Gohel & Rajesh Singh

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  1. Vivek R. Bora
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  2. Dhruv Gohel
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Contributions

VB was in charge of conducting the research work, gathering and analyzing the data, and writing the research paper. DG and RS were involved in gene expression studies. BP planned the study, the protocol was conducted under her guidance, data processing and research paper generation were conducted under her guidance and accepted the research paper. All the data were produced without the application of a paper mill and all the data were produced in-house.

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Correspondence to Bhoomika M. Patel.

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No potential commercial or financial relationships are involved in the present work and the authors declare that no conflicts of interest are involved in the present research work.

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The experimental work was performed after approval from the Institutional Animal Ethics Committee (IAEC), Institute of Pharmacy, Nirma University, Ahmedabad (Protocol Approval No. IP/PCOL/PHD/26/2019/007), as per the regulations of Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Government of India.

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Bora, V.R., Gohel, D., Singh, R. et al. Evaluation of selected antidiabetics in cardiovascular complications associated with cancer cachexia. Mol Cell Biochem 478, 807–820 (2023). https://doi.org/10.1007/s11010-022-04552-8

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